Multiple Myeloma

Photo by Chad McNeeley

The use of autologous transplant after a 3-drug induction regimen for multiple myeloma (MM) prolongs progression-free survival (PFS) but not overall survival (OS), according to new research.

In a phase 3 trial, newly diagnosed MM patients who received lenalidomide, bortezomib, and dexamethasone (RVD) followed by an autologous hematopoietic stem cell transplant (HSCT) had significantly better PFS but similar OS when compared to patients who only received RVD.

In addition, HSCT recipients had significantly higher rates of high-grade blood and lymphatic system disorders, gastrointestinal events, and infections.

The study also showed that OS outcomes were similar for patients who received HSCT after completing treatment with RVD and patients who were in the RVD-only treatment arm but underwent HSCT later, as salvage therapy.

Researchers believe this suggests MM patients can potentially choose when to undergo a transplant.

The team reported their findings in NEJM. The study was supported by grants from Celgene and Janssen and by funds from the French Ministry of Health Programme Hospitalier de Recherche Clinique and from the French National Research Agency.

“Over the past decade, drugs that modulate the immune system and agents known as proteasome inhibitors have shown a great deal of promise in patients with multiple myeloma, when used in combination with chemotherapy,” said study author Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“This led us to propose that these combinations could be used selectively with established modalities such as transplant for patients with newly diagnosed myeloma, and this, in turn, raised questions about where and how transplant should be fit into the therapeutic paradigm. Our trial sought to comprehensively address these issues in a prospective fashion, and provide a foundation for future studies as the next generation of agents, such as monoclonal antibodies, impact the field.”

The study enrolled 700 adult patients under the age of 65 who were newly diagnosed with MM. They were treated at 69 centers in France, Belgium, and Switzerland.

The patients were randomized to 2 treatment arms. Both groups received 3 initial cycles of RVD.

One group then received 5 more cycles of RVD. The other received high-dose chemotherapy (melphalan) followed by an autologous HSCT and 2 additional cycles of RVD.

Patients in both groups then received lenalidomide as maintenance therapy for 1 year or until they progressed, experienced unacceptable adverse events (AEs), or withdrew consent.

Response and survival

The complete response rate was significantly higher in the HSCT arm than the RVD-alone arm—59% and 48%, respectively (P=0.03).

And there was a significantly higher percentage of patients who were negative for minimal residual disease in the HSCT arm than in the RVD arm—79% and 65%, respectively (P<0.001).

The median PFS was significantly longer in the HSCT arm than the RVD arm—50 months and 36 months, respectively (P<0.001). The researchers said this benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk.

There was no significant between-group difference in the rate of OS at 4 years, which was 81% in the HSCT arm and 82% in the RVD arm.

Subsequent therapy

In the RVD arm, 207 patients progressed, and 172 received second-line therapy, which was followed by salvage HSCT in 136 patients (79%).

In the HSCT arm, 149 patients progressed, and 123 received second-line therapy, which was followed by a second HSCT in 21 patients (17%).

Safety

Nine percent of patients in the RVD arm and 11% in the HSCT arm discontinued treatment due to AEs. There were 2 treatment-related deaths in the RVD arm and 6 in the HSCT arm.

Grade 3/4 AEs with a significantly higher incidence in the HSCT arm than the RVD arm were blood and lymphatic system disorders (95% and 64%, respectively, P<0.001), gastrointestinal disorders (28% and 7%, respectively, P<0.001), and infections (20% and 9%, respectively, P<0.001).

Thirteen patients in the RVD arm and 17 in the HSCT arm had at least 1 invasive second primary malignancy (P=0.36). Acute myeloid leukemia occurred in 1 patient in the RVD arm and 4 in the HSCT arm (P=0.21).

The researchers said these results suggest the benefits of HSCT plus RVD must be weighed against the increased risk of toxicity associated with high-dose chemotherapy plus HSCT, particularly since HSCT after progression might be as effective as early HSCT for ensuring long-term OS. 

Photo by Chad McNeeley

The use of autologous transplant after a 3-drug induction regimen for multiple myeloma (MM) prolongs progression-free survival (PFS) but not overall survival (OS), according to new research.

In a phase 3 trial, newly diagnosed MM patients who received lenalidomide, bortezomib, and dexamethasone (RVD) followed by an autologous hematopoietic stem cell transplant (HSCT) had significantly better PFS but similar OS when compared to patients who only received RVD.

In addition, HSCT recipients had significantly higher rates of high-grade blood and lymphatic system disorders, gastrointestinal events, and infections.

The study also showed that OS outcomes were similar for patients who received HSCT after completing treatment with RVD and patients who were in the RVD-only treatment arm but underwent HSCT later, as salvage therapy.

Researchers believe this suggests MM patients can potentially choose when to undergo a transplant.

The team reported their findings in NEJM. The study was supported by grants from Celgene and Janssen and by funds from the French Ministry of Health Programme Hospitalier de Recherche Clinique and from the French National Research Agency.

“Over the past decade, drugs that modulate the immune system and agents known as proteasome inhibitors have shown a great deal of promise in patients with multiple myeloma, when used in combination with chemotherapy,” said study author Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“This led us to propose that these combinations could be used selectively with established modalities such as transplant for patients with newly diagnosed myeloma, and this, in turn, raised questions about where and how transplant should be fit into the therapeutic paradigm. Our trial sought to comprehensively address these issues in a prospective fashion, and provide a foundation for future studies as the next generation of agents, such as monoclonal antibodies, impact the field.”

The study enrolled 700 adult patients under the age of 65 who were newly diagnosed with MM. They were treated at 69 centers in France, Belgium, and Switzerland.

The patients were randomized to 2 treatment arms. Both groups received 3 initial cycles of RVD.

One group then received 5 more cycles of RVD. The other received high-dose chemotherapy (melphalan) followed by an autologous HSCT and 2 additional cycles of RVD.

Patients in both groups then received lenalidomide as maintenance therapy for 1 year or until they progressed, experienced unacceptable adverse events (AEs), or withdrew consent.

Response and survival

The complete response rate was significantly higher in the HSCT arm than the RVD-alone arm—59% and 48%, respectively (P=0.03).

And there was a significantly higher percentage of patients who were negative for minimal residual disease in the HSCT arm than in the RVD arm—79% and 65%, respectively (P<0.001).

The median PFS was significantly longer in the HSCT arm than the RVD arm—50 months and 36 months, respectively (P<0.001). The researchers said this benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk.

There was no significant between-group difference in the rate of OS at 4 years, which was 81% in the HSCT arm and 82% in the RVD arm.

Subsequent therapy

In the RVD arm, 207 patients progressed, and 172 received second-line therapy, which was followed by salvage HSCT in 136 patients (79%).

In the HSCT arm, 149 patients progressed, and 123 received second-line therapy, which was followed by a second HSCT in 21 patients (17%).

Safety

Nine percent of patients in the RVD arm and 11% in the HSCT arm discontinued treatment due to AEs. There were 2 treatment-related deaths in the RVD arm and 6 in the HSCT arm.

Grade 3/4 AEs with a significantly higher incidence in the HSCT arm than the RVD arm were blood and lymphatic system disorders (95% and 64%, respectively, P<0.001), gastrointestinal disorders (28% and 7%, respectively, P<0.001), and infections (20% and 9%, respectively, P<0.001).

Thirteen patients in the RVD arm and 17 in the HSCT arm had at least 1 invasive second primary malignancy (P=0.36). Acute myeloid leukemia occurred in 1 patient in the RVD arm and 4 in the HSCT arm (P=0.21).

The researchers said these results suggest the benefits of HSCT plus RVD must be weighed against the increased risk of toxicity associated with high-dose chemotherapy plus HSCT, particularly since HSCT after progression might be as effective as early HSCT for ensuring long-term OS. 

Photo by Chad McNeeley

The use of autologous transplant after a 3-drug induction regimen for multiple myeloma (MM) prolongs progression-free survival (PFS) but not overall survival (OS), according to new research.

In a phase 3 trial, newly diagnosed MM patients who received lenalidomide, bortezomib, and dexamethasone (RVD) followed by an autologous hematopoietic stem cell transplant (HSCT) had significantly better PFS but similar OS when compared to patients who only received RVD.

In addition, HSCT recipients had significantly higher rates of high-grade blood and lymphatic system disorders, gastrointestinal events, and infections.

The study also showed that OS outcomes were similar for patients who received HSCT after completing treatment with RVD and patients who were in the RVD-only treatment arm but underwent HSCT later, as salvage therapy.

Researchers believe this suggests MM patients can potentially choose when to undergo a transplant.

The team reported their findings in NEJM. The study was supported by grants from Celgene and Janssen and by funds from the French Ministry of Health Programme Hospitalier de Recherche Clinique and from the French National Research Agency.

“Over the past decade, drugs that modulate the immune system and agents known as proteasome inhibitors have shown a great deal of promise in patients with multiple myeloma, when used in combination with chemotherapy,” said study author Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“This led us to propose that these combinations could be used selectively with established modalities such as transplant for patients with newly diagnosed myeloma, and this, in turn, raised questions about where and how transplant should be fit into the therapeutic paradigm. Our trial sought to comprehensively address these issues in a prospective fashion, and provide a foundation for future studies as the next generation of agents, such as monoclonal antibodies, impact the field.”

The study enrolled 700 adult patients under the age of 65 who were newly diagnosed with MM. They were treated at 69 centers in France, Belgium, and Switzerland.

The patients were randomized to 2 treatment arms. Both groups received 3 initial cycles of RVD.

One group then received 5 more cycles of RVD. The other received high-dose chemotherapy (melphalan) followed by an autologous HSCT and 2 additional cycles of RVD.

Patients in both groups then received lenalidomide as maintenance therapy for 1 year or until they progressed, experienced unacceptable adverse events (AEs), or withdrew consent.

Response and survival

The complete response rate was significantly higher in the HSCT arm than the RVD-alone arm—59% and 48%, respectively (P=0.03).

And there was a significantly higher percentage of patients who were negative for minimal residual disease in the HSCT arm than in the RVD arm—79% and 65%, respectively (P<0.001).

The median PFS was significantly longer in the HSCT arm than the RVD arm—50 months and 36 months, respectively (P<0.001). The researchers said this benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk.

There was no significant between-group difference in the rate of OS at 4 years, which was 81% in the HSCT arm and 82% in the RVD arm.

Subsequent therapy

In the RVD arm, 207 patients progressed, and 172 received second-line therapy, which was followed by salvage HSCT in 136 patients (79%).

In the HSCT arm, 149 patients progressed, and 123 received second-line therapy, which was followed by a second HSCT in 21 patients (17%).

Safety

Nine percent of patients in the RVD arm and 11% in the HSCT arm discontinued treatment due to AEs. There were 2 treatment-related deaths in the RVD arm and 6 in the HSCT arm.

Grade 3/4 AEs with a significantly higher incidence in the HSCT arm than the RVD arm were blood and lymphatic system disorders (95% and 64%, respectively, P<0.001), gastrointestinal disorders (28% and 7%, respectively, P<0.001), and infections (20% and 9%, respectively, P<0.001).

Thirteen patients in the RVD arm and 17 in the HSCT arm had at least 1 invasive second primary malignancy (P=0.36). Acute myeloid leukemia occurred in 1 patient in the RVD arm and 4 in the HSCT arm (P=0.21).

The researchers said these results suggest the benefits of HSCT plus RVD must be weighed against the increased risk of toxicity associated with high-dose chemotherapy plus HSCT, particularly since HSCT after progression might be as effective as early HSCT for ensuring long-term OS. 

Bone marrow aspirate Photo by Chad McNeeley

Engineers say they have devised a microfluidic technique to capture and count circulating plasma cells from small samples of blood.

They believe the technique, described in Scientific Reports, may allow patients with multiple myeloma (MM) to avoid bone marrow biopsies in favor of conventional blood draws.

“Procedures of the traditional tissue biopsy are painful, associated with complications such as potential infections, and often available only in central hospitals, which require patients to travel long distances,” said Mohammad Qasaimeh, PhD, of New York University Abu Dhabi in United Arab Emirates.

“Capturing plasma cells from blood samples can serve as a liquid biopsy, which can be performed in clinics as often as required, and serve as a diagnostic and prognostic test during and after chemotherapy treatment. Moreover, captured cells can be used for drug testing and, thus, serve as a tool for personalized medicine.”

About the technique

The current microfluidic technique builds on a design that was developed by George Whitesides, PhD, of Harvard University in Cambridge, Massachusetts.

Dr Whitesides and his colleagues fabricated a microchip, the channel of which they etched with repeating, V-shaped grooves, similar to a herringbone pattern.

The grooves cause any fluid flowing through the microchip to swirl about in eddies, rather passing straight through. The cells within the fluid therefore have a higher chance of making contact with the floor of the device.

Researchers have since reproduced this microfluidic design, coating the microchip’s floor with certain molecules to attract cells of interest.

Qasaimeh and colleagues used the microfluidic herringbone design to capture circulating plasma cells. They coated the channels of a microchip with CD138, an antibody expressed on the membranes of plasma cells.

The team then flowed 1 mL samples of blood through the device. The herringbone grooves circulated the blood in the microfluidic channels, where the antibodies grabbed onto any passing plasma cells and let the rest of the blood flow out of the device.

Once the cells were isolated in the microchip, the researchers could count the cells, as well as determine the kinds of antibodies each cell secretes.

Capturing cells

The researchers tested the device using blood samples from healthy donors as well as MM patients.

The team observed very low numbers of circulating plasma cells in healthy samples—2 to 5 cells per mL of blood—and substantially higher counts in MM patients—45 to 184 cells per mL.

The researchers noted that MM patients in remission also exhibited higher counts of circulating plasma cells—20 to 24 cells per mL—than healthy donors.

Rahit Karnik, PhD, of Massachusetts Institute of Technology in Cambridge, said this device may reveal more subtle information about a patient’s state, even in remission.

“When patients go into remission, their antibody levels can look normal,” Dr Karnik said. “But we detect a level of circulating plasma cells that is above the baseline. It’s hard to tell whether these cells are cancerous, but at least this technique is giving us more information. With the ease of a blood draw, this may enable us to track cancer in a much better way.”

Analyzing antibodies

The researchers also looked at antibodies produced by the plasma cells captured in the device.

The team determined the ratio of plasma cells producing kappa- and lambda-type antibodies and compared them to conventional blood tests for the same antibodies, for both healthy subjects and MM patients.

Both sets of results matched, which validates the microfluidic device’s accuracy.

Next steps

Dr Karnik said, in the future, researchers may use this design to perform genetic tests on the captured cells or look for mutations in the cells that may further characterize MM.

“We can capture and stain these cells in the device, which opens the possibility of studying whether there are new mutations in the cells,” Dr Karnik said.

“With cancers like multiple myeloma, even for patients in remission, cancer can recur. Detecting the level or mutation of plasma cells in blood might provide an early detection method for these patients.”

Bone marrow aspirate Photo by Chad McNeeley

Engineers say they have devised a microfluidic technique to capture and count circulating plasma cells from small samples of blood.

They believe the technique, described in Scientific Reports, may allow patients with multiple myeloma (MM) to avoid bone marrow biopsies in favor of conventional blood draws.

“Procedures of the traditional tissue biopsy are painful, associated with complications such as potential infections, and often available only in central hospitals, which require patients to travel long distances,” said Mohammad Qasaimeh, PhD, of New York University Abu Dhabi in United Arab Emirates.

“Capturing plasma cells from blood samples can serve as a liquid biopsy, which can be performed in clinics as often as required, and serve as a diagnostic and prognostic test during and after chemotherapy treatment. Moreover, captured cells can be used for drug testing and, thus, serve as a tool for personalized medicine.”

About the technique

The current microfluidic technique builds on a design that was developed by George Whitesides, PhD, of Harvard University in Cambridge, Massachusetts.

Dr Whitesides and his colleagues fabricated a microchip, the channel of which they etched with repeating, V-shaped grooves, similar to a herringbone pattern.

The grooves cause any fluid flowing through the microchip to swirl about in eddies, rather passing straight through. The cells within the fluid therefore have a higher chance of making contact with the floor of the device.

Researchers have since reproduced this microfluidic design, coating the microchip’s floor with certain molecules to attract cells of interest.

Qasaimeh and colleagues used the microfluidic herringbone design to capture circulating plasma cells. They coated the channels of a microchip with CD138, an antibody expressed on the membranes of plasma cells.

The team then flowed 1 mL samples of blood through the device. The herringbone grooves circulated the blood in the microfluidic channels, where the antibodies grabbed onto any passing plasma cells and let the rest of the blood flow out of the device.

Once the cells were isolated in the microchip, the researchers could count the cells, as well as determine the kinds of antibodies each cell secretes.

Capturing cells

The researchers tested the device using blood samples from healthy donors as well as MM patients.

The team observed very low numbers of circulating plasma cells in healthy samples—2 to 5 cells per mL of blood—and substantially higher counts in MM patients—45 to 184 cells per mL.

The researchers noted that MM patients in remission also exhibited higher counts of circulating plasma cells—20 to 24 cells per mL—than healthy donors.

Rahit Karnik, PhD, of Massachusetts Institute of Technology in Cambridge, said this device may reveal more subtle information about a patient’s state, even in remission.

“When patients go into remission, their antibody levels can look normal,” Dr Karnik said. “But we detect a level of circulating plasma cells that is above the baseline. It’s hard to tell whether these cells are cancerous, but at least this technique is giving us more information. With the ease of a blood draw, this may enable us to track cancer in a much better way.”

Analyzing antibodies

The researchers also looked at antibodies produced by the plasma cells captured in the device.

The team determined the ratio of plasma cells producing kappa- and lambda-type antibodies and compared them to conventional blood tests for the same antibodies, for both healthy subjects and MM patients.

Both sets of results matched, which validates the microfluidic device’s accuracy.

Next steps

Dr Karnik said, in the future, researchers may use this design to perform genetic tests on the captured cells or look for mutations in the cells that may further characterize MM.

“We can capture and stain these cells in the device, which opens the possibility of studying whether there are new mutations in the cells,” Dr Karnik said.

“With cancers like multiple myeloma, even for patients in remission, cancer can recur. Detecting the level or mutation of plasma cells in blood might provide an early detection method for these patients.”

Bone marrow aspirate Photo by Chad McNeeley

Engineers say they have devised a microfluidic technique to capture and count circulating plasma cells from small samples of blood.

They believe the technique, described in Scientific Reports, may allow patients with multiple myeloma (MM) to avoid bone marrow biopsies in favor of conventional blood draws.

“Procedures of the traditional tissue biopsy are painful, associated with complications such as potential infections, and often available only in central hospitals, which require patients to travel long distances,” said Mohammad Qasaimeh, PhD, of New York University Abu Dhabi in United Arab Emirates.

“Capturing plasma cells from blood samples can serve as a liquid biopsy, which can be performed in clinics as often as required, and serve as a diagnostic and prognostic test during and after chemotherapy treatment. Moreover, captured cells can be used for drug testing and, thus, serve as a tool for personalized medicine.”

About the technique

The current microfluidic technique builds on a design that was developed by George Whitesides, PhD, of Harvard University in Cambridge, Massachusetts.

Dr Whitesides and his colleagues fabricated a microchip, the channel of which they etched with repeating, V-shaped grooves, similar to a herringbone pattern.

The grooves cause any fluid flowing through the microchip to swirl about in eddies, rather passing straight through. The cells within the fluid therefore have a higher chance of making contact with the floor of the device.

Researchers have since reproduced this microfluidic design, coating the microchip’s floor with certain molecules to attract cells of interest.

Qasaimeh and colleagues used the microfluidic herringbone design to capture circulating plasma cells. They coated the channels of a microchip with CD138, an antibody expressed on the membranes of plasma cells.

The team then flowed 1 mL samples of blood through the device. The herringbone grooves circulated the blood in the microfluidic channels, where the antibodies grabbed onto any passing plasma cells and let the rest of the blood flow out of the device.

Once the cells were isolated in the microchip, the researchers could count the cells, as well as determine the kinds of antibodies each cell secretes.

Capturing cells

The researchers tested the device using blood samples from healthy donors as well as MM patients.

The team observed very low numbers of circulating plasma cells in healthy samples—2 to 5 cells per mL of blood—and substantially higher counts in MM patients—45 to 184 cells per mL.

The researchers noted that MM patients in remission also exhibited higher counts of circulating plasma cells—20 to 24 cells per mL—than healthy donors.

Rahit Karnik, PhD, of Massachusetts Institute of Technology in Cambridge, said this device may reveal more subtle information about a patient’s state, even in remission.

“When patients go into remission, their antibody levels can look normal,” Dr Karnik said. “But we detect a level of circulating plasma cells that is above the baseline. It’s hard to tell whether these cells are cancerous, but at least this technique is giving us more information. With the ease of a blood draw, this may enable us to track cancer in a much better way.”

Analyzing antibodies

The researchers also looked at antibodies produced by the plasma cells captured in the device.

The team determined the ratio of plasma cells producing kappa- and lambda-type antibodies and compared them to conventional blood tests for the same antibodies, for both healthy subjects and MM patients.

Both sets of results matched, which validates the microfluidic device’s accuracy.

Next steps

Dr Karnik said, in the future, researchers may use this design to perform genetic tests on the captured cells or look for mutations in the cells that may further characterize MM.

“We can capture and stain these cells in the device, which opens the possibility of studying whether there are new mutations in the cells,” Dr Karnik said.

“With cancers like multiple myeloma, even for patients in remission, cancer can recur. Detecting the level or mutation of plasma cells in blood might provide an early detection method for these patients.”

Adding high-dose chemotherapy and autologous stem cell transplantation to two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) significantly improved progression-free survival in adults with newly diagnosed multiple myeloma, according to new analyses from the multicenter, randomized, phase III IFM 2009 Study.

Median PFS was 50 months in the transplantation group, versus 36 months when patients only received five cycles of VRD for consolidation (adjusted hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.53 to 0.80; P less than .001), reported Michel Attal, MD, of Institut Universitaire du Cancer de Toulouse-Oncopole in Toulouse, France, and his associates. “Transplantation was also associated with a higher rate of complete response, a lower rate of minimal residual disease detection, and a longer median time to progression,” they wrote (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMoa1611750).

Fnaq / Wikimedia Commons / CC BY-SA 4.0

Adding high-dose chemotherapy and autologous stem cell transplantation to two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) significantly improved progression-free survival in adults with newly diagnosed multiple myeloma, according to new analyses from the multicenter, randomized, phase III IFM 2009 Study.

Median PFS was 50 months in the transplantation group, versus 36 months when patients only received five cycles of VRD for consolidation (adjusted hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.53 to 0.80; P less than .001), reported Michel Attal, MD, of Institut Universitaire du Cancer de Toulouse-Oncopole in Toulouse, France, and his associates. “Transplantation was also associated with a higher rate of complete response, a lower rate of minimal residual disease detection, and a longer median time to progression,” they wrote (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMoa1611750).

Fnaq / Wikimedia Commons / CC BY-SA 4.0

Adding high-dose chemotherapy and autologous stem cell transplantation to two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) significantly improved progression-free survival in adults with newly diagnosed multiple myeloma, according to new analyses from the multicenter, randomized, phase III IFM 2009 Study.

Median PFS was 50 months in the transplantation group, versus 36 months when patients only received five cycles of VRD for consolidation (adjusted hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.53 to 0.80; P less than .001), reported Michel Attal, MD, of Institut Universitaire du Cancer de Toulouse-Oncopole in Toulouse, France, and his associates. “Transplantation was also associated with a higher rate of complete response, a lower rate of minimal residual disease detection, and a longer median time to progression,” they wrote (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMoa1611750).

Fnaq / Wikimedia Commons / CC BY-SA 4.0

Extramedullary plasmacytomas are rare ( > 5% of all plasma cell neoplasms), and the gastric version is even more rare. That rarity combined with unspecific symptoms that mimic other tumors “can mislead the clinician into a diagnosis of a more aggressive tumor,” say clinicians from University Hospital Center of Coimbra in Portugal. They reported on a patient who presented that diagnostic puzzle.

The patient arrived in the emergency department with symptoms of upper gastrointestinal bleeding. He had a history of tongue carcinoma, cirrhosis, diabetes mellitus, chronic gastritis, and obesity, among other health conditions, and was taking a panoply of medications. The patient’s family history included a grandmother with breast cancer and an aunt with head and neck cancer.

Related: Treatment and Management of Multiple Myeloma

The clinicians embarked on an extensive diagnostic process of elimination. Endoscopy, immunohistochemistry, and other tests helped rule out Helicobacter pylori infection, lymphoma, carcinoma, melanoma, and neuroendocrine carcinoma. “Rethinking our possibilities,” the clinicians say, and taking into account the presence of mature and immature plasmocytes in the periphery, they next considered plasmacytoma/multiple myeloma (MM). On the third immunohistochemical panel, they got the evidence they needed for the diagnosis: gastric plasmacytoma (GP)/ involvement by MM.

Gastric plasmacytomas have a good prognosis. Surgical excision normally is the treatment of choice with good results, the clinicians say. After endoscopic polypectomy without radiation, the patient was discharged with no further therapy. Although diagnosed with prostate cancer in the 6 years following, the patient has had no signs of plasmacytic relapse.

Related: Rare Cancer Gets Timely Right Treatment

Due to their cellular similarity, GP needs to be differentiated from MM. But GP may be the initial manifestation of a MM, the clinicians note. Therefore, the patient must undergo systemic evaluation to exclude bone marrow involvement and to make sure there is no clinical or laboratory evidence of myeloma.

Sources:

1. Oliveira RC, Amaro P, Julião MJ, Cipriano MA. BMJ Case Rep. 2017. pii: bcr2016218967.
doi: 10.1136/bcr-2016-218967.

2. International Myeloma Working Group. Br J Haematol. 2003;12(5):749-57.
doi: 10.1046/j.1365-2141.2003.04355.x

3. Kilciksiz S, Karakoyun-Celik O, Agaoglu FY, Haydaroglu A. A review for solitary

plasmacytoma of bone and extramedullary plasmacytoma. Sci World J. 2012;2012:895765.
doi: 10.1100/2012/895765.

Extramedullary plasmacytomas are rare ( > 5% of all plasma cell neoplasms), and the gastric version is even more rare. That rarity combined with unspecific symptoms that mimic other tumors “can mislead the clinician into a diagnosis of a more aggressive tumor,” say clinicians from University Hospital Center of Coimbra in Portugal. They reported on a patient who presented that diagnostic puzzle.

The patient arrived in the emergency department with symptoms of upper gastrointestinal bleeding. He had a history of tongue carcinoma, cirrhosis, diabetes mellitus, chronic gastritis, and obesity, among other health conditions, and was taking a panoply of medications. The patient’s family history included a grandmother with breast cancer and an aunt with head and neck cancer.

Related: Treatment and Management of Multiple Myeloma

The clinicians embarked on an extensive diagnostic process of elimination. Endoscopy, immunohistochemistry, and other tests helped rule out Helicobacter pylori infection, lymphoma, carcinoma, melanoma, and neuroendocrine carcinoma. “Rethinking our possibilities,” the clinicians say, and taking into account the presence of mature and immature plasmocytes in the periphery, they next considered plasmacytoma/multiple myeloma (MM). On the third immunohistochemical panel, they got the evidence they needed for the diagnosis: gastric plasmacytoma (GP)/ involvement by MM.

Gastric plasmacytomas have a good prognosis. Surgical excision normally is the treatment of choice with good results, the clinicians say. After endoscopic polypectomy without radiation, the patient was discharged with no further therapy. Although diagnosed with prostate cancer in the 6 years following, the patient has had no signs of plasmacytic relapse.

Related: Rare Cancer Gets Timely Right Treatment

Due to their cellular similarity, GP needs to be differentiated from MM. But GP may be the initial manifestation of a MM, the clinicians note. Therefore, the patient must undergo systemic evaluation to exclude bone marrow involvement and to make sure there is no clinical or laboratory evidence of myeloma.

Sources:

1. Oliveira RC, Amaro P, Julião MJ, Cipriano MA. BMJ Case Rep. 2017. pii: bcr2016218967.
doi: 10.1136/bcr-2016-218967.

2. International Myeloma Working Group. Br J Haematol. 2003;12(5):749-57.
doi: 10.1046/j.1365-2141.2003.04355.x

3. Kilciksiz S, Karakoyun-Celik O, Agaoglu FY, Haydaroglu A. A review for solitary

plasmacytoma of bone and extramedullary plasmacytoma. Sci World J. 2012;2012:895765.
doi: 10.1100/2012/895765.

Extramedullary plasmacytomas are rare ( > 5% of all plasma cell neoplasms), and the gastric version is even more rare. That rarity combined with unspecific symptoms that mimic other tumors “can mislead the clinician into a diagnosis of a more aggressive tumor,” say clinicians from University Hospital Center of Coimbra in Portugal. They reported on a patient who presented that diagnostic puzzle.

The patient arrived in the emergency department with symptoms of upper gastrointestinal bleeding. He had a history of tongue carcinoma, cirrhosis, diabetes mellitus, chronic gastritis, and obesity, among other health conditions, and was taking a panoply of medications. The patient’s family history included a grandmother with breast cancer and an aunt with head and neck cancer.

Related: Treatment and Management of Multiple Myeloma

The clinicians embarked on an extensive diagnostic process of elimination. Endoscopy, immunohistochemistry, and other tests helped rule out Helicobacter pylori infection, lymphoma, carcinoma, melanoma, and neuroendocrine carcinoma. “Rethinking our possibilities,” the clinicians say, and taking into account the presence of mature and immature plasmocytes in the periphery, they next considered plasmacytoma/multiple myeloma (MM). On the third immunohistochemical panel, they got the evidence they needed for the diagnosis: gastric plasmacytoma (GP)/ involvement by MM.

Gastric plasmacytomas have a good prognosis. Surgical excision normally is the treatment of choice with good results, the clinicians say. After endoscopic polypectomy without radiation, the patient was discharged with no further therapy. Although diagnosed with prostate cancer in the 6 years following, the patient has had no signs of plasmacytic relapse.

Related: Rare Cancer Gets Timely Right Treatment

Due to their cellular similarity, GP needs to be differentiated from MM. But GP may be the initial manifestation of a MM, the clinicians note. Therefore, the patient must undergo systemic evaluation to exclude bone marrow involvement and to make sure there is no clinical or laboratory evidence of myeloma.

Sources:

1. Oliveira RC, Amaro P, Julião MJ, Cipriano MA. BMJ Case Rep. 2017. pii: bcr2016218967.
doi: 10.1136/bcr-2016-218967.

2. International Myeloma Working Group. Br J Haematol. 2003;12(5):749-57.
doi: 10.1046/j.1365-2141.2003.04355.x

3. Kilciksiz S, Karakoyun-Celik O, Agaoglu FY, Haydaroglu A. A review for solitary

plasmacytoma of bone and extramedullary plasmacytoma. Sci World J. 2012;2012:895765.
doi: 10.1100/2012/895765.

Photo courtesy of the CDC

The American Society of Clinical Oncology (ASCO) has issued recommendations addressing the needs of sexual and gender minority (SGM) populations with cancer.

The recommendations are designed to focus attention on the challenges facing the SGM community—including discrimination and greater risk of anxiety and depression, resulting in disparate care—and concrete steps that can help minimize health disparities among SGM individuals.

The recommendations were published in a policy statement in the Journal of Clinical Oncology.

“Sexual and gender minorities face unique challenges related to cancer risk, discrimination, and other psychosocial issues,” said ASCO President Daniel F. Hayes, MD.

“Compounding these challenges is the fact that providers may have a lack of knowledge and sensitivity about the health risks and health needs facing their SGM patients.”

SGMs include individuals who are lesbian, gay, bisexual, transgender, and intersex (also referred to as those with differences in sex development).

ASCO’s policy statement notes that SGM populations bear a disproportionate cancer burden stemming from several factors, including:

• Lower rates of cancer screening, in part due to lower rates of insurance coverage, exclusion from traditional screening campaigns, and previous experience of discrimination in the healthcare system
• A hesitancy on the part of SGM patients to disclose their sexual orientation to providers due to a fear of stigmatization, which can create additional barriers to care.

ASCO’s statement calls for a coordinated effort to address health disparities among SGM populations, including:

• Increased patient access to culturally competent support services
• Expanded cancer prevention education for SGM individuals
• Robust policies prohibiting discrimination
• Adequate insurance coverage to meet the needs of SGM individuals affected by cancer
• Inclusion of SGM status as a required data element in cancer registries and clinical trials
• Increased focus on SGM populations in cancer research.

“Our objective was to raise awareness among oncology providers, patients, policy makers, and other stakeholders about the cancer care needs of SGM populations and the barriers that SGM individuals face in getting the highest-quality care,” said Jennifer J. Griggs, MD, lead author of the policy statement and a professor at the University of Michigan in Ann Arbor.

“To address these barriers, a coordinated effort is needed to enhance education for patients and providers, to improve outreach and support, and to encourage productive policy and legislative action.”

Photo courtesy of the CDC

The American Society of Clinical Oncology (ASCO) has issued recommendations addressing the needs of sexual and gender minority (SGM) populations with cancer.

The recommendations are designed to focus attention on the challenges facing the SGM community—including discrimination and greater risk of anxiety and depression, resulting in disparate care—and concrete steps that can help minimize health disparities among SGM individuals.

The recommendations were published in a policy statement in the Journal of Clinical Oncology.

“Sexual and gender minorities face unique challenges related to cancer risk, discrimination, and other psychosocial issues,” said ASCO President Daniel F. Hayes, MD.

“Compounding these challenges is the fact that providers may have a lack of knowledge and sensitivity about the health risks and health needs facing their SGM patients.”

SGMs include individuals who are lesbian, gay, bisexual, transgender, and intersex (also referred to as those with differences in sex development).

ASCO’s policy statement notes that SGM populations bear a disproportionate cancer burden stemming from several factors, including:

• Lower rates of cancer screening, in part due to lower rates of insurance coverage, exclusion from traditional screening campaigns, and previous experience of discrimination in the healthcare system
• A hesitancy on the part of SGM patients to disclose their sexual orientation to providers due to a fear of stigmatization, which can create additional barriers to care.

ASCO’s statement calls for a coordinated effort to address health disparities among SGM populations, including:

• Increased patient access to culturally competent support services
• Expanded cancer prevention education for SGM individuals
• Robust policies prohibiting discrimination
• Adequate insurance coverage to meet the needs of SGM individuals affected by cancer
• Inclusion of SGM status as a required data element in cancer registries and clinical trials
• Increased focus on SGM populations in cancer research.

“Our objective was to raise awareness among oncology providers, patients, policy makers, and other stakeholders about the cancer care needs of SGM populations and the barriers that SGM individuals face in getting the highest-quality care,” said Jennifer J. Griggs, MD, lead author of the policy statement and a professor at the University of Michigan in Ann Arbor.

“To address these barriers, a coordinated effort is needed to enhance education for patients and providers, to improve outreach and support, and to encourage productive policy and legislative action.”

Photo courtesy of the CDC

The American Society of Clinical Oncology (ASCO) has issued recommendations addressing the needs of sexual and gender minority (SGM) populations with cancer.

The recommendations are designed to focus attention on the challenges facing the SGM community—including discrimination and greater risk of anxiety and depression, resulting in disparate care—and concrete steps that can help minimize health disparities among SGM individuals.

The recommendations were published in a policy statement in the Journal of Clinical Oncology.

“Sexual and gender minorities face unique challenges related to cancer risk, discrimination, and other psychosocial issues,” said ASCO President Daniel F. Hayes, MD.

“Compounding these challenges is the fact that providers may have a lack of knowledge and sensitivity about the health risks and health needs facing their SGM patients.”

SGMs include individuals who are lesbian, gay, bisexual, transgender, and intersex (also referred to as those with differences in sex development).

ASCO’s policy statement notes that SGM populations bear a disproportionate cancer burden stemming from several factors, including:

• Lower rates of cancer screening, in part due to lower rates of insurance coverage, exclusion from traditional screening campaigns, and previous experience of discrimination in the healthcare system
• A hesitancy on the part of SGM patients to disclose their sexual orientation to providers due to a fear of stigmatization, which can create additional barriers to care.

ASCO’s statement calls for a coordinated effort to address health disparities among SGM populations, including:

• Increased patient access to culturally competent support services
• Expanded cancer prevention education for SGM individuals
• Robust policies prohibiting discrimination
• Adequate insurance coverage to meet the needs of SGM individuals affected by cancer
• Inclusion of SGM status as a required data element in cancer registries and clinical trials
• Increased focus on SGM populations in cancer research.

“Our objective was to raise awareness among oncology providers, patients, policy makers, and other stakeholders about the cancer care needs of SGM populations and the barriers that SGM individuals face in getting the highest-quality care,” said Jennifer J. Griggs, MD, lead author of the policy statement and a professor at the University of Michigan in Ann Arbor.

“To address these barriers, a coordinated effort is needed to enhance education for patients and providers, to improve outreach and support, and to encourage productive policy and legislative action.”

SNOWMASS, COLO. – Physicians can expect to encounter more and more patients with inflammatory arthritis and other rheumatic adverse events induced by immune checkpoint inhibitors as a result of anticipated exponential growth in the use of these drugs to treat an expanding list of cancers, Clifton O. Bingham III, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

These cancer immunotherapy–induced rheumatic diseases may superficially look like the classic forms of familiar autoimmune diseases, but they have highly atypical features that will affect treatment decisions.

Rheumatologic IRAE presentations

Inflammatory arthritis is the most common form of rheumatologic IRAE, followed by sicca syndrome. At the Johns Hopkins Arthritis Center, Dr. Bingham and his coworkers have 25 well-characterized patients with inflammatory arthritis resulting from an ICI, only 1 of whom is HLA-B27-positive.

“Also, just one is autoantibody-positive, even though they all look for all the world as though they have rheumatoid arthritis,” the rheumatologist observed.

This ICI-induced inflammatory arthritis initially presents most commonly in the midsize and large joints – knees, ankles, elbows – then expands to include small joints such as the wrists, proximal interphalangeal joints, and the metacarpophalangeal joints.

Notably, the Hopkins group also has three patients with classic reactive arthritis marked by conjunctivitis, urethritis, arthritis, and dactylitis.

“I don’t know about you, but, in our general rheumatology practice, we see maybe one case of reactive arthritis in several years, so this is something that has struck us as really quite interesting,” said Dr. Bingham, who is also director of research in the division of rheumatology at Johns Hopkins.

The arthritis center is also managing a group of patients with ICI-induced sicca syndrome, which is uniformly extremely severe and treatment resistant, as well as a couple of patients with myositis IRAE, one with polymyalgia rheumatica, and two with crystal disease that is highly inflammatory in nature, difficult to treat, and includes an inflammatory polyarthritis component not typical in patients with crystal arthritis.
 

Why physicians will see more rheumatologic IRAEs

ICIs have dramatically transformed the treatment of selected advanced-stage cancers. For example, whereas patients with metastatic melanoma historically had a 2-year survival rate of 5%, combination therapy with the ICIs ipilimumab (Yervoy) and nivolumab (Opdivo) resulted in a 60% rate of partial or complete remission in a landmark clinical trial.

The basis of cancer immunotherapy is the discovery that, in order for cancer cells to thrive, they emit blocking signals that downregulate the native ability of T cells to recognize and kill them. This is true for both solid tumors and hematologic malignancies. The ICIs inhibit these blocking signals, which include cytotoxic T-lymphocyte–associated protein 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PDL-1), thereby freeing up the T cells for tumor fighting.

Because of the nonspecific mechanism of this T-cell activation, however, ICIs have, as their main toxicities, T-cell–mediated autoimmune inflammatory tissue damage, which gets lumped under the umbrella term IRAEs. It can affect almost every organ system. Skin rashes are the most common, colitis second. Other commonly encountered IRAEs include thyroiditis, hypophysitis, hepatitis, peripheral neuropathy, and pneumonitis.

In addition to the four currently approved ICIs – ipilimumab, nivolumab, pembrolizumab (Keytruda), and atezolizumab (Tecentriq) – investigational ICIs targeting CTLA4, PD-1, and/or PDL-1 are in development. Plus, new ICIs targeting other blocking signals, including lymphocyte activation gene-3, CD137, and T-cell immunoglobulin and mucin domain-3, are now in clinical trials.

Clinical trials aimed at expanding the indications of existing ICIs and using ICIs in earlier-stage cancers in an effort to improve rates of lasting remission are also underway.

All told, probably at least 400 clinical trials of ICIs are ongoing worldwide, the rheumatologist estimated.

“More people will be exposed to these drugs, and we’ll see more and more of these rheumatologic IRAEs,” Dr. Bingham predicted.
 

Rheumatologic IRAEs are seriously underdiagnosed

Back in the pre-ICI days, Dr. Bingham was coauthor of a major study which concluded that clinical trialists in oncology consistently downgrade the severity of rheumatologic adverse events, often by 1 or 2 grades (J Rheumatol. 2007 Jun;34[6]:1401-14).

Unpublished details of ICI clinical trials in melanoma that he obtained from Bristol-Myers Squibb suggest that the true rate of rheumatologic IRAEs is about 20%, or roughly double that reported in the studies. That’s because the adverse events–grading system used in oncology undercalls the severity of arthritis and autoimmune disorders.

Indeed, the National Cancer Institute’s Common Terminology Criteria for Adverse Events, used in oncology clinical trials, is confusing on the topic of musculoskeletal and connective tissue disorders as treatment-emergent adverse events, according to Dr. Bingham. He noted that an oncologist can code a swollen joint in three different ways – joint effusion, arthritis, or arthralgia – and it takes disabling interference with self-care in activities of daily living for that swollen joint to rise to the level of a Grade 3 adverse event. From a rheumatology trialist’s perspective, that would be a Grade 4 disability.

Plus, neither the product labeling nor the patient information guides for the approved immunotherapy drugs mention the importance of monitoring for rheumatologic IRAEs or their management.

“There is poor awareness of musculoskeletal and rheumatic IRAEs in the general oncology community,” Dr. Bingham asserted. “But, if you talk with any oncology nurses who work in a clinical trial, they will tell you they’re seeing these events with significant frequency and severity.”
 

Treatment and response

It’s critical to gain control of rheumatologic IRAEs quickly so that patients can get on with their cancer immunotherapy. Dr. Bingham uses intra-articular steroid injections for patients with oligoarthritis and high-dose oral prednisone for polyarticular disease. He starts methotrexate and/or leflunomide early because the conventional disease-modifying antirheumatic drugs have roughly a 2-month delay in onset of action. He has had several patients who are unable to taper steroids despite background methotrexate.

In the most severely affected patients, he has turned to biologic agents in consultation with their oncologists. Tumor necrosis factor (TNF) inhibitors are the ones he and other rheumatologists have used most often.

“Notably, we have not been able to taper down very well. We have patients who are out more than 2 years now who still require their TNF inhibitor to treat their inflammatory arthritis, and these are patients on conventional disease–modifying antirheumatic drugs as well. As soon as it’s tapered, the arthritis begins to come back,” according to Dr. Bingham.

In marked contrast, colitis as an IRAE typically clears in response to just one or two doses of a TNF inhibitor.

One audience member related that she’d encountered a roadblock in trying to get authorization for a TNF inhibitor for a patient with a rheumatologic IRAE secondary to ICI treatment for metastatic melanoma because the labeling states these agents are relatively contraindicated in melanoma patients. Dr. Bingham offered a tip: Collaborate with the patient’s oncologist.

“In most cases, oncologists can get infliximab for these patients and administer it in their infusion centers. They are able to get things authorized with very little trouble,” he said.

Besides, most of these patients with severe inflammatory arthritis meet conventional criteria for TNF inhibitor therapy, based on their number of infected joints and elevated acute phase reactants for longer than 6 weeks, Dr. Bingham noted.

“We’ve had some very interesting conversations with patients. It’s impressive to see the impact arthritis can have on people. A lot of patients have said, ‘I don’t care if I die. Get me functional right now.’ That’s pretty profound. Quality of life is still very important for people, even when dealing with life-threatening diseases,” he observed.

Oncologists are actually eager for their patients to get on steroid-sparing therapy because of concern that high doses of steroids may reduce the efficacy of cancer immunotherapy. That’s not an issue with the TNF inhibitors, the rheumatologist continued.

Turning to the utility of other classes of biologic agents, Dr. Bingham advised avoiding abatacept (Orencia) because its mechanism of action is likely to cause interference with the cancer immunotherapy. Rituximab (Rituxan) takes too long to act. Anakinra (Kineret), tofacitinib (Xeljanz), and tocilizumab (Actemra), on the other hand, are agents he is interested in using as alternatives to TNF inhibitors, although he hasn’t done so yet.
 

Use of ICIs in patients with preexisting autoimmune disease

The experience here is entirely anecdotal, since such patients have been excluded from ICI clinical trials, but the available evidence suggests physicians should be prepared for higher rheumatologic IRAE rates in this setting. Investigators at Vanderbilt University reported that 8 of 30 cancer patients with known preexisting autoimmune disease experienced flares of that disease when treated with ipilimumab, and 10 developed a new IRAE (Therap Adv Gastroenterol. 2016 Jul;9[4]:457-62).

The Hopkins group has three patients with preexisting rheumatoid arthritis and two with preexisting scleroderma who have received ICIs. All three rheumatoid arthritis patients flared. Rheumatologists are trying to manage these flares so the patients can continue on their ICI. One of the scleroderma patients experienced no change in that disease while on an ICI, while the other showed a definite improvement in scleroderma symptoms.

“I think the jury’s still out in terms of what you do about ICI therapy in patients with preexisting autoimmunity. The data would say that there’s maybe a 50-50 chance of the autoimmune disease becoming worse, but, if patients have an otherwise fatal cancer, I think it’s probably worth the chance,” Dr. Bingham said.

Anecdotal reports suggest that more severe IRAEs may be a favorable prognostic sign in terms of cancer eradication, but a lot more patient experience will be needed in order to be sure, the rheumatologist said.

Dr. Bingham reported serving as a consultant to Bristol-Myers Squibb.

bjancin@frontlinemedcom.com
 

SNOWMASS, COLO. – Physicians can expect to encounter more and more patients with inflammatory arthritis and other rheumatic adverse events induced by immune checkpoint inhibitors as a result of anticipated exponential growth in the use of these drugs to treat an expanding list of cancers, Clifton O. Bingham III, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

These cancer immunotherapy–induced rheumatic diseases may superficially look like the classic forms of familiar autoimmune diseases, but they have highly atypical features that will affect treatment decisions.

Rheumatologic IRAE presentations

Inflammatory arthritis is the most common form of rheumatologic IRAE, followed by sicca syndrome. At the Johns Hopkins Arthritis Center, Dr. Bingham and his coworkers have 25 well-characterized patients with inflammatory arthritis resulting from an ICI, only 1 of whom is HLA-B27-positive.

“Also, just one is autoantibody-positive, even though they all look for all the world as though they have rheumatoid arthritis,” the rheumatologist observed.

This ICI-induced inflammatory arthritis initially presents most commonly in the midsize and large joints – knees, ankles, elbows – then expands to include small joints such as the wrists, proximal interphalangeal joints, and the metacarpophalangeal joints.

Notably, the Hopkins group also has three patients with classic reactive arthritis marked by conjunctivitis, urethritis, arthritis, and dactylitis.

“I don’t know about you, but, in our general rheumatology practice, we see maybe one case of reactive arthritis in several years, so this is something that has struck us as really quite interesting,” said Dr. Bingham, who is also director of research in the division of rheumatology at Johns Hopkins.

The arthritis center is also managing a group of patients with ICI-induced sicca syndrome, which is uniformly extremely severe and treatment resistant, as well as a couple of patients with myositis IRAE, one with polymyalgia rheumatica, and two with crystal disease that is highly inflammatory in nature, difficult to treat, and includes an inflammatory polyarthritis component not typical in patients with crystal arthritis.
 

Why physicians will see more rheumatologic IRAEs

ICIs have dramatically transformed the treatment of selected advanced-stage cancers. For example, whereas patients with metastatic melanoma historically had a 2-year survival rate of 5%, combination therapy with the ICIs ipilimumab (Yervoy) and nivolumab (Opdivo) resulted in a 60% rate of partial or complete remission in a landmark clinical trial.

The basis of cancer immunotherapy is the discovery that, in order for cancer cells to thrive, they emit blocking signals that downregulate the native ability of T cells to recognize and kill them. This is true for both solid tumors and hematologic malignancies. The ICIs inhibit these blocking signals, which include cytotoxic T-lymphocyte–associated protein 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PDL-1), thereby freeing up the T cells for tumor fighting.

Because of the nonspecific mechanism of this T-cell activation, however, ICIs have, as their main toxicities, T-cell–mediated autoimmune inflammatory tissue damage, which gets lumped under the umbrella term IRAEs. It can affect almost every organ system. Skin rashes are the most common, colitis second. Other commonly encountered IRAEs include thyroiditis, hypophysitis, hepatitis, peripheral neuropathy, and pneumonitis.

In addition to the four currently approved ICIs – ipilimumab, nivolumab, pembrolizumab (Keytruda), and atezolizumab (Tecentriq) – investigational ICIs targeting CTLA4, PD-1, and/or PDL-1 are in development. Plus, new ICIs targeting other blocking signals, including lymphocyte activation gene-3, CD137, and T-cell immunoglobulin and mucin domain-3, are now in clinical trials.

Clinical trials aimed at expanding the indications of existing ICIs and using ICIs in earlier-stage cancers in an effort to improve rates of lasting remission are also underway.

All told, probably at least 400 clinical trials of ICIs are ongoing worldwide, the rheumatologist estimated.

“More people will be exposed to these drugs, and we’ll see more and more of these rheumatologic IRAEs,” Dr. Bingham predicted.
 

Rheumatologic IRAEs are seriously underdiagnosed

Back in the pre-ICI days, Dr. Bingham was coauthor of a major study which concluded that clinical trialists in oncology consistently downgrade the severity of rheumatologic adverse events, often by 1 or 2 grades (J Rheumatol. 2007 Jun;34[6]:1401-14).

Unpublished details of ICI clinical trials in melanoma that he obtained from Bristol-Myers Squibb suggest that the true rate of rheumatologic IRAEs is about 20%, or roughly double that reported in the studies. That’s because the adverse events–grading system used in oncology undercalls the severity of arthritis and autoimmune disorders.

Indeed, the National Cancer Institute’s Common Terminology Criteria for Adverse Events, used in oncology clinical trials, is confusing on the topic of musculoskeletal and connective tissue disorders as treatment-emergent adverse events, according to Dr. Bingham. He noted that an oncologist can code a swollen joint in three different ways – joint effusion, arthritis, or arthralgia – and it takes disabling interference with self-care in activities of daily living for that swollen joint to rise to the level of a Grade 3 adverse event. From a rheumatology trialist’s perspective, that would be a Grade 4 disability.

Plus, neither the product labeling nor the patient information guides for the approved immunotherapy drugs mention the importance of monitoring for rheumatologic IRAEs or their management.

“There is poor awareness of musculoskeletal and rheumatic IRAEs in the general oncology community,” Dr. Bingham asserted. “But, if you talk with any oncology nurses who work in a clinical trial, they will tell you they’re seeing these events with significant frequency and severity.”
 

Treatment and response

It’s critical to gain control of rheumatologic IRAEs quickly so that patients can get on with their cancer immunotherapy. Dr. Bingham uses intra-articular steroid injections for patients with oligoarthritis and high-dose oral prednisone for polyarticular disease. He starts methotrexate and/or leflunomide early because the conventional disease-modifying antirheumatic drugs have roughly a 2-month delay in onset of action. He has had several patients who are unable to taper steroids despite background methotrexate.

In the most severely affected patients, he has turned to biologic agents in consultation with their oncologists. Tumor necrosis factor (TNF) inhibitors are the ones he and other rheumatologists have used most often.

“Notably, we have not been able to taper down very well. We have patients who are out more than 2 years now who still require their TNF inhibitor to treat their inflammatory arthritis, and these are patients on conventional disease–modifying antirheumatic drugs as well. As soon as it’s tapered, the arthritis begins to come back,” according to Dr. Bingham.

In marked contrast, colitis as an IRAE typically clears in response to just one or two doses of a TNF inhibitor.

One audience member related that she’d encountered a roadblock in trying to get authorization for a TNF inhibitor for a patient with a rheumatologic IRAE secondary to ICI treatment for metastatic melanoma because the labeling states these agents are relatively contraindicated in melanoma patients. Dr. Bingham offered a tip: Collaborate with the patient’s oncologist.

“In most cases, oncologists can get infliximab for these patients and administer it in their infusion centers. They are able to get things authorized with very little trouble,” he said.

Besides, most of these patients with severe inflammatory arthritis meet conventional criteria for TNF inhibitor therapy, based on their number of infected joints and elevated acute phase reactants for longer than 6 weeks, Dr. Bingham noted.

“We’ve had some very interesting conversations with patients. It’s impressive to see the impact arthritis can have on people. A lot of patients have said, ‘I don’t care if I die. Get me functional right now.’ That’s pretty profound. Quality of life is still very important for people, even when dealing with life-threatening diseases,” he observed.

Oncologists are actually eager for their patients to get on steroid-sparing therapy because of concern that high doses of steroids may reduce the efficacy of cancer immunotherapy. That’s not an issue with the TNF inhibitors, the rheumatologist continued.

Turning to the utility of other classes of biologic agents, Dr. Bingham advised avoiding abatacept (Orencia) because its mechanism of action is likely to cause interference with the cancer immunotherapy. Rituximab (Rituxan) takes too long to act. Anakinra (Kineret), tofacitinib (Xeljanz), and tocilizumab (Actemra), on the other hand, are agents he is interested in using as alternatives to TNF inhibitors, although he hasn’t done so yet.
 

Use of ICIs in patients with preexisting autoimmune disease

The experience here is entirely anecdotal, since such patients have been excluded from ICI clinical trials, but the available evidence suggests physicians should be prepared for higher rheumatologic IRAE rates in this setting. Investigators at Vanderbilt University reported that 8 of 30 cancer patients with known preexisting autoimmune disease experienced flares of that disease when treated with ipilimumab, and 10 developed a new IRAE (Therap Adv Gastroenterol. 2016 Jul;9[4]:457-62).

The Hopkins group has three patients with preexisting rheumatoid arthritis and two with preexisting scleroderma who have received ICIs. All three rheumatoid arthritis patients flared. Rheumatologists are trying to manage these flares so the patients can continue on their ICI. One of the scleroderma patients experienced no change in that disease while on an ICI, while the other showed a definite improvement in scleroderma symptoms.

“I think the jury’s still out in terms of what you do about ICI therapy in patients with preexisting autoimmunity. The data would say that there’s maybe a 50-50 chance of the autoimmune disease becoming worse, but, if patients have an otherwise fatal cancer, I think it’s probably worth the chance,” Dr. Bingham said.

Anecdotal reports suggest that more severe IRAEs may be a favorable prognostic sign in terms of cancer eradication, but a lot more patient experience will be needed in order to be sure, the rheumatologist said.

Dr. Bingham reported serving as a consultant to Bristol-Myers Squibb.

bjancin@frontlinemedcom.com
 

SNOWMASS, COLO. – Physicians can expect to encounter more and more patients with inflammatory arthritis and other rheumatic adverse events induced by immune checkpoint inhibitors as a result of anticipated exponential growth in the use of these drugs to treat an expanding list of cancers, Clifton O. Bingham III, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

These cancer immunotherapy–induced rheumatic diseases may superficially look like the classic forms of familiar autoimmune diseases, but they have highly atypical features that will affect treatment decisions.

Rheumatologic IRAE presentations

Inflammatory arthritis is the most common form of rheumatologic IRAE, followed by sicca syndrome. At the Johns Hopkins Arthritis Center, Dr. Bingham and his coworkers have 25 well-characterized patients with inflammatory arthritis resulting from an ICI, only 1 of whom is HLA-B27-positive.

“Also, just one is autoantibody-positive, even though they all look for all the world as though they have rheumatoid arthritis,” the rheumatologist observed.

This ICI-induced inflammatory arthritis initially presents most commonly in the midsize and large joints – knees, ankles, elbows – then expands to include small joints such as the wrists, proximal interphalangeal joints, and the metacarpophalangeal joints.

Notably, the Hopkins group also has three patients with classic reactive arthritis marked by conjunctivitis, urethritis, arthritis, and dactylitis.

“I don’t know about you, but, in our general rheumatology practice, we see maybe one case of reactive arthritis in several years, so this is something that has struck us as really quite interesting,” said Dr. Bingham, who is also director of research in the division of rheumatology at Johns Hopkins.

The arthritis center is also managing a group of patients with ICI-induced sicca syndrome, which is uniformly extremely severe and treatment resistant, as well as a couple of patients with myositis IRAE, one with polymyalgia rheumatica, and two with crystal disease that is highly inflammatory in nature, difficult to treat, and includes an inflammatory polyarthritis component not typical in patients with crystal arthritis.
 

Why physicians will see more rheumatologic IRAEs

ICIs have dramatically transformed the treatment of selected advanced-stage cancers. For example, whereas patients with metastatic melanoma historically had a 2-year survival rate of 5%, combination therapy with the ICIs ipilimumab (Yervoy) and nivolumab (Opdivo) resulted in a 60% rate of partial or complete remission in a landmark clinical trial.

The basis of cancer immunotherapy is the discovery that, in order for cancer cells to thrive, they emit blocking signals that downregulate the native ability of T cells to recognize and kill them. This is true for both solid tumors and hematologic malignancies. The ICIs inhibit these blocking signals, which include cytotoxic T-lymphocyte–associated protein 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PDL-1), thereby freeing up the T cells for tumor fighting.

Because of the nonspecific mechanism of this T-cell activation, however, ICIs have, as their main toxicities, T-cell–mediated autoimmune inflammatory tissue damage, which gets lumped under the umbrella term IRAEs. It can affect almost every organ system. Skin rashes are the most common, colitis second. Other commonly encountered IRAEs include thyroiditis, hypophysitis, hepatitis, peripheral neuropathy, and pneumonitis.

In addition to the four currently approved ICIs – ipilimumab, nivolumab, pembrolizumab (Keytruda), and atezolizumab (Tecentriq) – investigational ICIs targeting CTLA4, PD-1, and/or PDL-1 are in development. Plus, new ICIs targeting other blocking signals, including lymphocyte activation gene-3, CD137, and T-cell immunoglobulin and mucin domain-3, are now in clinical trials.

Clinical trials aimed at expanding the indications of existing ICIs and using ICIs in earlier-stage cancers in an effort to improve rates of lasting remission are also underway.

All told, probably at least 400 clinical trials of ICIs are ongoing worldwide, the rheumatologist estimated.

“More people will be exposed to these drugs, and we’ll see more and more of these rheumatologic IRAEs,” Dr. Bingham predicted.
 

Rheumatologic IRAEs are seriously underdiagnosed

Back in the pre-ICI days, Dr. Bingham was coauthor of a major study which concluded that clinical trialists in oncology consistently downgrade the severity of rheumatologic adverse events, often by 1 or 2 grades (J Rheumatol. 2007 Jun;34[6]:1401-14).

Unpublished details of ICI clinical trials in melanoma that he obtained from Bristol-Myers Squibb suggest that the true rate of rheumatologic IRAEs is about 20%, or roughly double that reported in the studies. That’s because the adverse events–grading system used in oncology undercalls the severity of arthritis and autoimmune disorders.

Indeed, the National Cancer Institute’s Common Terminology Criteria for Adverse Events, used in oncology clinical trials, is confusing on the topic of musculoskeletal and connective tissue disorders as treatment-emergent adverse events, according to Dr. Bingham. He noted that an oncologist can code a swollen joint in three different ways – joint effusion, arthritis, or arthralgia – and it takes disabling interference with self-care in activities of daily living for that swollen joint to rise to the level of a Grade 3 adverse event. From a rheumatology trialist’s perspective, that would be a Grade 4 disability.

Plus, neither the product labeling nor the patient information guides for the approved immunotherapy drugs mention the importance of monitoring for rheumatologic IRAEs or their management.

“There is poor awareness of musculoskeletal and rheumatic IRAEs in the general oncology community,” Dr. Bingham asserted. “But, if you talk with any oncology nurses who work in a clinical trial, they will tell you they’re seeing these events with significant frequency and severity.”
 

Treatment and response

It’s critical to gain control of rheumatologic IRAEs quickly so that patients can get on with their cancer immunotherapy. Dr. Bingham uses intra-articular steroid injections for patients with oligoarthritis and high-dose oral prednisone for polyarticular disease. He starts methotrexate and/or leflunomide early because the conventional disease-modifying antirheumatic drugs have roughly a 2-month delay in onset of action. He has had several patients who are unable to taper steroids despite background methotrexate.

In the most severely affected patients, he has turned to biologic agents in consultation with their oncologists. Tumor necrosis factor (TNF) inhibitors are the ones he and other rheumatologists have used most often.

“Notably, we have not been able to taper down very well. We have patients who are out more than 2 years now who still require their TNF inhibitor to treat their inflammatory arthritis, and these are patients on conventional disease–modifying antirheumatic drugs as well. As soon as it’s tapered, the arthritis begins to come back,” according to Dr. Bingham.

In marked contrast, colitis as an IRAE typically clears in response to just one or two doses of a TNF inhibitor.

One audience member related that she’d encountered a roadblock in trying to get authorization for a TNF inhibitor for a patient with a rheumatologic IRAE secondary to ICI treatment for metastatic melanoma because the labeling states these agents are relatively contraindicated in melanoma patients. Dr. Bingham offered a tip: Collaborate with the patient’s oncologist.

“In most cases, oncologists can get infliximab for these patients and administer it in their infusion centers. They are able to get things authorized with very little trouble,” he said.

Besides, most of these patients with severe inflammatory arthritis meet conventional criteria for TNF inhibitor therapy, based on their number of infected joints and elevated acute phase reactants for longer than 6 weeks, Dr. Bingham noted.

“We’ve had some very interesting conversations with patients. It’s impressive to see the impact arthritis can have on people. A lot of patients have said, ‘I don’t care if I die. Get me functional right now.’ That’s pretty profound. Quality of life is still very important for people, even when dealing with life-threatening diseases,” he observed.

Oncologists are actually eager for their patients to get on steroid-sparing therapy because of concern that high doses of steroids may reduce the efficacy of cancer immunotherapy. That’s not an issue with the TNF inhibitors, the rheumatologist continued.

Turning to the utility of other classes of biologic agents, Dr. Bingham advised avoiding abatacept (Orencia) because its mechanism of action is likely to cause interference with the cancer immunotherapy. Rituximab (Rituxan) takes too long to act. Anakinra (Kineret), tofacitinib (Xeljanz), and tocilizumab (Actemra), on the other hand, are agents he is interested in using as alternatives to TNF inhibitors, although he hasn’t done so yet.
 

Use of ICIs in patients with preexisting autoimmune disease

The experience here is entirely anecdotal, since such patients have been excluded from ICI clinical trials, but the available evidence suggests physicians should be prepared for higher rheumatologic IRAE rates in this setting. Investigators at Vanderbilt University reported that 8 of 30 cancer patients with known preexisting autoimmune disease experienced flares of that disease when treated with ipilimumab, and 10 developed a new IRAE (Therap Adv Gastroenterol. 2016 Jul;9[4]:457-62).

The Hopkins group has three patients with preexisting rheumatoid arthritis and two with preexisting scleroderma who have received ICIs. All three rheumatoid arthritis patients flared. Rheumatologists are trying to manage these flares so the patients can continue on their ICI. One of the scleroderma patients experienced no change in that disease while on an ICI, while the other showed a definite improvement in scleroderma symptoms.

“I think the jury’s still out in terms of what you do about ICI therapy in patients with preexisting autoimmunity. The data would say that there’s maybe a 50-50 chance of the autoimmune disease becoming worse, but, if patients have an otherwise fatal cancer, I think it’s probably worth the chance,” Dr. Bingham said.

Anecdotal reports suggest that more severe IRAEs may be a favorable prognostic sign in terms of cancer eradication, but a lot more patient experience will be needed in order to be sure, the rheumatologist said.

Dr. Bingham reported serving as a consultant to Bristol-Myers Squibb.

bjancin@frontlinemedcom.com
 

Photo by Rhoda Baer

A report on cancer in the US suggests the incidence of leukemia and myeloma has been on the rise in recent years, but the incidence of non-Hodgkin lymphoma (NHL) has been on the decline.

Meanwhile, annual death rates for leukemia and NHL have decreased, and annual death rates for myeloma have decreased in men but not in women.

Furthermore, patients with leukemia, NHL, and myeloma have seen a substantial improvement in 5-year survival rates in recent years relative to patients in the late 1970s.

These findings are part of the Annual Report to the Nation on the Status of Cancer, 1975-2014, which has been published in the Journal of the National Cancer Institute.

This report is released each year, but the current edition includes a special section focused on survival.

“While trends in death rates are the most commonly used measure to assess progress against cancer, survival trends are also an important measure to evaluate progress in improvement of cancer outcomes,” said Ahmedin Jemal, DVM, PhD, of the American Cancer Society.

“We last included a special section on cancer survival in 2004, and, as we found then, survival improved over time for almost all cancers at every stage of diagnosis.”

For the current report, researchers calculated the 5-year average annual percent changes (AAPCs) for 2009 to 2013 for cancer incidence and for 2010 to 2014 for cancer mortality.

Cancer incidence (2009-2013)

In women, the AAPC increased 1.5% for leukemia (P<0.05), decreased 0.5% for NHL (P<0.05), and increased 2.2% for myeloma (P<0.05).

In men, the AAPC increased 1.7% for leukemia (P<0.05), decreased 0.2% for NHL, and increased 2.8% for myeloma (P<0.05).

Cancer mortality (2010-2014)

In women, the AAPC decreased 1.2% for leukemia (P<0.05), decreased 2.2% for NHL (P<0.05), and increased 0.5% for myeloma.

In men, the AAPC decreased 1.0% for leukemia (P<0.05), decreased 2.0% for NHL (P<0.05), and decreased 0.9% for myeloma (P<0.05).

5-year survival

The researchers compared 5-year relative survival for cancers diagnosed from 1975 to 1977 and those diagnosed from 2006 to 2012.

The absolute percentage change over time (for both sexes combined) was 26.1% for NHL, 25.7% for myeloma, and 28.5% for leukemia.

Five-year survival for patients diagnosed in 1975-1977 was 46.5% for NHL, 24.6% for myeloma, and 34.2% for leukemia.

Five-year survival for patients diagnosed in 2006-2012 was 72.6% for NHL, 50.2% for myeloma, and 62.7% for leukemia.

Photo by Rhoda Baer

A report on cancer in the US suggests the incidence of leukemia and myeloma has been on the rise in recent years, but the incidence of non-Hodgkin lymphoma (NHL) has been on the decline.

Meanwhile, annual death rates for leukemia and NHL have decreased, and annual death rates for myeloma have decreased in men but not in women.

Furthermore, patients with leukemia, NHL, and myeloma have seen a substantial improvement in 5-year survival rates in recent years relative to patients in the late 1970s.

These findings are part of the Annual Report to the Nation on the Status of Cancer, 1975-2014, which has been published in the Journal of the National Cancer Institute.

This report is released each year, but the current edition includes a special section focused on survival.

“While trends in death rates are the most commonly used measure to assess progress against cancer, survival trends are also an important measure to evaluate progress in improvement of cancer outcomes,” said Ahmedin Jemal, DVM, PhD, of the American Cancer Society.

“We last included a special section on cancer survival in 2004, and, as we found then, survival improved over time for almost all cancers at every stage of diagnosis.”

For the current report, researchers calculated the 5-year average annual percent changes (AAPCs) for 2009 to 2013 for cancer incidence and for 2010 to 2014 for cancer mortality.

Cancer incidence (2009-2013)

In women, the AAPC increased 1.5% for leukemia (P<0.05), decreased 0.5% for NHL (P<0.05), and increased 2.2% for myeloma (P<0.05).

In men, the AAPC increased 1.7% for leukemia (P<0.05), decreased 0.2% for NHL, and increased 2.8% for myeloma (P<0.05).

Cancer mortality (2010-2014)

In women, the AAPC decreased 1.2% for leukemia (P<0.05), decreased 2.2% for NHL (P<0.05), and increased 0.5% for myeloma.

In men, the AAPC decreased 1.0% for leukemia (P<0.05), decreased 2.0% for NHL (P<0.05), and decreased 0.9% for myeloma (P<0.05).

5-year survival

The researchers compared 5-year relative survival for cancers diagnosed from 1975 to 1977 and those diagnosed from 2006 to 2012.

The absolute percentage change over time (for both sexes combined) was 26.1% for NHL, 25.7% for myeloma, and 28.5% for leukemia.

Five-year survival for patients diagnosed in 1975-1977 was 46.5% for NHL, 24.6% for myeloma, and 34.2% for leukemia.

Five-year survival for patients diagnosed in 2006-2012 was 72.6% for NHL, 50.2% for myeloma, and 62.7% for leukemia.

Photo by Rhoda Baer

A report on cancer in the US suggests the incidence of leukemia and myeloma has been on the rise in recent years, but the incidence of non-Hodgkin lymphoma (NHL) has been on the decline.

Meanwhile, annual death rates for leukemia and NHL have decreased, and annual death rates for myeloma have decreased in men but not in women.

Furthermore, patients with leukemia, NHL, and myeloma have seen a substantial improvement in 5-year survival rates in recent years relative to patients in the late 1970s.

These findings are part of the Annual Report to the Nation on the Status of Cancer, 1975-2014, which has been published in the Journal of the National Cancer Institute.

This report is released each year, but the current edition includes a special section focused on survival.

“While trends in death rates are the most commonly used measure to assess progress against cancer, survival trends are also an important measure to evaluate progress in improvement of cancer outcomes,” said Ahmedin Jemal, DVM, PhD, of the American Cancer Society.

“We last included a special section on cancer survival in 2004, and, as we found then, survival improved over time for almost all cancers at every stage of diagnosis.”

For the current report, researchers calculated the 5-year average annual percent changes (AAPCs) for 2009 to 2013 for cancer incidence and for 2010 to 2014 for cancer mortality.

Cancer incidence (2009-2013)

In women, the AAPC increased 1.5% for leukemia (P<0.05), decreased 0.5% for NHL (P<0.05), and increased 2.2% for myeloma (P<0.05).

In men, the AAPC increased 1.7% for leukemia (P<0.05), decreased 0.2% for NHL, and increased 2.8% for myeloma (P<0.05).

Cancer mortality (2010-2014)

In women, the AAPC decreased 1.2% for leukemia (P<0.05), decreased 2.2% for NHL (P<0.05), and increased 0.5% for myeloma.

In men, the AAPC decreased 1.0% for leukemia (P<0.05), decreased 2.0% for NHL (P<0.05), and decreased 0.9% for myeloma (P<0.05).

5-year survival

The researchers compared 5-year relative survival for cancers diagnosed from 1975 to 1977 and those diagnosed from 2006 to 2012.

The absolute percentage change over time (for both sexes combined) was 26.1% for NHL, 25.7% for myeloma, and 28.5% for leukemia.

Five-year survival for patients diagnosed in 1975-1977 was 46.5% for NHL, 24.6% for myeloma, and 34.2% for leukemia.

Five-year survival for patients diagnosed in 2006-2012 was 72.6% for NHL, 50.2% for myeloma, and 62.7% for leukemia.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of selinexor (KPT-330) in patients with hematologic malignancies.

The partial hold, which was announced on March 10, was placed on all trials of the drug, including those in patients with solid tumor malignancies.

The hold meant that no new patients could be enrolled in selinexor trials.

Patients who were already enrolled and had stable disease or better could remain on selinexor therapy.

Now, the FDA has lifted the hold on trials of patients with hematologic malignancies, so new patients can be enrolled in these trials and begin receiving selinexor.

The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, noted that the hold was not the result of patient deaths or any new information regarding the safety profile of selinexor.

In response to the hold, Karyopharm amended the investigator’s brochure, updated informed consent documents, and submitted the documents to the FDA.

“The Karyopharm team worked diligently to update and submit the required documents to the FDA, which allowed the hematology division to expeditiously remove the partial clinical hold,” said Michael G. Kauffman, MD, PhD, chief executive officer of Karyopharm.

“We anticipate that the solid tumor divisions will follow suit shortly. Patient enrollment is again underway in our hematologic oncology studies. Our previously disclosed enrollment rates and timelines for both ongoing and planned trials are not expected to be materially impacted.”

About selinexor

Selinexor is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor.

The drug is currently being evaluated in clinical trials across multiple cancer indications, including in acute myeloid leukemia (SOPRA), in multiple myeloma in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), as well as in diffuse large B-cell lymphoma (SADAL). 

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of selinexor (KPT-330) in patients with hematologic malignancies.

The partial hold, which was announced on March 10, was placed on all trials of the drug, including those in patients with solid tumor malignancies.

The hold meant that no new patients could be enrolled in selinexor trials.

Patients who were already enrolled and had stable disease or better could remain on selinexor therapy.

Now, the FDA has lifted the hold on trials of patients with hematologic malignancies, so new patients can be enrolled in these trials and begin receiving selinexor.

The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, noted that the hold was not the result of patient deaths or any new information regarding the safety profile of selinexor.

In response to the hold, Karyopharm amended the investigator’s brochure, updated informed consent documents, and submitted the documents to the FDA.

“The Karyopharm team worked diligently to update and submit the required documents to the FDA, which allowed the hematology division to expeditiously remove the partial clinical hold,” said Michael G. Kauffman, MD, PhD, chief executive officer of Karyopharm.

“We anticipate that the solid tumor divisions will follow suit shortly. Patient enrollment is again underway in our hematologic oncology studies. Our previously disclosed enrollment rates and timelines for both ongoing and planned trials are not expected to be materially impacted.”

About selinexor

Selinexor is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor.

The drug is currently being evaluated in clinical trials across multiple cancer indications, including in acute myeloid leukemia (SOPRA), in multiple myeloma in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), as well as in diffuse large B-cell lymphoma (SADAL). 

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of selinexor (KPT-330) in patients with hematologic malignancies.

The partial hold, which was announced on March 10, was placed on all trials of the drug, including those in patients with solid tumor malignancies.

The hold meant that no new patients could be enrolled in selinexor trials.

Patients who were already enrolled and had stable disease or better could remain on selinexor therapy.

Now, the FDA has lifted the hold on trials of patients with hematologic malignancies, so new patients can be enrolled in these trials and begin receiving selinexor.

The FDA had placed the hold due to a lack of information in the investigator’s brochure, including an incomplete list of serious adverse events associated with selinexor.

Karyopharm Therapeutics Inc., the company developing selinexor, noted that the hold was not the result of patient deaths or any new information regarding the safety profile of selinexor.

In response to the hold, Karyopharm amended the investigator’s brochure, updated informed consent documents, and submitted the documents to the FDA.

“The Karyopharm team worked diligently to update and submit the required documents to the FDA, which allowed the hematology division to expeditiously remove the partial clinical hold,” said Michael G. Kauffman, MD, PhD, chief executive officer of Karyopharm.

“We anticipate that the solid tumor divisions will follow suit shortly. Patient enrollment is again underway in our hematologic oncology studies. Our previously disclosed enrollment rates and timelines for both ongoing and planned trials are not expected to be materially impacted.”

About selinexor

Selinexor is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

To date, more than 1900 patients have been treated with selinexor.

The drug is currently being evaluated in clinical trials across multiple cancer indications, including in acute myeloid leukemia (SOPRA), in multiple myeloma in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), as well as in diffuse large B-cell lymphoma (SADAL). 

Photo by Rhoda Baer

The National Comprehensive Cancer Network® (NCCN®) recently launched the NCCN Radiation Therapy Compendium™, which provides a single access point for NCCN recommendations pertaining to radiation therapy.

The compendium provides guidance on all radiation therapy modalities recommended within NCCN guidelines, including intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative radiotherapy, image-guided radiotherapy, low dose-rate brachytherapy/high dose-rate brachytherapy, radioisotope, and particle therapy.

“As a single source for all radiation therapy recommendations within the NCCN guidelines, the compendium benefits patients with cancer by assisting providers and payers in making evidence-based treatment and coverage decisions,” said Robert W. Carlson, MD, chief executive officer of NCCN.

The NCCN Radiation Therapy Compendium™ includes recommendations for the following 24 cancer types:

Acute myeloid leukemia

Anal cancer

B-cell lymphomas

Bladder cancer

Breast cancer

Chronic lymphocytic leukemia/small lymphoblastic lymphoma

Colon cancer

Hepatobiliary cancers

Kidney cancer

Malignant pleural mesothelioma

Melanoma

Multiple myeloma

Neuroendocrine tumors

Non-small cell lung cancer

Occult primary cancer

Pancreatic adenocarcinoma

Penile cancer

Primary cutaneous B-cell lymphomas

Prostate cancer

Rectal cancer

Small cell lung cancer

Soft tissue sarcoma

T-cell lymphomas

Testicular cancer

NCCN said additional cancer types will be published on a rolling basis over the coming months.

Photo by Rhoda Baer

The National Comprehensive Cancer Network® (NCCN®) recently launched the NCCN Radiation Therapy Compendium™, which provides a single access point for NCCN recommendations pertaining to radiation therapy.

The compendium provides guidance on all radiation therapy modalities recommended within NCCN guidelines, including intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative radiotherapy, image-guided radiotherapy, low dose-rate brachytherapy/high dose-rate brachytherapy, radioisotope, and particle therapy.

“As a single source for all radiation therapy recommendations within the NCCN guidelines, the compendium benefits patients with cancer by assisting providers and payers in making evidence-based treatment and coverage decisions,” said Robert W. Carlson, MD, chief executive officer of NCCN.

The NCCN Radiation Therapy Compendium™ includes recommendations for the following 24 cancer types:

Acute myeloid leukemia

Anal cancer

B-cell lymphomas

Bladder cancer

Breast cancer

Chronic lymphocytic leukemia/small lymphoblastic lymphoma

Colon cancer

Hepatobiliary cancers

Kidney cancer

Malignant pleural mesothelioma

Melanoma

Multiple myeloma

Neuroendocrine tumors

Non-small cell lung cancer

Occult primary cancer

Pancreatic adenocarcinoma

Penile cancer

Primary cutaneous B-cell lymphomas

Prostate cancer

Rectal cancer

Small cell lung cancer

Soft tissue sarcoma

T-cell lymphomas

Testicular cancer

NCCN said additional cancer types will be published on a rolling basis over the coming months.

Photo by Rhoda Baer

The National Comprehensive Cancer Network® (NCCN®) recently launched the NCCN Radiation Therapy Compendium™, which provides a single access point for NCCN recommendations pertaining to radiation therapy.

The compendium provides guidance on all radiation therapy modalities recommended within NCCN guidelines, including intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative radiotherapy, image-guided radiotherapy, low dose-rate brachytherapy/high dose-rate brachytherapy, radioisotope, and particle therapy.

“As a single source for all radiation therapy recommendations within the NCCN guidelines, the compendium benefits patients with cancer by assisting providers and payers in making evidence-based treatment and coverage decisions,” said Robert W. Carlson, MD, chief executive officer of NCCN.

The NCCN Radiation Therapy Compendium™ includes recommendations for the following 24 cancer types:

Acute myeloid leukemia

Anal cancer

B-cell lymphomas

Bladder cancer

Breast cancer

Chronic lymphocytic leukemia/small lymphoblastic lymphoma

Colon cancer

Hepatobiliary cancers

Kidney cancer

Malignant pleural mesothelioma

Melanoma

Multiple myeloma

Neuroendocrine tumors

Non-small cell lung cancer

Occult primary cancer

Pancreatic adenocarcinoma

Penile cancer

Primary cutaneous B-cell lymphomas

Prostate cancer

Rectal cancer

Small cell lung cancer

Soft tissue sarcoma

T-cell lymphomas

Testicular cancer

NCCN said additional cancer types will be published on a rolling basis over the coming months.

Photo by Rhoda Baer

The US cancer care delivery system is undergoing changes to better meet the needs of cancer patients, but persistent hurdles threaten to slow progress, according to the American Society of Clinical Oncology (ASCO).

ASCO’s “The State of Cancer Care in America, 2017” report describes areas of progress, including new approaches for cancer diagnosis and treatment, improved data sharing to drive innovation, and an increased focus on value-based healthcare.

However, the report also suggests that access and affordability challenges, along with increased practice burdens, continue to pose barriers to high-value, high-quality cancer care.

The report was published in the Journal of Oncology Practice.

Challenges

The report notes that the US population is growing rapidly, changing demographically, and living longer. And all of these factors contribute to a record number of cancer cases/survivors.

It has been estimated that the number of cancer survivors in the US will grow from 15.5 million to 20.3 million by 2026.

Unfortunately, the report says, cancer care is unaffordable for many patients, even those with health insurance.

And significant health disparities persist that are independent of insurance status. Socioeconomic status, geography, and race/ethnicity all impact patient health outcomes.

The report also suggests that oncology practices are facing increased administrative burdens that divert time and resources from their patients.

Progress

Despite the aforementioned challenges, the report paints an optimistic vision about the future of cancer care and highlights activity in the past year aimed at improving care.

For instance, the Food and Drug Administration approved 5 new anticancer therapies, expanded the use of 13, and approved several diagnostic tests in 2016.

In addition, overall cancer incidence and mortality rates were lower in 2016 than in previous decades.

“Since 1991, we’ve been able to save 2.1 million lives because of significant advances in prevention, diagnosis, and treatment—something unimaginable even a decade ago,” said ASCO President Daniel F. Hayes, MD.

“But there’s still more work to be done to ensure that every patient with cancer, no matter who they are or where they live, has access to high-quality, high-value cancer care.”

The report includes a list of recommendations that, ASCO believes, could help bring the US closer to achieving that goal.

Photo by Rhoda Baer

The US cancer care delivery system is undergoing changes to better meet the needs of cancer patients, but persistent hurdles threaten to slow progress, according to the American Society of Clinical Oncology (ASCO).

ASCO’s “The State of Cancer Care in America, 2017” report describes areas of progress, including new approaches for cancer diagnosis and treatment, improved data sharing to drive innovation, and an increased focus on value-based healthcare.

However, the report also suggests that access and affordability challenges, along with increased practice burdens, continue to pose barriers to high-value, high-quality cancer care.

The report was published in the Journal of Oncology Practice.

Challenges

The report notes that the US population is growing rapidly, changing demographically, and living longer. And all of these factors contribute to a record number of cancer cases/survivors.

It has been estimated that the number of cancer survivors in the US will grow from 15.5 million to 20.3 million by 2026.

Unfortunately, the report says, cancer care is unaffordable for many patients, even those with health insurance.

And significant health disparities persist that are independent of insurance status. Socioeconomic status, geography, and race/ethnicity all impact patient health outcomes.

The report also suggests that oncology practices are facing increased administrative burdens that divert time and resources from their patients.

Progress

Despite the aforementioned challenges, the report paints an optimistic vision about the future of cancer care and highlights activity in the past year aimed at improving care.

For instance, the Food and Drug Administration approved 5 new anticancer therapies, expanded the use of 13, and approved several diagnostic tests in 2016.

In addition, overall cancer incidence and mortality rates were lower in 2016 than in previous decades.

“Since 1991, we’ve been able to save 2.1 million lives because of significant advances in prevention, diagnosis, and treatment—something unimaginable even a decade ago,” said ASCO President Daniel F. Hayes, MD.

“But there’s still more work to be done to ensure that every patient with cancer, no matter who they are or where they live, has access to high-quality, high-value cancer care.”

The report includes a list of recommendations that, ASCO believes, could help bring the US closer to achieving that goal.

Photo by Rhoda Baer

The US cancer care delivery system is undergoing changes to better meet the needs of cancer patients, but persistent hurdles threaten to slow progress, according to the American Society of Clinical Oncology (ASCO).

ASCO’s “The State of Cancer Care in America, 2017” report describes areas of progress, including new approaches for cancer diagnosis and treatment, improved data sharing to drive innovation, and an increased focus on value-based healthcare.

However, the report also suggests that access and affordability challenges, along with increased practice burdens, continue to pose barriers to high-value, high-quality cancer care.

The report was published in the Journal of Oncology Practice.

Challenges

The report notes that the US population is growing rapidly, changing demographically, and living longer. And all of these factors contribute to a record number of cancer cases/survivors.

It has been estimated that the number of cancer survivors in the US will grow from 15.5 million to 20.3 million by 2026.

Unfortunately, the report says, cancer care is unaffordable for many patients, even those with health insurance.

And significant health disparities persist that are independent of insurance status. Socioeconomic status, geography, and race/ethnicity all impact patient health outcomes.

The report also suggests that oncology practices are facing increased administrative burdens that divert time and resources from their patients.

Progress

Despite the aforementioned challenges, the report paints an optimistic vision about the future of cancer care and highlights activity in the past year aimed at improving care.

For instance, the Food and Drug Administration approved 5 new anticancer therapies, expanded the use of 13, and approved several diagnostic tests in 2016.

In addition, overall cancer incidence and mortality rates were lower in 2016 than in previous decades.

“Since 1991, we’ve been able to save 2.1 million lives because of significant advances in prevention, diagnosis, and treatment—something unimaginable even a decade ago,” said ASCO President Daniel F. Hayes, MD.

“But there’s still more work to be done to ensure that every patient with cancer, no matter who they are or where they live, has access to high-quality, high-value cancer care.”

The report includes a list of recommendations that, ASCO believes, could help bring the US closer to achieving that goal.