Gene Therapy

NEW YORK — When patients with multiple myeloma (MM) relapse following chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsABs), or both, likely salvage options remain that are being overlooked, including a second course of immunotherapy. Two independent experts, addressing this issue at the 2024 Lymphoma, Leukemia & Myeloma Congress, offered several practical recommendations for eliciting a therapeutic response after patients with multi-refractory MM have failed everything. One approach they endorsed was allowing patients to recover from T-cell exhaustion.

“We used to think that as soon as multiple myeloma patients progress on a CAR T-cell therapy, it was sort of game over,” said Joseph Mikhael, MD, professor, Translational Genomics Research Institute, City of Hope Cancer Center Phoenix, Arizona.

“But I think we are seeing many ways to salvage these patients, including going back to a CAR T product,” said Mikhael, who also serves as the chief medical officer of the International Myeloma Foundation.

Now that CAR T cells and BsABs are widely available, Mikhael warned that there will be a growing need for other strategies to offer when these therapies fail.

A similar point was made by Jorge Monge, MD, an assistant professor, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York City. He largely focused on newer therapies with the potential to provide salvage opportunities in advanced refractory MM, but he pointed out that one application might be to permit T-cell recovery after exhaustion following B-cell maturation antigen (BCMA)–targeted therapies.

The two talks covered some of the same ground. Both, for example, discussed a potential role for the exportin 1 (XPO1) inhibitor selinexor (Xpovio) in the multidrug refractory setting. In combination with bortezomib and dexamethasone, selinexor was approved in 2020 for treatment-experienced patients but is often overlooked in late-stage disease.

As a strategy to elicit a response following BCMA-targeted therapies, both Mikhael and Monge cited data showing selinexor to be active and that side effects are relatively well managed if antiemetics are offered preemptively to control nausea, one of its most common side effects.

Monge also talked about the promise of cereblon E3 ligase modulatory drugs (CELMoDs) that are now in clinical trials. These drugs, such as mezigdomide and iberdomide, both of which are in advanced stages of clinical testing, are similar to the immunomodulatory agents lenalidomide and pomalidomide. However, their greater potency does not appear to substantially increase risk for adverse events, according to Monge.
 

CELMoDs Active After CAR T-Cell Therapy

Most importantly, from the standpoint of their potential role in multidrug-refractory MM, both mezigdomide and iberdomide have so far shown substantial activity in patients previously exposed to BCMA-targeted therapies, according to Monge. Although the data have been generated in small numbers of patients, he reported that objective response rates have ranged from 37% to 50%.

These rates in treatment-experience patients are lower relative to those achieved in patients with no prior exposure to BCMA-targeted drugs, but Monge said that the durations of response, exceeding 6 months in some studies, might provide enough time for the T-cell recovery needed for a second course of CAR T-cell therapy.

There are other promising therapies on the horizon relevant to controlling multidrug refractory MM, including the likely return of the antibody drug conjugate (ADC) belantamab mafodotin (Blenrep^®). This drug was withdrawn in 2022, when the DREAMM-3 trial failed to show an advantage on the primary endpoint of progression-free survival (PFS) for this drug alone over pomalidomide and dexamethasone. The failed results of the DREAMM-3 trial meant that the drug did not meet FDA requirements for confirmatory trials of drugs approved through the agency’s accelerated approval program.

However, recently published results from the phase 3 DREAMM-8 trial did show a PFS advantage for belantamab mafodotin, pomalidomide, and dexamethasone over pomalidomide, bortezomib, and dexamethasone at 12 months (HR 0.50; P < .0010). On the basis of this result and other positive findings, including a deeper response, Mikhael predicted that this drug will be reintroduced.

It “might take a year or more” to find its way through the approval process, but Mikhael said that he is among those who think it will have value in advanced MM.*

Many of the newer MM drugs, including bispecifics that engage proteins on the surface of the myeloma cell other than BCMA, such as G protein–coupled receptor family C group, might provide alternatives to BCMA-targeted therapies in late stages of disease, but at least some newer drugs, as well as existing drugs in combinations, might play an important role in refractory MM by restoring BCMA as a target.

“The BCMA target is not easily lost, and I think we can leverage it more than once,” Mikhael said.

This potential, which Mikhael acknowledged is mostly supported with relatively small sets of data, involves “a lot of question marks, a lot of maybes,” so the strategies are hard to compared. However, the “incredible evolution in multiple myeloma therapy” over the past few years is not necessarily linear, according to Mikhael.
 

Recycling MM Therapies Deserves Consideration

In other words, CAR T cells and BsABs are not the last stop in the available lines of therapy for MM. The next best therapy is dependent on numerous considerations, including prior therapy exposure, but Mikhael pointed out that many patients in advanced stages have not been exposed to therapies known to be active or are not being considered for therapies to which they were exposed but are not necessarily resistant.

Monge made similar comments. He agreed with Mikhael that clinicians faced with a patient with multitherapy-refractory MM might forget about the XPO1 inhibitor selinexor, the alkylating agent bendamustine, or even the B-cell lymphoma 2 inhibitor venetoclax.

Any of these agents alone or in combination could be considered to “give the patient some time to improve” T-cell function, Monge said.

This approach will have even more promise if better assays of T-cell function become available, Mikhael said. Although he explained that T-cell exhaustion is clearly one of the reasons that CAR T-cell therapies stop working, this cannot be measured accurately at this time.

“Better T-cell assays may help,” he said.

Mikhael reported financial relationships with Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm Therapeutics, Sanofi, and Takeda. Monge disclosed ties with Bristol Myers Squibb and Karyopharm Therapeutics.

*Correction, 10/29/24: We are correcting the name of the DREAMM-3 trial and clarifying that its failed results meant that the drug did not meet the FDA’s requirements for confirmatory trials of drugs to be approved through the agency’s accelerated approval program.
 

A version of this article appeared on Medscape.com.

NEW YORK — When patients with multiple myeloma (MM) relapse following chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsABs), or both, likely salvage options remain that are being overlooked, including a second course of immunotherapy. Two independent experts, addressing this issue at the 2024 Lymphoma, Leukemia & Myeloma Congress, offered several practical recommendations for eliciting a therapeutic response after patients with multi-refractory MM have failed everything. One approach they endorsed was allowing patients to recover from T-cell exhaustion.

“We used to think that as soon as multiple myeloma patients progress on a CAR T-cell therapy, it was sort of game over,” said Joseph Mikhael, MD, professor, Translational Genomics Research Institute, City of Hope Cancer Center Phoenix, Arizona.

“But I think we are seeing many ways to salvage these patients, including going back to a CAR T product,” said Mikhael, who also serves as the chief medical officer of the International Myeloma Foundation.

Now that CAR T cells and BsABs are widely available, Mikhael warned that there will be a growing need for other strategies to offer when these therapies fail.

A similar point was made by Jorge Monge, MD, an assistant professor, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York City. He largely focused on newer therapies with the potential to provide salvage opportunities in advanced refractory MM, but he pointed out that one application might be to permit T-cell recovery after exhaustion following B-cell maturation antigen (BCMA)–targeted therapies.

The two talks covered some of the same ground. Both, for example, discussed a potential role for the exportin 1 (XPO1) inhibitor selinexor (Xpovio) in the multidrug refractory setting. In combination with bortezomib and dexamethasone, selinexor was approved in 2020 for treatment-experienced patients but is often overlooked in late-stage disease.

As a strategy to elicit a response following BCMA-targeted therapies, both Mikhael and Monge cited data showing selinexor to be active and that side effects are relatively well managed if antiemetics are offered preemptively to control nausea, one of its most common side effects.

Monge also talked about the promise of cereblon E3 ligase modulatory drugs (CELMoDs) that are now in clinical trials. These drugs, such as mezigdomide and iberdomide, both of which are in advanced stages of clinical testing, are similar to the immunomodulatory agents lenalidomide and pomalidomide. However, their greater potency does not appear to substantially increase risk for adverse events, according to Monge.
 

CELMoDs Active After CAR T-Cell Therapy

Most importantly, from the standpoint of their potential role in multidrug-refractory MM, both mezigdomide and iberdomide have so far shown substantial activity in patients previously exposed to BCMA-targeted therapies, according to Monge. Although the data have been generated in small numbers of patients, he reported that objective response rates have ranged from 37% to 50%.

These rates in treatment-experience patients are lower relative to those achieved in patients with no prior exposure to BCMA-targeted drugs, but Monge said that the durations of response, exceeding 6 months in some studies, might provide enough time for the T-cell recovery needed for a second course of CAR T-cell therapy.

There are other promising therapies on the horizon relevant to controlling multidrug refractory MM, including the likely return of the antibody drug conjugate (ADC) belantamab mafodotin (Blenrep^®). This drug was withdrawn in 2022, when the DREAMM-3 trial failed to show an advantage on the primary endpoint of progression-free survival (PFS) for this drug alone over pomalidomide and dexamethasone. The failed results of the DREAMM-3 trial meant that the drug did not meet FDA requirements for confirmatory trials of drugs approved through the agency’s accelerated approval program.

However, recently published results from the phase 3 DREAMM-8 trial did show a PFS advantage for belantamab mafodotin, pomalidomide, and dexamethasone over pomalidomide, bortezomib, and dexamethasone at 12 months (HR 0.50; P < .0010). On the basis of this result and other positive findings, including a deeper response, Mikhael predicted that this drug will be reintroduced.

It “might take a year or more” to find its way through the approval process, but Mikhael said that he is among those who think it will have value in advanced MM.*

Many of the newer MM drugs, including bispecifics that engage proteins on the surface of the myeloma cell other than BCMA, such as G protein–coupled receptor family C group, might provide alternatives to BCMA-targeted therapies in late stages of disease, but at least some newer drugs, as well as existing drugs in combinations, might play an important role in refractory MM by restoring BCMA as a target.

“The BCMA target is not easily lost, and I think we can leverage it more than once,” Mikhael said.

This potential, which Mikhael acknowledged is mostly supported with relatively small sets of data, involves “a lot of question marks, a lot of maybes,” so the strategies are hard to compared. However, the “incredible evolution in multiple myeloma therapy” over the past few years is not necessarily linear, according to Mikhael.
 

Recycling MM Therapies Deserves Consideration

In other words, CAR T cells and BsABs are not the last stop in the available lines of therapy for MM. The next best therapy is dependent on numerous considerations, including prior therapy exposure, but Mikhael pointed out that many patients in advanced stages have not been exposed to therapies known to be active or are not being considered for therapies to which they were exposed but are not necessarily resistant.

Monge made similar comments. He agreed with Mikhael that clinicians faced with a patient with multitherapy-refractory MM might forget about the XPO1 inhibitor selinexor, the alkylating agent bendamustine, or even the B-cell lymphoma 2 inhibitor venetoclax.

Any of these agents alone or in combination could be considered to “give the patient some time to improve” T-cell function, Monge said.

This approach will have even more promise if better assays of T-cell function become available, Mikhael said. Although he explained that T-cell exhaustion is clearly one of the reasons that CAR T-cell therapies stop working, this cannot be measured accurately at this time.

“Better T-cell assays may help,” he said.

Mikhael reported financial relationships with Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm Therapeutics, Sanofi, and Takeda. Monge disclosed ties with Bristol Myers Squibb and Karyopharm Therapeutics.

*Correction, 10/29/24: We are correcting the name of the DREAMM-3 trial and clarifying that its failed results meant that the drug did not meet the FDA’s requirements for confirmatory trials of drugs to be approved through the agency’s accelerated approval program.
 

A version of this article appeared on Medscape.com.

NEW YORK — When patients with multiple myeloma (MM) relapse following chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsABs), or both, likely salvage options remain that are being overlooked, including a second course of immunotherapy. Two independent experts, addressing this issue at the 2024 Lymphoma, Leukemia & Myeloma Congress, offered several practical recommendations for eliciting a therapeutic response after patients with multi-refractory MM have failed everything. One approach they endorsed was allowing patients to recover from T-cell exhaustion.

“We used to think that as soon as multiple myeloma patients progress on a CAR T-cell therapy, it was sort of game over,” said Joseph Mikhael, MD, professor, Translational Genomics Research Institute, City of Hope Cancer Center Phoenix, Arizona.

“But I think we are seeing many ways to salvage these patients, including going back to a CAR T product,” said Mikhael, who also serves as the chief medical officer of the International Myeloma Foundation.

Now that CAR T cells and BsABs are widely available, Mikhael warned that there will be a growing need for other strategies to offer when these therapies fail.

A similar point was made by Jorge Monge, MD, an assistant professor, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York City. He largely focused on newer therapies with the potential to provide salvage opportunities in advanced refractory MM, but he pointed out that one application might be to permit T-cell recovery after exhaustion following B-cell maturation antigen (BCMA)–targeted therapies.

The two talks covered some of the same ground. Both, for example, discussed a potential role for the exportin 1 (XPO1) inhibitor selinexor (Xpovio) in the multidrug refractory setting. In combination with bortezomib and dexamethasone, selinexor was approved in 2020 for treatment-experienced patients but is often overlooked in late-stage disease.

As a strategy to elicit a response following BCMA-targeted therapies, both Mikhael and Monge cited data showing selinexor to be active and that side effects are relatively well managed if antiemetics are offered preemptively to control nausea, one of its most common side effects.

Monge also talked about the promise of cereblon E3 ligase modulatory drugs (CELMoDs) that are now in clinical trials. These drugs, such as mezigdomide and iberdomide, both of which are in advanced stages of clinical testing, are similar to the immunomodulatory agents lenalidomide and pomalidomide. However, their greater potency does not appear to substantially increase risk for adverse events, according to Monge.
 

CELMoDs Active After CAR T-Cell Therapy

Most importantly, from the standpoint of their potential role in multidrug-refractory MM, both mezigdomide and iberdomide have so far shown substantial activity in patients previously exposed to BCMA-targeted therapies, according to Monge. Although the data have been generated in small numbers of patients, he reported that objective response rates have ranged from 37% to 50%.

These rates in treatment-experience patients are lower relative to those achieved in patients with no prior exposure to BCMA-targeted drugs, but Monge said that the durations of response, exceeding 6 months in some studies, might provide enough time for the T-cell recovery needed for a second course of CAR T-cell therapy.

There are other promising therapies on the horizon relevant to controlling multidrug refractory MM, including the likely return of the antibody drug conjugate (ADC) belantamab mafodotin (Blenrep^®). This drug was withdrawn in 2022, when the DREAMM-3 trial failed to show an advantage on the primary endpoint of progression-free survival (PFS) for this drug alone over pomalidomide and dexamethasone. The failed results of the DREAMM-3 trial meant that the drug did not meet FDA requirements for confirmatory trials of drugs approved through the agency’s accelerated approval program.

However, recently published results from the phase 3 DREAMM-8 trial did show a PFS advantage for belantamab mafodotin, pomalidomide, and dexamethasone over pomalidomide, bortezomib, and dexamethasone at 12 months (HR 0.50; P < .0010). On the basis of this result and other positive findings, including a deeper response, Mikhael predicted that this drug will be reintroduced.

It “might take a year or more” to find its way through the approval process, but Mikhael said that he is among those who think it will have value in advanced MM.*

Many of the newer MM drugs, including bispecifics that engage proteins on the surface of the myeloma cell other than BCMA, such as G protein–coupled receptor family C group, might provide alternatives to BCMA-targeted therapies in late stages of disease, but at least some newer drugs, as well as existing drugs in combinations, might play an important role in refractory MM by restoring BCMA as a target.

“The BCMA target is not easily lost, and I think we can leverage it more than once,” Mikhael said.

This potential, which Mikhael acknowledged is mostly supported with relatively small sets of data, involves “a lot of question marks, a lot of maybes,” so the strategies are hard to compared. However, the “incredible evolution in multiple myeloma therapy” over the past few years is not necessarily linear, according to Mikhael.
 

Recycling MM Therapies Deserves Consideration

In other words, CAR T cells and BsABs are not the last stop in the available lines of therapy for MM. The next best therapy is dependent on numerous considerations, including prior therapy exposure, but Mikhael pointed out that many patients in advanced stages have not been exposed to therapies known to be active or are not being considered for therapies to which they were exposed but are not necessarily resistant.

Monge made similar comments. He agreed with Mikhael that clinicians faced with a patient with multitherapy-refractory MM might forget about the XPO1 inhibitor selinexor, the alkylating agent bendamustine, or even the B-cell lymphoma 2 inhibitor venetoclax.

Any of these agents alone or in combination could be considered to “give the patient some time to improve” T-cell function, Monge said.

This approach will have even more promise if better assays of T-cell function become available, Mikhael said. Although he explained that T-cell exhaustion is clearly one of the reasons that CAR T-cell therapies stop working, this cannot be measured accurately at this time.

“Better T-cell assays may help,” he said.

Mikhael reported financial relationships with Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm Therapeutics, Sanofi, and Takeda. Monge disclosed ties with Bristol Myers Squibb and Karyopharm Therapeutics.

*Correction, 10/29/24: We are correcting the name of the DREAMM-3 trial and clarifying that its failed results meant that the drug did not meet the FDA’s requirements for confirmatory trials of drugs to be approved through the agency’s accelerated approval program.
 

A version of this article appeared on Medscape.com.

NEW YORK — In a three-way debate on whether to prioritize chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsAbs), or one of the novel oral targeted therapies for relapsed/refractory follicular lymphoma (R/R FL), no expert conceded.

Acknowledging that hers was the weakest position, even the specialist who defended novel targeted therapies mounted a staunch defense of real-world patients being treated outside of tertiary centers.

“I was told by many of my colleagues that I got the short end of the stick in this debate, but I am actually here to convince everybody that targeted therapies continue to play an important role, despite the fact that they are the least sexy of these treatment options,” said Joanna Rhodes, MD, director of the Lymphoma Program at Rutgers Cancer Institute, Hoboken, New Jersey.
 

Targeted Therapies Still Relevant to Advanced FL

Although even the newest or coming targeted therapies, such as the EZH2 inhibitor tazemetostat or next-generation Bruton tyrosine kinase inhibitors, are not likely to achieve the deep responses and long-term progression-free survival possible with BsAbs or CAR T-cell therapy, the sustained disease control they offer for many patients with R/R FL is not trivial, according to Rhodes.

“The majority of these [advanced follicular lymphoma] patients are being managed in the community,” Rhodes argued at the 2024 Lymphoma, Leukemia, & Myeloma Congress. Access to tertiary centers where the most advanced therapies are available in some cases might not even be feasible. 

Moreover, there are barriers to CAR T cells and BsAbs even at centers where these are available, Rhodes said. On a long list of barriers, lack of caregiver support is an example of one common disqualification at her own institution. 

The experience with CAR T cells in R/R FL has been relatively short, so Rhodes used data on CAR T cells for B-cell lymphoma to make her point. It is not just that the proportion of eligible patients is limited. 

“The majority of B-cell lymphoma patients who are eligible for CAR T cells are not getting them,” she said. “It will be the same for FL.”

In other words, Rhodes indicated that it is premature to count out targeted oral agents or lenalidomide despite the excitement surrounding BsAbs and CAR T cells. The targeted agents and immunomodulatory drugs remain appropriate choices for patients unable or unwilling to travel to tertiary centers for treatment, for frail patients, and for well-informed patients who understand their options and still consider better tolerated therapies to be more consistent with their perception of an adequate risk-benefit ratio. 
 

BsAbs Vie With CAR T Cells in Advanced FL

Hers might be a valid summary, but it did not derail arguments about whether CAR T-cell therapy should be prioritized over BsAbs or the other way around for patients who are candidates for both. 

There are two BsAbs currently approved for R/R FL: glofitamab and mosunetuzumab. More are coming, according to Nina Wagner-Johnston, MD, director of hematologic malignancies at Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland. She provided several reasons why BsAbs might be considered before CAR T-cell therapies in at least some individuals. 

“The biggest advantage is that these therapies…are off the shelf,” she said. This avoids the delay of T-cell manufacturing, the potential need for bridging therapies, and the need for conditioning regimens. With more experience, BsAbs offer the potential for treatment even in a community-practice setting, particularly for maintenance dosing.

“I do think this is a safe treatment in patients who are elderly or unfit,” Wagner-Johnston said, suggesting she tends to lean toward prioritizing BsAbs over CAR T cells when the ability to tolerate an aggressive strategy is a concern. She specified that these drugs are associated with a low relative incidence of grade 3 or higher cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome, and faster B-cell aplasia recovery. 

The third participant in the debate, who described the efficacy and safety of the three currently approved CAR T-cell therapies for R/R FL, did not agree with this characterization. Daniel J. Landsburg, MD, associate professor of clinical medicine at the University of Pennsylvania, Philadelphia, acknowledged that BsAb agents have an important role to play in the advanced FL setting, but he thinks that CAR T-cell therapies should be prioritized in at least some patients. 

In particular, he would not rule out CAR T-cell therapy in patients with comorbidities or other characteristics that raise questions about fitness for aggressive treatment. 

“In fact, you might want to treat a frail patient just one time with CAR T-cell therapy rather than dose after dose with a bispecific drug,” he said. 
 

No Data to Compare BsAbs and CAR T-Cells Directly

Both agreed that there have been no trials directly comparing a BsAb therapy vs CAR T cells, so there is no definitive answer, and Landsburg was reluctant to take a hard line on reserving BsAbs until after CAR T-cell therapy has been tried.

“Because BsAbs and CAR Ts are approved in the third-line setting, you might consider debulking a patient getting ready for a CAR T with a bispecific,” Landsburg said. However, he acknowledged that the next step becomes complex if patients achieved a complete response after just a few BsAb doses.

“Do you stop what is already working?” Landsburg asked rhetorically, suggesting that the best way forward is not always clear.

For R/R FL, currently there are three approved products: axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (Breyanzi). The entry criteria and design of the three pivotal trials differed, so their specific indications vary. Looking across the trials, Landsburg suggested that there might be differences in activity as defined by objective response rates or risk for cytokine release syndrome, but these remain theoretical without head-to-head comparisons.

“My suspicion is we are going to see very similar — quote, unquote — long-term survival curves for patients treated with any of these therapies,” he said, noting that progression-free survival at 3 years has been in the vicinity of 50% for the trials that have had long enough follow-up to judge.

Rather than trying to pick the best agent, he suggested that it makes more sense now to concentrate on strategies to improve response irrespective of CAR T-cell product; these include paying attention to total metabolic tumor volume at the time of infusion, optimizing bridging therapies, and thinking about T-cell fitness, which might be impaired in some patients by recent exposure to bendamustine.

Overall, with multiple ongoing studies with both CAR T-cell therapies and BsAbs in R/R FL — as well with targeted small-molecule agents and immunomodulatory drugs — all of the debate participants acknowledged that choices in R/R FL will evolve. 

“I actually think that combinations will be the future,” Wagner-Johnston said. Singling out tazemetostat and a BsAb and one approach that seems promising, she also predicted that some of the therapies in advanced disease are likely to be moved forward to earlier stages of FL therapy.

Rhodes reported ties with AbbVie, AstraZeneca, ADC Therapeutics, BeiGene, Bristol Myers Squibb, Epizyme, Genentech, Genmab, Janssen, Loxo Oncology, MorphoSys, Pharmacyclics, and Pfizer. Wagner-Johnston disclosed relationships with Cuno Science, Dava Oncology, Epizyme, Grünenthal, Karyopharm, and Seagen. Landsburg reported ties with ADC Therapeutics, Calithera, Curis, Epizyme, Karyopharm, MorphoSys, and Novartis.
 

A version of this article appeared on Medscape.com.

NEW YORK — In a three-way debate on whether to prioritize chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsAbs), or one of the novel oral targeted therapies for relapsed/refractory follicular lymphoma (R/R FL), no expert conceded.

Acknowledging that hers was the weakest position, even the specialist who defended novel targeted therapies mounted a staunch defense of real-world patients being treated outside of tertiary centers.

“I was told by many of my colleagues that I got the short end of the stick in this debate, but I am actually here to convince everybody that targeted therapies continue to play an important role, despite the fact that they are the least sexy of these treatment options,” said Joanna Rhodes, MD, director of the Lymphoma Program at Rutgers Cancer Institute, Hoboken, New Jersey.
 

Targeted Therapies Still Relevant to Advanced FL

Although even the newest or coming targeted therapies, such as the EZH2 inhibitor tazemetostat or next-generation Bruton tyrosine kinase inhibitors, are not likely to achieve the deep responses and long-term progression-free survival possible with BsAbs or CAR T-cell therapy, the sustained disease control they offer for many patients with R/R FL is not trivial, according to Rhodes.

“The majority of these [advanced follicular lymphoma] patients are being managed in the community,” Rhodes argued at the 2024 Lymphoma, Leukemia, & Myeloma Congress. Access to tertiary centers where the most advanced therapies are available in some cases might not even be feasible. 

Moreover, there are barriers to CAR T cells and BsAbs even at centers where these are available, Rhodes said. On a long list of barriers, lack of caregiver support is an example of one common disqualification at her own institution. 

The experience with CAR T cells in R/R FL has been relatively short, so Rhodes used data on CAR T cells for B-cell lymphoma to make her point. It is not just that the proportion of eligible patients is limited. 

“The majority of B-cell lymphoma patients who are eligible for CAR T cells are not getting them,” she said. “It will be the same for FL.”

In other words, Rhodes indicated that it is premature to count out targeted oral agents or lenalidomide despite the excitement surrounding BsAbs and CAR T cells. The targeted agents and immunomodulatory drugs remain appropriate choices for patients unable or unwilling to travel to tertiary centers for treatment, for frail patients, and for well-informed patients who understand their options and still consider better tolerated therapies to be more consistent with their perception of an adequate risk-benefit ratio. 
 

BsAbs Vie With CAR T Cells in Advanced FL

Hers might be a valid summary, but it did not derail arguments about whether CAR T-cell therapy should be prioritized over BsAbs or the other way around for patients who are candidates for both. 

There are two BsAbs currently approved for R/R FL: glofitamab and mosunetuzumab. More are coming, according to Nina Wagner-Johnston, MD, director of hematologic malignancies at Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland. She provided several reasons why BsAbs might be considered before CAR T-cell therapies in at least some individuals. 

“The biggest advantage is that these therapies…are off the shelf,” she said. This avoids the delay of T-cell manufacturing, the potential need for bridging therapies, and the need for conditioning regimens. With more experience, BsAbs offer the potential for treatment even in a community-practice setting, particularly for maintenance dosing.

“I do think this is a safe treatment in patients who are elderly or unfit,” Wagner-Johnston said, suggesting she tends to lean toward prioritizing BsAbs over CAR T cells when the ability to tolerate an aggressive strategy is a concern. She specified that these drugs are associated with a low relative incidence of grade 3 or higher cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome, and faster B-cell aplasia recovery. 

The third participant in the debate, who described the efficacy and safety of the three currently approved CAR T-cell therapies for R/R FL, did not agree with this characterization. Daniel J. Landsburg, MD, associate professor of clinical medicine at the University of Pennsylvania, Philadelphia, acknowledged that BsAb agents have an important role to play in the advanced FL setting, but he thinks that CAR T-cell therapies should be prioritized in at least some patients. 

In particular, he would not rule out CAR T-cell therapy in patients with comorbidities or other characteristics that raise questions about fitness for aggressive treatment. 

“In fact, you might want to treat a frail patient just one time with CAR T-cell therapy rather than dose after dose with a bispecific drug,” he said. 
 

No Data to Compare BsAbs and CAR T-Cells Directly

Both agreed that there have been no trials directly comparing a BsAb therapy vs CAR T cells, so there is no definitive answer, and Landsburg was reluctant to take a hard line on reserving BsAbs until after CAR T-cell therapy has been tried.

“Because BsAbs and CAR Ts are approved in the third-line setting, you might consider debulking a patient getting ready for a CAR T with a bispecific,” Landsburg said. However, he acknowledged that the next step becomes complex if patients achieved a complete response after just a few BsAb doses.

“Do you stop what is already working?” Landsburg asked rhetorically, suggesting that the best way forward is not always clear.

For R/R FL, currently there are three approved products: axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (Breyanzi). The entry criteria and design of the three pivotal trials differed, so their specific indications vary. Looking across the trials, Landsburg suggested that there might be differences in activity as defined by objective response rates or risk for cytokine release syndrome, but these remain theoretical without head-to-head comparisons.

“My suspicion is we are going to see very similar — quote, unquote — long-term survival curves for patients treated with any of these therapies,” he said, noting that progression-free survival at 3 years has been in the vicinity of 50% for the trials that have had long enough follow-up to judge.

Rather than trying to pick the best agent, he suggested that it makes more sense now to concentrate on strategies to improve response irrespective of CAR T-cell product; these include paying attention to total metabolic tumor volume at the time of infusion, optimizing bridging therapies, and thinking about T-cell fitness, which might be impaired in some patients by recent exposure to bendamustine.

Overall, with multiple ongoing studies with both CAR T-cell therapies and BsAbs in R/R FL — as well with targeted small-molecule agents and immunomodulatory drugs — all of the debate participants acknowledged that choices in R/R FL will evolve. 

“I actually think that combinations will be the future,” Wagner-Johnston said. Singling out tazemetostat and a BsAb and one approach that seems promising, she also predicted that some of the therapies in advanced disease are likely to be moved forward to earlier stages of FL therapy.

Rhodes reported ties with AbbVie, AstraZeneca, ADC Therapeutics, BeiGene, Bristol Myers Squibb, Epizyme, Genentech, Genmab, Janssen, Loxo Oncology, MorphoSys, Pharmacyclics, and Pfizer. Wagner-Johnston disclosed relationships with Cuno Science, Dava Oncology, Epizyme, Grünenthal, Karyopharm, and Seagen. Landsburg reported ties with ADC Therapeutics, Calithera, Curis, Epizyme, Karyopharm, MorphoSys, and Novartis.
 

A version of this article appeared on Medscape.com.

NEW YORK — In a three-way debate on whether to prioritize chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsAbs), or one of the novel oral targeted therapies for relapsed/refractory follicular lymphoma (R/R FL), no expert conceded.

Acknowledging that hers was the weakest position, even the specialist who defended novel targeted therapies mounted a staunch defense of real-world patients being treated outside of tertiary centers.

“I was told by many of my colleagues that I got the short end of the stick in this debate, but I am actually here to convince everybody that targeted therapies continue to play an important role, despite the fact that they are the least sexy of these treatment options,” said Joanna Rhodes, MD, director of the Lymphoma Program at Rutgers Cancer Institute, Hoboken, New Jersey.
 

Targeted Therapies Still Relevant to Advanced FL

Although even the newest or coming targeted therapies, such as the EZH2 inhibitor tazemetostat or next-generation Bruton tyrosine kinase inhibitors, are not likely to achieve the deep responses and long-term progression-free survival possible with BsAbs or CAR T-cell therapy, the sustained disease control they offer for many patients with R/R FL is not trivial, according to Rhodes.

“The majority of these [advanced follicular lymphoma] patients are being managed in the community,” Rhodes argued at the 2024 Lymphoma, Leukemia, & Myeloma Congress. Access to tertiary centers where the most advanced therapies are available in some cases might not even be feasible. 

Moreover, there are barriers to CAR T cells and BsAbs even at centers where these are available, Rhodes said. On a long list of barriers, lack of caregiver support is an example of one common disqualification at her own institution. 

The experience with CAR T cells in R/R FL has been relatively short, so Rhodes used data on CAR T cells for B-cell lymphoma to make her point. It is not just that the proportion of eligible patients is limited. 

“The majority of B-cell lymphoma patients who are eligible for CAR T cells are not getting them,” she said. “It will be the same for FL.”

In other words, Rhodes indicated that it is premature to count out targeted oral agents or lenalidomide despite the excitement surrounding BsAbs and CAR T cells. The targeted agents and immunomodulatory drugs remain appropriate choices for patients unable or unwilling to travel to tertiary centers for treatment, for frail patients, and for well-informed patients who understand their options and still consider better tolerated therapies to be more consistent with their perception of an adequate risk-benefit ratio. 
 

BsAbs Vie With CAR T Cells in Advanced FL

Hers might be a valid summary, but it did not derail arguments about whether CAR T-cell therapy should be prioritized over BsAbs or the other way around for patients who are candidates for both. 

There are two BsAbs currently approved for R/R FL: glofitamab and mosunetuzumab. More are coming, according to Nina Wagner-Johnston, MD, director of hematologic malignancies at Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland. She provided several reasons why BsAbs might be considered before CAR T-cell therapies in at least some individuals. 

“The biggest advantage is that these therapies…are off the shelf,” she said. This avoids the delay of T-cell manufacturing, the potential need for bridging therapies, and the need for conditioning regimens. With more experience, BsAbs offer the potential for treatment even in a community-practice setting, particularly for maintenance dosing.

“I do think this is a safe treatment in patients who are elderly or unfit,” Wagner-Johnston said, suggesting she tends to lean toward prioritizing BsAbs over CAR T cells when the ability to tolerate an aggressive strategy is a concern. She specified that these drugs are associated with a low relative incidence of grade 3 or higher cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome, and faster B-cell aplasia recovery. 

The third participant in the debate, who described the efficacy and safety of the three currently approved CAR T-cell therapies for R/R FL, did not agree with this characterization. Daniel J. Landsburg, MD, associate professor of clinical medicine at the University of Pennsylvania, Philadelphia, acknowledged that BsAb agents have an important role to play in the advanced FL setting, but he thinks that CAR T-cell therapies should be prioritized in at least some patients. 

In particular, he would not rule out CAR T-cell therapy in patients with comorbidities or other characteristics that raise questions about fitness for aggressive treatment. 

“In fact, you might want to treat a frail patient just one time with CAR T-cell therapy rather than dose after dose with a bispecific drug,” he said. 
 

No Data to Compare BsAbs and CAR T-Cells Directly

Both agreed that there have been no trials directly comparing a BsAb therapy vs CAR T cells, so there is no definitive answer, and Landsburg was reluctant to take a hard line on reserving BsAbs until after CAR T-cell therapy has been tried.

“Because BsAbs and CAR Ts are approved in the third-line setting, you might consider debulking a patient getting ready for a CAR T with a bispecific,” Landsburg said. However, he acknowledged that the next step becomes complex if patients achieved a complete response after just a few BsAb doses.

“Do you stop what is already working?” Landsburg asked rhetorically, suggesting that the best way forward is not always clear.

For R/R FL, currently there are three approved products: axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (Breyanzi). The entry criteria and design of the three pivotal trials differed, so their specific indications vary. Looking across the trials, Landsburg suggested that there might be differences in activity as defined by objective response rates or risk for cytokine release syndrome, but these remain theoretical without head-to-head comparisons.

“My suspicion is we are going to see very similar — quote, unquote — long-term survival curves for patients treated with any of these therapies,” he said, noting that progression-free survival at 3 years has been in the vicinity of 50% for the trials that have had long enough follow-up to judge.

Rather than trying to pick the best agent, he suggested that it makes more sense now to concentrate on strategies to improve response irrespective of CAR T-cell product; these include paying attention to total metabolic tumor volume at the time of infusion, optimizing bridging therapies, and thinking about T-cell fitness, which might be impaired in some patients by recent exposure to bendamustine.

Overall, with multiple ongoing studies with both CAR T-cell therapies and BsAbs in R/R FL — as well with targeted small-molecule agents and immunomodulatory drugs — all of the debate participants acknowledged that choices in R/R FL will evolve. 

“I actually think that combinations will be the future,” Wagner-Johnston said. Singling out tazemetostat and a BsAb and one approach that seems promising, she also predicted that some of the therapies in advanced disease are likely to be moved forward to earlier stages of FL therapy.

Rhodes reported ties with AbbVie, AstraZeneca, ADC Therapeutics, BeiGene, Bristol Myers Squibb, Epizyme, Genentech, Genmab, Janssen, Loxo Oncology, MorphoSys, Pharmacyclics, and Pfizer. Wagner-Johnston disclosed relationships with Cuno Science, Dava Oncology, Epizyme, Grünenthal, Karyopharm, and Seagen. Landsburg reported ties with ADC Therapeutics, Calithera, Curis, Epizyme, Karyopharm, MorphoSys, and Novartis.
 

A version of this article appeared on Medscape.com.

NEW YORK — In the wake of details about the molecular pathophysiology of Waldenström macroglobulinemia (WM), an expert gave an update on current and expanding options for treatment.

Most importantly, determining the mutational status of patients with WM has become a first or early step in guiding first- and second-line therapies, according to Edward A. Stadtmauer, MD, professor of medicine, University of Pennsylvania, Philadelphia.

Presenting at the 2024 Lymphoma, Leukemia & Myeloma Congress in New York City, Stadtmauer discussed how MYD88 and CXCR4 gene mutations influence his therapeutic choices.

While delivering the Bruce Waterfall Memorial Lecture, funded by the International WM Foundation, he explained that the vast majority of patients with WM have a MYD88 mutation that is highly sensitive to Bruton tyrosine kinase (BTK) inhibitors.

Due to greater specificity on the BTK target, which has implications for safety and efficacy, the first-generation BTK inhibitor ibrutinib has been largely supplanted by next generation drugs such as zanubrutinib.
 

Deep Responses in WM Remain Elusive

The support for next-generation BTK inhibitors over ibrutinib; bendamustine plus rituximab (BR); or cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is, in his opinion, “a superior toxicity profile, high response rates, and prolonged response.” However, he conceded that the weaknesses of this approach include a low chance of a deep remission and the need for continuous therapy.

On account of these limitations, he typically favors the alkylating agent bendamustine plus the anti-CD20 rituximab over BTK inhibitors in the absence of MYD88 mutations. This once standard approach has become less commonly used in the era of BTK inhibitors, but it is also highly effective, is generally administered in a time-limited regimen, and may be more likely to push patients into a deep remission.

A similar rationale might be considered for CyBorD, but Stadtmauer believes that BR provides a higher rate of PFS with a lower risk for neuropathy, although he admitted this opinion is based on cross-study comparisons, not comparative trials.

While efforts to develop therapies capable of producing a deep response “should not be abandoned,” particularly with the T-cell engager therapies on the horizon, he is not convinced that the benefit-to-risk ratio of aggressive therapies is yet warranted in a disease the often progresses slowly.

“I must admit I am still under the philosophy that Waldenström’s is a chronic disease even if we are seeing a growing list of options for relapsed or poorly responding disease, so I am still not pushing patients too aggressively to knock them into a complete remission,” he said.

MYD88 mutations are not unique to WM, an uncommon, slow-growing form of non-Hodgkin lymphoma. They are found in a small proportion of patients with other hematologic disorders, such as marginal zone lymphomas, but Stadtmauer estimated they occur in 90% of patients with WM. They are common enough that they can help with diagnosis.
 

CXCR4 Mutations Predict Worse Outcomes

The CXCR4 mutation occurs in an estimated 40% of patients with WM. When present, they are associated with worse outcomes, including a faster time to progression and a reduced overall survival, according to Stadtmauer.

The prognostic impact of less common mutations, such as TP53 and TERT or deletions in LYN, are less well characterized, but Stadtmauer said that most mutations associated with WM result in constitutive or continuous activation in BTK, which, in turn drives WM cell proliferation and survival.

The importance of BTK in WM progression is the reason targeted inhibitors have assumed such a key role in first-line treatment, but Stadtmauer cautioned that these drugs, like other therapies, should not be initiated in asymptomatic patients. This has been stated in past and current guidelines.

More accurately, therapy should be held until just prior to symptomatic manifestations of disease, Stadtmauer specified.

For an optimal response, “you want to start therapy about 3 or 4 months before the symptoms begin,” said Stadtmauer characterizing efforts to do so as “the art of medicine.” Starting therapy just prior to symptoms is advantageous, but it involves following patients closely. Any single biomarker might not be enough.

“In an asymptomatic patient, the level of monoclonal IgM is not an indication to start therapy,” he said, citing studies showing no effect on subsequent disease control from treating this biomarker alone.

However, he listed the development of moderate peripheral neuropathy (PN) as an exception. Essentially, anything greater than mild PN is “still bad” in Stadtmauer’s opinion, so treatment is warranted.

The growing number of second-line options relieves some of the concern when patients progress. Stadtmauer said he is now using BR more often in the second-line drug now that he is using BTK inhibitor more in the first line.

The Bcl-2 inhibitor venetoclax is highly effective and is another first- or second-line option even if this agent, like BTK inhibitors, also appears to require continuous dosing, said Stadtmauer, citing a study that showed patients relapsed relatively rapidly when the drug was stopped.

He now thinks of regimens with proteasome inhibitors as third line.

In selected patients who do not tolerate the non-covalent second-generation BTK inhibitors in the first or second line, he said, “I move quickly to the covalent BTKi pirtobrutinib,” based on data suggesting responses that are at least as good but with a better tolerability profile.
 

T-Cell Engager Data Are Limited

Without spending much time on the T-cell engagers, such as CAR T-cells or bispecific antibodies, Stadtmauer said that the advances he sees on the horizon “are tremendous,” and the “future is bright.” Such approaches could yield deep responses that could extend control or even provide cure, but these are speculations until more patients have been treated and followed long term.

Morton Coleman, MD, director of the Center for Lymphoma and Myeloma at Weill Cornell Medicine and the chairperson of the LLM Congress, called the talk a valuable and practical summary from a knowledgeable source. BTK inhibitors have represented a major evolution in WM management, but Coleman appreciated the underlying concept that treatment still has to be individualized.

“I think one of the most important take home messages is that the characterization of the mutational profile in patients with Waldenström should be considered a standard of care,” Coleman said. Helpful now, the mutational profile is likely to have a more valuable role as treatment is increasingly individualized.

Stadtmauer reported financial relationships with AbbVie, Bristol Myers Squibb, Celgene, Janssen, and Sorrento. Coleman disclosed ties with AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Gilead, Loxo Oncology, Janssen, and Pharmacyclics.
 

A version of this article appeared on Medscape.com.

NEW YORK — In the wake of details about the molecular pathophysiology of Waldenström macroglobulinemia (WM), an expert gave an update on current and expanding options for treatment.

Most importantly, determining the mutational status of patients with WM has become a first or early step in guiding first- and second-line therapies, according to Edward A. Stadtmauer, MD, professor of medicine, University of Pennsylvania, Philadelphia.

Presenting at the 2024 Lymphoma, Leukemia & Myeloma Congress in New York City, Stadtmauer discussed how MYD88 and CXCR4 gene mutations influence his therapeutic choices.

While delivering the Bruce Waterfall Memorial Lecture, funded by the International WM Foundation, he explained that the vast majority of patients with WM have a MYD88 mutation that is highly sensitive to Bruton tyrosine kinase (BTK) inhibitors.

Due to greater specificity on the BTK target, which has implications for safety and efficacy, the first-generation BTK inhibitor ibrutinib has been largely supplanted by next generation drugs such as zanubrutinib.
 

Deep Responses in WM Remain Elusive

The support for next-generation BTK inhibitors over ibrutinib; bendamustine plus rituximab (BR); or cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is, in his opinion, “a superior toxicity profile, high response rates, and prolonged response.” However, he conceded that the weaknesses of this approach include a low chance of a deep remission and the need for continuous therapy.

On account of these limitations, he typically favors the alkylating agent bendamustine plus the anti-CD20 rituximab over BTK inhibitors in the absence of MYD88 mutations. This once standard approach has become less commonly used in the era of BTK inhibitors, but it is also highly effective, is generally administered in a time-limited regimen, and may be more likely to push patients into a deep remission.

A similar rationale might be considered for CyBorD, but Stadtmauer believes that BR provides a higher rate of PFS with a lower risk for neuropathy, although he admitted this opinion is based on cross-study comparisons, not comparative trials.

While efforts to develop therapies capable of producing a deep response “should not be abandoned,” particularly with the T-cell engager therapies on the horizon, he is not convinced that the benefit-to-risk ratio of aggressive therapies is yet warranted in a disease the often progresses slowly.

“I must admit I am still under the philosophy that Waldenström’s is a chronic disease even if we are seeing a growing list of options for relapsed or poorly responding disease, so I am still not pushing patients too aggressively to knock them into a complete remission,” he said.

MYD88 mutations are not unique to WM, an uncommon, slow-growing form of non-Hodgkin lymphoma. They are found in a small proportion of patients with other hematologic disorders, such as marginal zone lymphomas, but Stadtmauer estimated they occur in 90% of patients with WM. They are common enough that they can help with diagnosis.
 

CXCR4 Mutations Predict Worse Outcomes

The CXCR4 mutation occurs in an estimated 40% of patients with WM. When present, they are associated with worse outcomes, including a faster time to progression and a reduced overall survival, according to Stadtmauer.

The prognostic impact of less common mutations, such as TP53 and TERT or deletions in LYN, are less well characterized, but Stadtmauer said that most mutations associated with WM result in constitutive or continuous activation in BTK, which, in turn drives WM cell proliferation and survival.

The importance of BTK in WM progression is the reason targeted inhibitors have assumed such a key role in first-line treatment, but Stadtmauer cautioned that these drugs, like other therapies, should not be initiated in asymptomatic patients. This has been stated in past and current guidelines.

More accurately, therapy should be held until just prior to symptomatic manifestations of disease, Stadtmauer specified.

For an optimal response, “you want to start therapy about 3 or 4 months before the symptoms begin,” said Stadtmauer characterizing efforts to do so as “the art of medicine.” Starting therapy just prior to symptoms is advantageous, but it involves following patients closely. Any single biomarker might not be enough.

“In an asymptomatic patient, the level of monoclonal IgM is not an indication to start therapy,” he said, citing studies showing no effect on subsequent disease control from treating this biomarker alone.

However, he listed the development of moderate peripheral neuropathy (PN) as an exception. Essentially, anything greater than mild PN is “still bad” in Stadtmauer’s opinion, so treatment is warranted.

The growing number of second-line options relieves some of the concern when patients progress. Stadtmauer said he is now using BR more often in the second-line drug now that he is using BTK inhibitor more in the first line.

The Bcl-2 inhibitor venetoclax is highly effective and is another first- or second-line option even if this agent, like BTK inhibitors, also appears to require continuous dosing, said Stadtmauer, citing a study that showed patients relapsed relatively rapidly when the drug was stopped.

He now thinks of regimens with proteasome inhibitors as third line.

In selected patients who do not tolerate the non-covalent second-generation BTK inhibitors in the first or second line, he said, “I move quickly to the covalent BTKi pirtobrutinib,” based on data suggesting responses that are at least as good but with a better tolerability profile.
 

T-Cell Engager Data Are Limited

Without spending much time on the T-cell engagers, such as CAR T-cells or bispecific antibodies, Stadtmauer said that the advances he sees on the horizon “are tremendous,” and the “future is bright.” Such approaches could yield deep responses that could extend control or even provide cure, but these are speculations until more patients have been treated and followed long term.

Morton Coleman, MD, director of the Center for Lymphoma and Myeloma at Weill Cornell Medicine and the chairperson of the LLM Congress, called the talk a valuable and practical summary from a knowledgeable source. BTK inhibitors have represented a major evolution in WM management, but Coleman appreciated the underlying concept that treatment still has to be individualized.

“I think one of the most important take home messages is that the characterization of the mutational profile in patients with Waldenström should be considered a standard of care,” Coleman said. Helpful now, the mutational profile is likely to have a more valuable role as treatment is increasingly individualized.

Stadtmauer reported financial relationships with AbbVie, Bristol Myers Squibb, Celgene, Janssen, and Sorrento. Coleman disclosed ties with AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Gilead, Loxo Oncology, Janssen, and Pharmacyclics.
 

A version of this article appeared on Medscape.com.

NEW YORK — In the wake of details about the molecular pathophysiology of Waldenström macroglobulinemia (WM), an expert gave an update on current and expanding options for treatment.

Most importantly, determining the mutational status of patients with WM has become a first or early step in guiding first- and second-line therapies, according to Edward A. Stadtmauer, MD, professor of medicine, University of Pennsylvania, Philadelphia.

Presenting at the 2024 Lymphoma, Leukemia & Myeloma Congress in New York City, Stadtmauer discussed how MYD88 and CXCR4 gene mutations influence his therapeutic choices.

While delivering the Bruce Waterfall Memorial Lecture, funded by the International WM Foundation, he explained that the vast majority of patients with WM have a MYD88 mutation that is highly sensitive to Bruton tyrosine kinase (BTK) inhibitors.

Due to greater specificity on the BTK target, which has implications for safety and efficacy, the first-generation BTK inhibitor ibrutinib has been largely supplanted by next generation drugs such as zanubrutinib.
 

Deep Responses in WM Remain Elusive

The support for next-generation BTK inhibitors over ibrutinib; bendamustine plus rituximab (BR); or cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is, in his opinion, “a superior toxicity profile, high response rates, and prolonged response.” However, he conceded that the weaknesses of this approach include a low chance of a deep remission and the need for continuous therapy.

On account of these limitations, he typically favors the alkylating agent bendamustine plus the anti-CD20 rituximab over BTK inhibitors in the absence of MYD88 mutations. This once standard approach has become less commonly used in the era of BTK inhibitors, but it is also highly effective, is generally administered in a time-limited regimen, and may be more likely to push patients into a deep remission.

A similar rationale might be considered for CyBorD, but Stadtmauer believes that BR provides a higher rate of PFS with a lower risk for neuropathy, although he admitted this opinion is based on cross-study comparisons, not comparative trials.

While efforts to develop therapies capable of producing a deep response “should not be abandoned,” particularly with the T-cell engager therapies on the horizon, he is not convinced that the benefit-to-risk ratio of aggressive therapies is yet warranted in a disease the often progresses slowly.

“I must admit I am still under the philosophy that Waldenström’s is a chronic disease even if we are seeing a growing list of options for relapsed or poorly responding disease, so I am still not pushing patients too aggressively to knock them into a complete remission,” he said.

MYD88 mutations are not unique to WM, an uncommon, slow-growing form of non-Hodgkin lymphoma. They are found in a small proportion of patients with other hematologic disorders, such as marginal zone lymphomas, but Stadtmauer estimated they occur in 90% of patients with WM. They are common enough that they can help with diagnosis.
 

CXCR4 Mutations Predict Worse Outcomes

The CXCR4 mutation occurs in an estimated 40% of patients with WM. When present, they are associated with worse outcomes, including a faster time to progression and a reduced overall survival, according to Stadtmauer.

The prognostic impact of less common mutations, such as TP53 and TERT or deletions in LYN, are less well characterized, but Stadtmauer said that most mutations associated with WM result in constitutive or continuous activation in BTK, which, in turn drives WM cell proliferation and survival.

The importance of BTK in WM progression is the reason targeted inhibitors have assumed such a key role in first-line treatment, but Stadtmauer cautioned that these drugs, like other therapies, should not be initiated in asymptomatic patients. This has been stated in past and current guidelines.

More accurately, therapy should be held until just prior to symptomatic manifestations of disease, Stadtmauer specified.

For an optimal response, “you want to start therapy about 3 or 4 months before the symptoms begin,” said Stadtmauer characterizing efforts to do so as “the art of medicine.” Starting therapy just prior to symptoms is advantageous, but it involves following patients closely. Any single biomarker might not be enough.

“In an asymptomatic patient, the level of monoclonal IgM is not an indication to start therapy,” he said, citing studies showing no effect on subsequent disease control from treating this biomarker alone.

However, he listed the development of moderate peripheral neuropathy (PN) as an exception. Essentially, anything greater than mild PN is “still bad” in Stadtmauer’s opinion, so treatment is warranted.

The growing number of second-line options relieves some of the concern when patients progress. Stadtmauer said he is now using BR more often in the second-line drug now that he is using BTK inhibitor more in the first line.

The Bcl-2 inhibitor venetoclax is highly effective and is another first- or second-line option even if this agent, like BTK inhibitors, also appears to require continuous dosing, said Stadtmauer, citing a study that showed patients relapsed relatively rapidly when the drug was stopped.

He now thinks of regimens with proteasome inhibitors as third line.

In selected patients who do not tolerate the non-covalent second-generation BTK inhibitors in the first or second line, he said, “I move quickly to the covalent BTKi pirtobrutinib,” based on data suggesting responses that are at least as good but with a better tolerability profile.
 

T-Cell Engager Data Are Limited

Without spending much time on the T-cell engagers, such as CAR T-cells or bispecific antibodies, Stadtmauer said that the advances he sees on the horizon “are tremendous,” and the “future is bright.” Such approaches could yield deep responses that could extend control or even provide cure, but these are speculations until more patients have been treated and followed long term.

Morton Coleman, MD, director of the Center for Lymphoma and Myeloma at Weill Cornell Medicine and the chairperson of the LLM Congress, called the talk a valuable and practical summary from a knowledgeable source. BTK inhibitors have represented a major evolution in WM management, but Coleman appreciated the underlying concept that treatment still has to be individualized.

“I think one of the most important take home messages is that the characterization of the mutational profile in patients with Waldenström should be considered a standard of care,” Coleman said. Helpful now, the mutational profile is likely to have a more valuable role as treatment is increasingly individualized.

Stadtmauer reported financial relationships with AbbVie, Bristol Myers Squibb, Celgene, Janssen, and Sorrento. Coleman disclosed ties with AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Gilead, Loxo Oncology, Janssen, and Pharmacyclics.
 

A version of this article appeared on Medscape.com.

The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.

As the push toward prompt testing and treatment of rare diseases continues building momentum, it has cast a growing spotlight on genetic testing and its potential. To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
 

The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing

When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.

“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”

Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea

Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.

One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.

Unfortunately, the drawbacks do not stop there.

“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”

Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
 

Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress

Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.

In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.

Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.

“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”

Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
 

Establishing Social Support Networks Typically Falls on the Patient and Loved Ones

Another con in rare genetic diseases is the lack of adoption across the community.

Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.

Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
 

Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases

As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.

In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.

Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”

As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.

Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.

Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.

“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
 

Accessibility and Lack of Geneticists Often a Rate-Limiting Step

The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”

Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.

Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.

In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
 

Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity

Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”

Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family ­— and patient — is different.

“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”

Suggested Reading

Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.

Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.

The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.

As the push toward prompt testing and treatment of rare diseases continues building momentum, it has cast a growing spotlight on genetic testing and its potential. To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
 

The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing

When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.

“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”

Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea

Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.

One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.

Unfortunately, the drawbacks do not stop there.

“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”

Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
 

Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress

Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.

In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.

Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.

“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”

Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
 

Establishing Social Support Networks Typically Falls on the Patient and Loved Ones

Another con in rare genetic diseases is the lack of adoption across the community.

Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.

Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
 

Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases

As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.

In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.

Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”

As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.

Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.

Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.

“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
 

Accessibility and Lack of Geneticists Often a Rate-Limiting Step

The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”

Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.

Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.

In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
 

Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity

Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”

Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family ­— and patient — is different.

“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”

Suggested Reading

Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.

Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.

The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.

As the push toward prompt testing and treatment of rare diseases continues building momentum, it has cast a growing spotlight on genetic testing and its potential. To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
 

The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing

When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.

“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”

Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea

Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.

One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.

Unfortunately, the drawbacks do not stop there.

“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”

Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
 

Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress

Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.

In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.

Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.

“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”

Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
 

Establishing Social Support Networks Typically Falls on the Patient and Loved Ones

Another con in rare genetic diseases is the lack of adoption across the community.

Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.

Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
 

Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases

As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.

In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.

Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”

As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.

Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.

Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.

“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
 

Accessibility and Lack of Geneticists Often a Rate-Limiting Step

The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”

Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.

Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.

In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
 

Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity

Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”

Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family ­— and patient — is different.

“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”

Suggested Reading

Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.

Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.

On any given day, oncologist Mark Lewis, MD, feels like he’s seesawing between two eras of technology. 

One minute, he’s working on sequencing a tumor genome. The next, he’s sifting through pages of disorganized data from a device that has been around for decades: the fax machine. 

“If two doctors’ offices aren’t on the same electronic medical record, one of the main ways to transfer records is still by fax,” said Dr. Lewis, director of gastrointestinal oncology at Intermountain Healthcare in Murray, Utah. “I can go from cutting-edge innovation to relying on, at best, 1980s information technology. It just boggles my mind.”

Dr. Lewis, who has posted about his frustration with fax machines, is far from alone. Oncologists are among the many specialists across the country at the mercy of telecopiers. 

According to a 2021 report by the Office of the National Coordinator for Health Information Technology, fax and mail continue to be the most common methods for hospitals and health systems to exchange care record summaries. In 2019, nearly 8 in 10 hospitals used mail or fax to send and receive health information, the report found. 

Fax machines are still commonplace across the healthcare spectrum, said Robert Havasy, MS, senior director for informatics strategy at the Healthcare Information and Management Systems Society (HIMSS). Inertia, cost, and more pressing priorities for hospitals and medical institutions contribute to the technology sticking around, he explained. 

“Post-COVID, my guess is we’re still at over 50% of healthcare practices using fax for some reason, on a daily basis,” Mr. Havasy said in an interview. “A lot of hospitals just don’t have the time, the money, or the staff to fix that problem because there’s always something a little higher up the priority chain they need to focus on.” 

If, for instance, “you’re going to do a process redesign to reduce hospital total acquired infections, your fax machine replacement might be 10th or 12th on the list. It just never gets up to 1 or 2 because it’s ‘not that much of a problem,’ ” he added.

Or is it?

Administrators may not view fax machines as a top concern, but clinicians who deal with the machines daily see it differently. 

“What worries me is we’re taking records out of an electronic storehouse [and] converting them to a paper medium,” Dr. Lewis said. “And then we are scanning into another electronic storehouse. The more steps, the more can be lost.”

And when information is lost, patient care can be compromised. 

Slower Workflows, Care Concerns

Although there are no published data on fax machine use in oncology specifically, this outdated technology does come into play in a variety of ways along the cancer care continuum. 

Radiation oncologist David R. Penberthy, MD, said patients often seek his cancer center’s expertise for second opinions, and that requires collecting patient records from many different practices. 

“Ideally, it would come electronically, but sometimes it does come by fax,” said Dr. Penberthy, program director of radiation oncology at the University of Virginia School of Medicine in Charlottesville. “The quality of the fax is not always the best. Sometimes it’s literally a fax of a fax. You’re reading something that’s very difficult to read.” 

Orders for new tests are also typically sent and received via fax temporarily while IT teams work to integrate them into the electronic health record (EHR), Dr. Penberthy said. 

Insurers and third-party laboratories often send test results back by fax as well.

“Even if I haven’t actually sent my patient out of our institution, this crucial result may only be entered back into the record as a scanned document from a fax, which is not great because it can get lost in the other results that are reported electronically,” Dr. Lewis said. The risk here is that an ordering physician won’t see these results, which can lead to delayed or overlooked care for patients, he explained.

“To me, it’s like a blind spot,” Dr. Lewis said. “Every time we use a fax, I see it actually as an opportunity for oversight and missed opportunity to collect data.”

Dr. Penberthy said faxing can slow things down at his practice, particularly if he faxes a document to another office but receives no confirmation and has to track down what happened. 

As for cybersecurity, data that are in transit during faxing are generally considered secure and compliant with the Health Insurance Portability and Accountability Act (HIPAA), said Mr. Havasy of HIMSS. However, the Privacy Rule also requires that data remain secure while at rest, which isn’t always possible, he added. 

“That’s where faxes fall down, because generally fax machines are in public, if you will, or open areas in a hospital,” he said. “They just sit on a desk. I don’t know that the next nurse who comes up and looks through that stack was the nurse who was treating the patient.” 

Important decisions or results can also be missed when sent by fax, creating headaches for physicians and care problems for patients. 

Dr. Lewis recently experienced an insurance-related fax mishap over Memorial Day weekend. He believed his patient had access to the antinausea medication he had prescribed. When Dr. Lewis happened to check the fax machine over the weekend, he found a coverage denial for the medication from the insurer but, at that point, had no recourse to appeal because it was a long holiday weekend. 

“Had the denial been sent by an electronic means that was quicker and more readily available, it would have been possible to appeal before the holiday weekend,” he said. 

Hematologist Aaron Goodman, MD, encountered a similar problem after an insurer denied coverage of an expensive cancer drug for a patient and faxed over its reason for the denial. Dr. Goodman was not directly notified that the information arrived and didn’t learn about the denial for a week, he said. 

“There’s no ‘ding’ in my inbox if something is faxed over and scanned,” said Dr. Goodman, associate professor of medicine at UC San Diego Health. “Once I realized it was denied, I was able to rectify it, but it wasted a week of a patient not getting a drug that I felt would be beneficial for them.”

Broader Health Policy Impacts

The use of outdated technology, such as fax machines, also creates ripple effects that burden the health system, health policy experts say. 

Duplicate testing and unnecessary care are top impacts, said Julia Adler-Milstein, PhD, professor of medicine and chief of the division of clinical informatics and digital transformation at the University of California, San Francisco.

Studies show that 20%-30% of the $65 billion spent annually on lab tests is used on unnecessary duplicate tests, and another estimated $30 billion is spent each year on unnecessary duplicate medical imaging. These duplicate tests may be mitigated if hospitals adopt certified EHR technology, research shows.

Still, without EHR interoperability between institutions, new providers may be unaware that tests or past labs for patients exist, leading to repeat tests, said Dr. Adler-Milstein, who researches health IT policy with a focus on EHRs. Patients can sometimes fill in the gaps, but not always. 

“Fax machines only help close information gaps if the clinician is aware of where to seek out the information and there is someone at the other organization to locate and transmit the information in a timely manner,” Dr. Adler-Milstein said. 

Old technology and poor interoperability also greatly affect data collection for disease surveillance and monitoring, said Janet Hamilton, MPH, executive director for the Council of State and Territorial Epidemiologists. This issue was keenly demonstrated during the pandemic, Ms. Hamilton said. 

“It was tragic, quite honestly,” she said. “There was such an immense amount of data that needed to be moved quickly, and that’s when computers are at their best.”

But, she said, “we didn’t have the level of systems in place to do it well.”

Specifically, the lack of electronic case reporting in place during the pandemic — where diagnoses are documented in the record and then immediately sent to the public health system — led to reports that were delayed, not made, or had missing or incomplete information, such as patients’ race and ethnicity or other health conditions, Ms. Hamilton said. 

Incomplete or missing data hampered the ability of public health officials and researchers to understand how the virus might affect different patients.

“If you had a chronic condition like cancer, you were less likely to have a positive outcome with COVID,” Ms. Hamilton said. “But because electronic case reporting was not in place, we didn’t get some of those additional pieces of information. We didn’t have people’s underlying oncology status to then say, ‘Here are individuals with these types of characteristics, and these are the things that happen if they also have a cancer.’” 

Slow, but Steady, Improvements

Efforts at the state and federal levels have targeted improved health information exchange, but progress takes time, Dr. Adler-Milstein said.

Most states have some form of health information exchange, such as statewide exchanges, regional health information organizations, or clinical data registries. Maryland is often held up as a notable example for its health information exchange, Dr. Adler-Milstein noted.

According to Maryland law, all hospitals under the jurisdiction of the Maryland Health Care Commission are required to electronically connect to the state-designated health information exchange. In 2012, Maryland became the first state to connect all its 46 acute care hospitals in the sharing of real-time data. 

The Health Information Technology for Economic and Clinical Health (HITECH) Act provided federal-enhanced Medicaid matching funds to states through 2021 to support efforts to advance electronic exchange. Nearly all states used these funds, and most have identified other sources to sustain the efforts, according to a recent US Government Accountability Office (GAO) report. However, GAO found that small and rural providers are less likely to have the financial and technological resources to participate in or maintain electronic exchange capabilities.

Nationally, several recent initiatives have targeted health data interoperability, including for cancer care. The Centers for Disease Control and Prevention’s Data Modernization Initiative is a multiyear, multi–billion-dollar effort to improve data sharing across the federal and state public health landscape. 

Meanwhile, in March 2024, the Biden-Harris administration launched United States Core Data for Interoperability Plus Cancer. The program will define a recommended minimum set of cancer-related data to be included in a patient’s EHR to enhance data exchange for research and clinical care. 

EHR vendors are also key to improving the landscape, said Dr. Adler-Milstein. Vendors such as Epic have developed strong sharing capabilities for transmitting health information from site to site, but of course, that only helps if providers have Epic, she said. 

“That’s where these national frameworks should help, because we don’t want it to break down by what EHR vendor you have,” she said. “It’s a patchwork. You can go to some places and hear success stories because they have Epic or a state health information exchange, but it’s very heterogeneous. In some places, they have nothing and are using a fax machine.”

Mr. Havasy believes fax machines will ultimately go extinct, particularly as a younger, more digitally savvy generation enters the healthcare workforce. He also foresees that the growing use of artificial intelligence will help eradicate the outdated technology. 

But, Ms. Hamilton noted, “unless we have consistent, ongoing, sustained funding, it is very hard to move off [an older] technology that can work. That’s one of the biggest barriers.” 

“Public health is about protecting the lives of every single person everywhere,” Ms. Hamilton said, “but when we don’t have the data that comes into the system, we can’t achieve our mission.”
 

A version of this article appeared on Medscape.com.

On any given day, oncologist Mark Lewis, MD, feels like he’s seesawing between two eras of technology. 

One minute, he’s working on sequencing a tumor genome. The next, he’s sifting through pages of disorganized data from a device that has been around for decades: the fax machine. 

“If two doctors’ offices aren’t on the same electronic medical record, one of the main ways to transfer records is still by fax,” said Dr. Lewis, director of gastrointestinal oncology at Intermountain Healthcare in Murray, Utah. “I can go from cutting-edge innovation to relying on, at best, 1980s information technology. It just boggles my mind.”

Dr. Lewis, who has posted about his frustration with fax machines, is far from alone. Oncologists are among the many specialists across the country at the mercy of telecopiers. 

According to a 2021 report by the Office of the National Coordinator for Health Information Technology, fax and mail continue to be the most common methods for hospitals and health systems to exchange care record summaries. In 2019, nearly 8 in 10 hospitals used mail or fax to send and receive health information, the report found. 

Fax machines are still commonplace across the healthcare spectrum, said Robert Havasy, MS, senior director for informatics strategy at the Healthcare Information and Management Systems Society (HIMSS). Inertia, cost, and more pressing priorities for hospitals and medical institutions contribute to the technology sticking around, he explained. 

“Post-COVID, my guess is we’re still at over 50% of healthcare practices using fax for some reason, on a daily basis,” Mr. Havasy said in an interview. “A lot of hospitals just don’t have the time, the money, or the staff to fix that problem because there’s always something a little higher up the priority chain they need to focus on.” 

If, for instance, “you’re going to do a process redesign to reduce hospital total acquired infections, your fax machine replacement might be 10th or 12th on the list. It just never gets up to 1 or 2 because it’s ‘not that much of a problem,’ ” he added.

Or is it?

Administrators may not view fax machines as a top concern, but clinicians who deal with the machines daily see it differently. 

“What worries me is we’re taking records out of an electronic storehouse [and] converting them to a paper medium,” Dr. Lewis said. “And then we are scanning into another electronic storehouse. The more steps, the more can be lost.”

And when information is lost, patient care can be compromised. 

Slower Workflows, Care Concerns

Although there are no published data on fax machine use in oncology specifically, this outdated technology does come into play in a variety of ways along the cancer care continuum. 

Radiation oncologist David R. Penberthy, MD, said patients often seek his cancer center’s expertise for second opinions, and that requires collecting patient records from many different practices. 

“Ideally, it would come electronically, but sometimes it does come by fax,” said Dr. Penberthy, program director of radiation oncology at the University of Virginia School of Medicine in Charlottesville. “The quality of the fax is not always the best. Sometimes it’s literally a fax of a fax. You’re reading something that’s very difficult to read.” 

Orders for new tests are also typically sent and received via fax temporarily while IT teams work to integrate them into the electronic health record (EHR), Dr. Penberthy said. 

Insurers and third-party laboratories often send test results back by fax as well.

“Even if I haven’t actually sent my patient out of our institution, this crucial result may only be entered back into the record as a scanned document from a fax, which is not great because it can get lost in the other results that are reported electronically,” Dr. Lewis said. The risk here is that an ordering physician won’t see these results, which can lead to delayed or overlooked care for patients, he explained.

“To me, it’s like a blind spot,” Dr. Lewis said. “Every time we use a fax, I see it actually as an opportunity for oversight and missed opportunity to collect data.”

Dr. Penberthy said faxing can slow things down at his practice, particularly if he faxes a document to another office but receives no confirmation and has to track down what happened. 

As for cybersecurity, data that are in transit during faxing are generally considered secure and compliant with the Health Insurance Portability and Accountability Act (HIPAA), said Mr. Havasy of HIMSS. However, the Privacy Rule also requires that data remain secure while at rest, which isn’t always possible, he added. 

“That’s where faxes fall down, because generally fax machines are in public, if you will, or open areas in a hospital,” he said. “They just sit on a desk. I don’t know that the next nurse who comes up and looks through that stack was the nurse who was treating the patient.” 

Important decisions or results can also be missed when sent by fax, creating headaches for physicians and care problems for patients. 

Dr. Lewis recently experienced an insurance-related fax mishap over Memorial Day weekend. He believed his patient had access to the antinausea medication he had prescribed. When Dr. Lewis happened to check the fax machine over the weekend, he found a coverage denial for the medication from the insurer but, at that point, had no recourse to appeal because it was a long holiday weekend. 

“Had the denial been sent by an electronic means that was quicker and more readily available, it would have been possible to appeal before the holiday weekend,” he said. 

Hematologist Aaron Goodman, MD, encountered a similar problem after an insurer denied coverage of an expensive cancer drug for a patient and faxed over its reason for the denial. Dr. Goodman was not directly notified that the information arrived and didn’t learn about the denial for a week, he said. 

“There’s no ‘ding’ in my inbox if something is faxed over and scanned,” said Dr. Goodman, associate professor of medicine at UC San Diego Health. “Once I realized it was denied, I was able to rectify it, but it wasted a week of a patient not getting a drug that I felt would be beneficial for them.”

Broader Health Policy Impacts

The use of outdated technology, such as fax machines, also creates ripple effects that burden the health system, health policy experts say. 

Duplicate testing and unnecessary care are top impacts, said Julia Adler-Milstein, PhD, professor of medicine and chief of the division of clinical informatics and digital transformation at the University of California, San Francisco.

Studies show that 20%-30% of the $65 billion spent annually on lab tests is used on unnecessary duplicate tests, and another estimated $30 billion is spent each year on unnecessary duplicate medical imaging. These duplicate tests may be mitigated if hospitals adopt certified EHR technology, research shows.

Still, without EHR interoperability between institutions, new providers may be unaware that tests or past labs for patients exist, leading to repeat tests, said Dr. Adler-Milstein, who researches health IT policy with a focus on EHRs. Patients can sometimes fill in the gaps, but not always. 

“Fax machines only help close information gaps if the clinician is aware of where to seek out the information and there is someone at the other organization to locate and transmit the information in a timely manner,” Dr. Adler-Milstein said. 

Old technology and poor interoperability also greatly affect data collection for disease surveillance and monitoring, said Janet Hamilton, MPH, executive director for the Council of State and Territorial Epidemiologists. This issue was keenly demonstrated during the pandemic, Ms. Hamilton said. 

“It was tragic, quite honestly,” she said. “There was such an immense amount of data that needed to be moved quickly, and that’s when computers are at their best.”

But, she said, “we didn’t have the level of systems in place to do it well.”

Specifically, the lack of electronic case reporting in place during the pandemic — where diagnoses are documented in the record and then immediately sent to the public health system — led to reports that were delayed, not made, or had missing or incomplete information, such as patients’ race and ethnicity or other health conditions, Ms. Hamilton said. 

Incomplete or missing data hampered the ability of public health officials and researchers to understand how the virus might affect different patients.

“If you had a chronic condition like cancer, you were less likely to have a positive outcome with COVID,” Ms. Hamilton said. “But because electronic case reporting was not in place, we didn’t get some of those additional pieces of information. We didn’t have people’s underlying oncology status to then say, ‘Here are individuals with these types of characteristics, and these are the things that happen if they also have a cancer.’” 

Slow, but Steady, Improvements

Efforts at the state and federal levels have targeted improved health information exchange, but progress takes time, Dr. Adler-Milstein said.

Most states have some form of health information exchange, such as statewide exchanges, regional health information organizations, or clinical data registries. Maryland is often held up as a notable example for its health information exchange, Dr. Adler-Milstein noted.

According to Maryland law, all hospitals under the jurisdiction of the Maryland Health Care Commission are required to electronically connect to the state-designated health information exchange. In 2012, Maryland became the first state to connect all its 46 acute care hospitals in the sharing of real-time data. 

The Health Information Technology for Economic and Clinical Health (HITECH) Act provided federal-enhanced Medicaid matching funds to states through 2021 to support efforts to advance electronic exchange. Nearly all states used these funds, and most have identified other sources to sustain the efforts, according to a recent US Government Accountability Office (GAO) report. However, GAO found that small and rural providers are less likely to have the financial and technological resources to participate in or maintain electronic exchange capabilities.

Nationally, several recent initiatives have targeted health data interoperability, including for cancer care. The Centers for Disease Control and Prevention’s Data Modernization Initiative is a multiyear, multi–billion-dollar effort to improve data sharing across the federal and state public health landscape. 

Meanwhile, in March 2024, the Biden-Harris administration launched United States Core Data for Interoperability Plus Cancer. The program will define a recommended minimum set of cancer-related data to be included in a patient’s EHR to enhance data exchange for research and clinical care. 

EHR vendors are also key to improving the landscape, said Dr. Adler-Milstein. Vendors such as Epic have developed strong sharing capabilities for transmitting health information from site to site, but of course, that only helps if providers have Epic, she said. 

“That’s where these national frameworks should help, because we don’t want it to break down by what EHR vendor you have,” she said. “It’s a patchwork. You can go to some places and hear success stories because they have Epic or a state health information exchange, but it’s very heterogeneous. In some places, they have nothing and are using a fax machine.”

Mr. Havasy believes fax machines will ultimately go extinct, particularly as a younger, more digitally savvy generation enters the healthcare workforce. He also foresees that the growing use of artificial intelligence will help eradicate the outdated technology. 

But, Ms. Hamilton noted, “unless we have consistent, ongoing, sustained funding, it is very hard to move off [an older] technology that can work. That’s one of the biggest barriers.” 

“Public health is about protecting the lives of every single person everywhere,” Ms. Hamilton said, “but when we don’t have the data that comes into the system, we can’t achieve our mission.”
 

A version of this article appeared on Medscape.com.

On any given day, oncologist Mark Lewis, MD, feels like he’s seesawing between two eras of technology. 

One minute, he’s working on sequencing a tumor genome. The next, he’s sifting through pages of disorganized data from a device that has been around for decades: the fax machine. 

“If two doctors’ offices aren’t on the same electronic medical record, one of the main ways to transfer records is still by fax,” said Dr. Lewis, director of gastrointestinal oncology at Intermountain Healthcare in Murray, Utah. “I can go from cutting-edge innovation to relying on, at best, 1980s information technology. It just boggles my mind.”

Dr. Lewis, who has posted about his frustration with fax machines, is far from alone. Oncologists are among the many specialists across the country at the mercy of telecopiers. 

According to a 2021 report by the Office of the National Coordinator for Health Information Technology, fax and mail continue to be the most common methods for hospitals and health systems to exchange care record summaries. In 2019, nearly 8 in 10 hospitals used mail or fax to send and receive health information, the report found. 

Fax machines are still commonplace across the healthcare spectrum, said Robert Havasy, MS, senior director for informatics strategy at the Healthcare Information and Management Systems Society (HIMSS). Inertia, cost, and more pressing priorities for hospitals and medical institutions contribute to the technology sticking around, he explained. 

“Post-COVID, my guess is we’re still at over 50% of healthcare practices using fax for some reason, on a daily basis,” Mr. Havasy said in an interview. “A lot of hospitals just don’t have the time, the money, or the staff to fix that problem because there’s always something a little higher up the priority chain they need to focus on.” 

If, for instance, “you’re going to do a process redesign to reduce hospital total acquired infections, your fax machine replacement might be 10th or 12th on the list. It just never gets up to 1 or 2 because it’s ‘not that much of a problem,’ ” he added.

Or is it?

Administrators may not view fax machines as a top concern, but clinicians who deal with the machines daily see it differently. 

“What worries me is we’re taking records out of an electronic storehouse [and] converting them to a paper medium,” Dr. Lewis said. “And then we are scanning into another electronic storehouse. The more steps, the more can be lost.”

And when information is lost, patient care can be compromised. 

Slower Workflows, Care Concerns

Although there are no published data on fax machine use in oncology specifically, this outdated technology does come into play in a variety of ways along the cancer care continuum. 

Radiation oncologist David R. Penberthy, MD, said patients often seek his cancer center’s expertise for second opinions, and that requires collecting patient records from many different practices. 

“Ideally, it would come electronically, but sometimes it does come by fax,” said Dr. Penberthy, program director of radiation oncology at the University of Virginia School of Medicine in Charlottesville. “The quality of the fax is not always the best. Sometimes it’s literally a fax of a fax. You’re reading something that’s very difficult to read.” 

Orders for new tests are also typically sent and received via fax temporarily while IT teams work to integrate them into the electronic health record (EHR), Dr. Penberthy said. 

Insurers and third-party laboratories often send test results back by fax as well.

“Even if I haven’t actually sent my patient out of our institution, this crucial result may only be entered back into the record as a scanned document from a fax, which is not great because it can get lost in the other results that are reported electronically,” Dr. Lewis said. The risk here is that an ordering physician won’t see these results, which can lead to delayed or overlooked care for patients, he explained.

“To me, it’s like a blind spot,” Dr. Lewis said. “Every time we use a fax, I see it actually as an opportunity for oversight and missed opportunity to collect data.”

Dr. Penberthy said faxing can slow things down at his practice, particularly if he faxes a document to another office but receives no confirmation and has to track down what happened. 

As for cybersecurity, data that are in transit during faxing are generally considered secure and compliant with the Health Insurance Portability and Accountability Act (HIPAA), said Mr. Havasy of HIMSS. However, the Privacy Rule also requires that data remain secure while at rest, which isn’t always possible, he added. 

“That’s where faxes fall down, because generally fax machines are in public, if you will, or open areas in a hospital,” he said. “They just sit on a desk. I don’t know that the next nurse who comes up and looks through that stack was the nurse who was treating the patient.” 

Important decisions or results can also be missed when sent by fax, creating headaches for physicians and care problems for patients. 

Dr. Lewis recently experienced an insurance-related fax mishap over Memorial Day weekend. He believed his patient had access to the antinausea medication he had prescribed. When Dr. Lewis happened to check the fax machine over the weekend, he found a coverage denial for the medication from the insurer but, at that point, had no recourse to appeal because it was a long holiday weekend. 

“Had the denial been sent by an electronic means that was quicker and more readily available, it would have been possible to appeal before the holiday weekend,” he said. 

Hematologist Aaron Goodman, MD, encountered a similar problem after an insurer denied coverage of an expensive cancer drug for a patient and faxed over its reason for the denial. Dr. Goodman was not directly notified that the information arrived and didn’t learn about the denial for a week, he said. 

“There’s no ‘ding’ in my inbox if something is faxed over and scanned,” said Dr. Goodman, associate professor of medicine at UC San Diego Health. “Once I realized it was denied, I was able to rectify it, but it wasted a week of a patient not getting a drug that I felt would be beneficial for them.”

Broader Health Policy Impacts

The use of outdated technology, such as fax machines, also creates ripple effects that burden the health system, health policy experts say. 

Duplicate testing and unnecessary care are top impacts, said Julia Adler-Milstein, PhD, professor of medicine and chief of the division of clinical informatics and digital transformation at the University of California, San Francisco.

Studies show that 20%-30% of the $65 billion spent annually on lab tests is used on unnecessary duplicate tests, and another estimated $30 billion is spent each year on unnecessary duplicate medical imaging. These duplicate tests may be mitigated if hospitals adopt certified EHR technology, research shows.

Still, without EHR interoperability between institutions, new providers may be unaware that tests or past labs for patients exist, leading to repeat tests, said Dr. Adler-Milstein, who researches health IT policy with a focus on EHRs. Patients can sometimes fill in the gaps, but not always. 

“Fax machines only help close information gaps if the clinician is aware of where to seek out the information and there is someone at the other organization to locate and transmit the information in a timely manner,” Dr. Adler-Milstein said. 

Old technology and poor interoperability also greatly affect data collection for disease surveillance and monitoring, said Janet Hamilton, MPH, executive director for the Council of State and Territorial Epidemiologists. This issue was keenly demonstrated during the pandemic, Ms. Hamilton said. 

“It was tragic, quite honestly,” she said. “There was such an immense amount of data that needed to be moved quickly, and that’s when computers are at their best.”

But, she said, “we didn’t have the level of systems in place to do it well.”

Specifically, the lack of electronic case reporting in place during the pandemic — where diagnoses are documented in the record and then immediately sent to the public health system — led to reports that were delayed, not made, or had missing or incomplete information, such as patients’ race and ethnicity or other health conditions, Ms. Hamilton said. 

Incomplete or missing data hampered the ability of public health officials and researchers to understand how the virus might affect different patients.

“If you had a chronic condition like cancer, you were less likely to have a positive outcome with COVID,” Ms. Hamilton said. “But because electronic case reporting was not in place, we didn’t get some of those additional pieces of information. We didn’t have people’s underlying oncology status to then say, ‘Here are individuals with these types of characteristics, and these are the things that happen if they also have a cancer.’” 

Slow, but Steady, Improvements

Efforts at the state and federal levels have targeted improved health information exchange, but progress takes time, Dr. Adler-Milstein said.

Most states have some form of health information exchange, such as statewide exchanges, regional health information organizations, or clinical data registries. Maryland is often held up as a notable example for its health information exchange, Dr. Adler-Milstein noted.

According to Maryland law, all hospitals under the jurisdiction of the Maryland Health Care Commission are required to electronically connect to the state-designated health information exchange. In 2012, Maryland became the first state to connect all its 46 acute care hospitals in the sharing of real-time data. 

The Health Information Technology for Economic and Clinical Health (HITECH) Act provided federal-enhanced Medicaid matching funds to states through 2021 to support efforts to advance electronic exchange. Nearly all states used these funds, and most have identified other sources to sustain the efforts, according to a recent US Government Accountability Office (GAO) report. However, GAO found that small and rural providers are less likely to have the financial and technological resources to participate in or maintain electronic exchange capabilities.

Nationally, several recent initiatives have targeted health data interoperability, including for cancer care. The Centers for Disease Control and Prevention’s Data Modernization Initiative is a multiyear, multi–billion-dollar effort to improve data sharing across the federal and state public health landscape. 

Meanwhile, in March 2024, the Biden-Harris administration launched United States Core Data for Interoperability Plus Cancer. The program will define a recommended minimum set of cancer-related data to be included in a patient’s EHR to enhance data exchange for research and clinical care. 

EHR vendors are also key to improving the landscape, said Dr. Adler-Milstein. Vendors such as Epic have developed strong sharing capabilities for transmitting health information from site to site, but of course, that only helps if providers have Epic, she said. 

“That’s where these national frameworks should help, because we don’t want it to break down by what EHR vendor you have,” she said. “It’s a patchwork. You can go to some places and hear success stories because they have Epic or a state health information exchange, but it’s very heterogeneous. In some places, they have nothing and are using a fax machine.”

Mr. Havasy believes fax machines will ultimately go extinct, particularly as a younger, more digitally savvy generation enters the healthcare workforce. He also foresees that the growing use of artificial intelligence will help eradicate the outdated technology. 

But, Ms. Hamilton noted, “unless we have consistent, ongoing, sustained funding, it is very hard to move off [an older] technology that can work. That’s one of the biggest barriers.” 

“Public health is about protecting the lives of every single person everywhere,” Ms. Hamilton said, “but when we don’t have the data that comes into the system, we can’t achieve our mission.”
 

A version of this article appeared on Medscape.com.

Nearly one in three physicians endorsing drugs and devices on the social media platform X did not disclose that they received payments from the manufacturers, according to a new study published in JAMA.

Lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, told this news organization that he and his colleagues undertook the study in part to see whether physicians were adhering to professional and industry guidelines regarding marketing communications.

The team reviewed posts by physicians on X during 2022, looking for key words that might indicate that the posts were intended as endorsements of a product. The researchers then delved into the Centers for Medicare and Medicaid Services Open Payments database to see how many of those identified as having endorsed a product were paid by the manufacturers.

What Dr. Mitchell found concerned him, he said.

Overall, the researchers identified 28 physician endorsers who received a total of $1.4 million from sponsors in 2022. Among these, 26 physicians (93%) received payments from the product’s manufacturer, totaling $713,976, and 24 physicians (86%) accepted payments related to the endorsed drug or device, totaling $492,098.

While most did disclose that the posts were sponsored — by adding the word “sponsored” or using #sponsored — nine physicians did not.

Although 28 physician endorsers represent a “small fraction” of the overall number of physicians who use X, each endorsement was ultimately posted dozens, if not hundreds of times, said Dr. Mitchell. In fact, he said he saw the same particular endorsement post every time he opened his X app for months.

Overall, Dr. Mitchell noted that it’s less about the fact that the endorsements are occurring on social media and more that there are these paid endorsements taking place at all.

Among the physician specialties promoting a product, urologists and oncologists dominated. Almost one third were urologists, and 57% were oncologists — six medical oncologists, six radiation oncologists, and four gynecologic oncologists. Of the remaining three physicians, two were internists and one was a pulmonary and critical care medicine specialist.

The authors tracked posts from physicians and industry accounts. Many of the posts on industry accounts were physician testimonials, usually videos. Almost half — 8 of 17 — of those testimonials did not disclose that the doctor was being paid by the manufacturer. In another case, a physician did not disclose that they were paid to endorse a white paper.

Fifteen promotional posts were for a Boston Scientific product, followed by six for GlaxoSmithKline, two for Eisai, two for Exelixis, and one each for AstraZeneca, Novartis, and Pfizer.

In general, Dr. Mitchell said, industry guidelines suggest that manufacturer-paid speakers or consultants should have well-regarded expertise in the area they are being asked to weigh in on, but most physician endorsers in the study were not key opinion leaders or experts.

The authors examined the paid endorsers’ H-index — a measure of academic productivity provided by Scopus. Overall, 19 of the 28 physicians had an H-index below 20, which is considered less accomplished, and 14 had no published research related to the endorsed product.

Ten received payments from manufacturers for research purposes, and only one received research payments related to the endorsed product ($224,577).

“Physicians’ participation in industry marketing raises questions regarding professionalism and their responsibilities as patient advocates,” the JAMA authors wrote.

The study was supported by grants from the National Cancer Institute. Dr. Mitchell reported no relevant financial relationships. Coauthors Samer Al Hadidi, MD, reported receiving personal fees from Pfizer, Sanofi, and Janssen during the conduct of the study, and Timothy S. Anderson, MD, reported receiving grants from the National Institute on Aging, the American Heart Association, and the American College of Cardiology, and receiving consulting fees from the American Medical Student Association. Dr. Anderson is also an associate editor of JAMA Internal Medicine.

A version of this article appeared on Medscape.com.

Nearly one in three physicians endorsing drugs and devices on the social media platform X did not disclose that they received payments from the manufacturers, according to a new study published in JAMA.

Lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, told this news organization that he and his colleagues undertook the study in part to see whether physicians were adhering to professional and industry guidelines regarding marketing communications.

The team reviewed posts by physicians on X during 2022, looking for key words that might indicate that the posts were intended as endorsements of a product. The researchers then delved into the Centers for Medicare and Medicaid Services Open Payments database to see how many of those identified as having endorsed a product were paid by the manufacturers.

What Dr. Mitchell found concerned him, he said.

Overall, the researchers identified 28 physician endorsers who received a total of $1.4 million from sponsors in 2022. Among these, 26 physicians (93%) received payments from the product’s manufacturer, totaling $713,976, and 24 physicians (86%) accepted payments related to the endorsed drug or device, totaling $492,098.

While most did disclose that the posts were sponsored — by adding the word “sponsored” or using #sponsored — nine physicians did not.

Although 28 physician endorsers represent a “small fraction” of the overall number of physicians who use X, each endorsement was ultimately posted dozens, if not hundreds of times, said Dr. Mitchell. In fact, he said he saw the same particular endorsement post every time he opened his X app for months.

Overall, Dr. Mitchell noted that it’s less about the fact that the endorsements are occurring on social media and more that there are these paid endorsements taking place at all.

Among the physician specialties promoting a product, urologists and oncologists dominated. Almost one third were urologists, and 57% were oncologists — six medical oncologists, six radiation oncologists, and four gynecologic oncologists. Of the remaining three physicians, two were internists and one was a pulmonary and critical care medicine specialist.

The authors tracked posts from physicians and industry accounts. Many of the posts on industry accounts were physician testimonials, usually videos. Almost half — 8 of 17 — of those testimonials did not disclose that the doctor was being paid by the manufacturer. In another case, a physician did not disclose that they were paid to endorse a white paper.

Fifteen promotional posts were for a Boston Scientific product, followed by six for GlaxoSmithKline, two for Eisai, two for Exelixis, and one each for AstraZeneca, Novartis, and Pfizer.

In general, Dr. Mitchell said, industry guidelines suggest that manufacturer-paid speakers or consultants should have well-regarded expertise in the area they are being asked to weigh in on, but most physician endorsers in the study were not key opinion leaders or experts.

The authors examined the paid endorsers’ H-index — a measure of academic productivity provided by Scopus. Overall, 19 of the 28 physicians had an H-index below 20, which is considered less accomplished, and 14 had no published research related to the endorsed product.

Ten received payments from manufacturers for research purposes, and only one received research payments related to the endorsed product ($224,577).

“Physicians’ participation in industry marketing raises questions regarding professionalism and their responsibilities as patient advocates,” the JAMA authors wrote.

The study was supported by grants from the National Cancer Institute. Dr. Mitchell reported no relevant financial relationships. Coauthors Samer Al Hadidi, MD, reported receiving personal fees from Pfizer, Sanofi, and Janssen during the conduct of the study, and Timothy S. Anderson, MD, reported receiving grants from the National Institute on Aging, the American Heart Association, and the American College of Cardiology, and receiving consulting fees from the American Medical Student Association. Dr. Anderson is also an associate editor of JAMA Internal Medicine.

A version of this article appeared on Medscape.com.

Nearly one in three physicians endorsing drugs and devices on the social media platform X did not disclose that they received payments from the manufacturers, according to a new study published in JAMA.

Lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, told this news organization that he and his colleagues undertook the study in part to see whether physicians were adhering to professional and industry guidelines regarding marketing communications.

The team reviewed posts by physicians on X during 2022, looking for key words that might indicate that the posts were intended as endorsements of a product. The researchers then delved into the Centers for Medicare and Medicaid Services Open Payments database to see how many of those identified as having endorsed a product were paid by the manufacturers.

What Dr. Mitchell found concerned him, he said.

Overall, the researchers identified 28 physician endorsers who received a total of $1.4 million from sponsors in 2022. Among these, 26 physicians (93%) received payments from the product’s manufacturer, totaling $713,976, and 24 physicians (86%) accepted payments related to the endorsed drug or device, totaling $492,098.

While most did disclose that the posts were sponsored — by adding the word “sponsored” or using #sponsored — nine physicians did not.

Although 28 physician endorsers represent a “small fraction” of the overall number of physicians who use X, each endorsement was ultimately posted dozens, if not hundreds of times, said Dr. Mitchell. In fact, he said he saw the same particular endorsement post every time he opened his X app for months.

Overall, Dr. Mitchell noted that it’s less about the fact that the endorsements are occurring on social media and more that there are these paid endorsements taking place at all.

Among the physician specialties promoting a product, urologists and oncologists dominated. Almost one third were urologists, and 57% were oncologists — six medical oncologists, six radiation oncologists, and four gynecologic oncologists. Of the remaining three physicians, two were internists and one was a pulmonary and critical care medicine specialist.

The authors tracked posts from physicians and industry accounts. Many of the posts on industry accounts were physician testimonials, usually videos. Almost half — 8 of 17 — of those testimonials did not disclose that the doctor was being paid by the manufacturer. In another case, a physician did not disclose that they were paid to endorse a white paper.

Fifteen promotional posts were for a Boston Scientific product, followed by six for GlaxoSmithKline, two for Eisai, two for Exelixis, and one each for AstraZeneca, Novartis, and Pfizer.

In general, Dr. Mitchell said, industry guidelines suggest that manufacturer-paid speakers or consultants should have well-regarded expertise in the area they are being asked to weigh in on, but most physician endorsers in the study were not key opinion leaders or experts.

The authors examined the paid endorsers’ H-index — a measure of academic productivity provided by Scopus. Overall, 19 of the 28 physicians had an H-index below 20, which is considered less accomplished, and 14 had no published research related to the endorsed product.

Ten received payments from manufacturers for research purposes, and only one received research payments related to the endorsed product ($224,577).

“Physicians’ participation in industry marketing raises questions regarding professionalism and their responsibilities as patient advocates,” the JAMA authors wrote.

The study was supported by grants from the National Cancer Institute. Dr. Mitchell reported no relevant financial relationships. Coauthors Samer Al Hadidi, MD, reported receiving personal fees from Pfizer, Sanofi, and Janssen during the conduct of the study, and Timothy S. Anderson, MD, reported receiving grants from the National Institute on Aging, the American Heart Association, and the American College of Cardiology, and receiving consulting fees from the American Medical Student Association. Dr. Anderson is also an associate editor of JAMA Internal Medicine.

A version of this article appeared on Medscape.com.

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

A version of this article first appeared on Medscape.com.

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

A version of this article first appeared on Medscape.com.

SAN DIEGO — Compared with medical oncologists, dermatologists were more likely to correctly classify and grade dermatologic adverse events from cancer therapies, results from a multicenter survey showed.

“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.

The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”

To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.

Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).

“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”

Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”

Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.

“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”

Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
 

A version of this article first appeared on Medscape.com.

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Fewer than half of the cancer drugs approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway between 2013 and 2017 have been shown to improve overall survival or quality of life, despite being on the US market for more than 5 years, according to a new study. 

Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response. 

Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.

The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.

In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.

To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits. 

Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.

Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results. 

The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff. 

However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials. 

In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”

There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit. 

The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious. 

In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial. 

“There have been some promising steps,” Dr. Cliff said, but much work needs to be done. 

Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.” 

But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.

Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.” 

Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.” 

As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together. 

The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures. 
 

A version of this article appeared on Medscape.com.