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Stopping TKI therapy can be safe, study suggests
COPENHAGEN—Results of a large study suggest that stopping treatment with tyrosine kinase inhibitors (TKIs) can be safe for patients with chronic myeloid leukemia (CML) in deep molecular response (MR4).
Six months after patients stopped receiving a TKI, the relapse-free survival was 62%. At 12 months, it was 56%.
Havinga longer duration of TKI treatment and a longer duration of deep molecular response were both associated with a higher likelihood of relapse-free survival.
These results, from the EURO-SKI trial, were presented at the 21st Congress of the European Hematology Association (abstract S145*) by Johan Richter, MD, PhD, of Skåne University Hospital in Lund, Sweden.
The goal of the EURO-SKI study was to define prognostic markers to increase the proportion of patients in durable deep molecular response after stopping TKI treatment.
The trial included 760 adults with chronic phase CML who were on TKI treatment for at least 3 years. Patients were either on their first TKI or on their second TKI due to toxicity with their first. (None had failed TKI treatment.)
Patients had been in MR4 (BCR/ABL <0.01%) for at least a year, which was confirmed by 3 consecutive polymerase chain reaction (PCR) results during the last 12 months. The final MR4 confirmation was performed in a EUTOS standardized laboratory.
After the final MR4 confirmation, patients stopped TKI treatment. They underwent real-time quantitative PCR (RQ-PCR) every 4 weeks for the first 6 months and every 6 weeks for the next 6 months. In years 2 and 3, they underwent RQ-PCR every third month.
The patients had a median age at diagnosis of 52 (range, 11.2-85.5) and a median age at TKI stop of 60.3 (range, 19.5-89.9). The median duration of TKI therapy was 7.6 years (range, 3.0-14.2), and the median duration of MR4 before TKI stop was 4.7 years (range, 1.0-13.3).
Most patients had received imatinib (n=710) as first-line TKI treatment, though some received nilotinib (n=35) or dasatinib (n=14). The type of first-line TKI was unknown in 1 patient. Second-line TKI treatment included imatinib (n=7), nilotinib (n=47), and dasatinib (n=57).
Relapse, survival, and safety
Six months after stopping TKI treatment, the cumulative incidence of molecular relapse was 37%. It was 43% at 12 months, 47% at 24 months, and 50% at 36 months.
In all, 347 patients had a molecular relapse. Seventy-two patients had BCR/ABL >1%, and 11 lost their complete cytogenetic response. None of the patients progressed to accelerated phase or blast crisis.
Among patients who restarted TKI treatment, the median time to restart was 4.1 months. Fourteen patients restarted treatment without a loss of major molecular response.
Dr Richter noted that the study is still ongoing, but, thus far, more than 80% of patients who restarted TKI therapy have achieved MR4 again.
The molecular relapse-free survival was 62% at 6 months after TKI stop, 56% at 12 months, 52% at 24 months, and 49% at 36 months.
There were 9 on-trial deaths, none of which were related to CML. Five patients died while in remission.
Previous studies revealed a TKI withdrawal syndrome that consists of (mostly transient) musculoskeletal pain or discomfort. In this study, 30.9% of patients (n=235) reported musculoskeletal symptoms, 226 with grade 1-2 events and 9 with grade 3 events.
Prognostic factors
The researchers performed prognostic modeling in 448 patients who previously received imatinib. Univariate analysis revealed no significant association between molecular relapse-free survival at 6 months and age, gender, depth of molecular response, Sokal score, EURO score, EUTOS score, or ELTS score.
However, TKI treatment duration and MR4 duration were both significantly (P<0.001) associated with major molecular response status at 6 months.
The odds ratio for treatment duration was 1.16 (95% CI, 1.08-1.25), which means that an additional year of imatinib treatment increases a patient’s odds of staying in major molecular response at 6 months by 16%.
The odds ratio for MR4 duration was also 1.16 (95% CI, 1.076-1.253), which means that an additional year in MR4 before TKI stop increases a patient’s odds of staying in major molecular response at 6 months by 16%.
Dr Richter noted that treatment duration and MR4 duration were highly correlated, which prevented a significant multiple model including both variables. He said the researchers will conduct further analyses to overcome the correlation between the 2 variables and determine an optimal cutoff for MR4 duration.
The team also plans to collect more data on pretreatment with interferon, as there is reason to suspect it has an influence on major molecular response duration after TKI discontinuation. 
*Data in the abstract differ from data presented at the meeting.
COPENHAGEN—Results of a large study suggest that stopping treatment with tyrosine kinase inhibitors (TKIs) can be safe for patients with chronic myeloid leukemia (CML) in deep molecular response (MR4).
Six months after patients stopped receiving a TKI, the relapse-free survival was 62%. At 12 months, it was 56%.
Havinga longer duration of TKI treatment and a longer duration of deep molecular response were both associated with a higher likelihood of relapse-free survival.
These results, from the EURO-SKI trial, were presented at the 21st Congress of the European Hematology Association (abstract S145*) by Johan Richter, MD, PhD, of Skåne University Hospital in Lund, Sweden.
The goal of the EURO-SKI study was to define prognostic markers to increase the proportion of patients in durable deep molecular response after stopping TKI treatment.
The trial included 760 adults with chronic phase CML who were on TKI treatment for at least 3 years. Patients were either on their first TKI or on their second TKI due to toxicity with their first. (None had failed TKI treatment.)
Patients had been in MR4 (BCR/ABL <0.01%) for at least a year, which was confirmed by 3 consecutive polymerase chain reaction (PCR) results during the last 12 months. The final MR4 confirmation was performed in a EUTOS standardized laboratory.
After the final MR4 confirmation, patients stopped TKI treatment. They underwent real-time quantitative PCR (RQ-PCR) every 4 weeks for the first 6 months and every 6 weeks for the next 6 months. In years 2 and 3, they underwent RQ-PCR every third month.
The patients had a median age at diagnosis of 52 (range, 11.2-85.5) and a median age at TKI stop of 60.3 (range, 19.5-89.9). The median duration of TKI therapy was 7.6 years (range, 3.0-14.2), and the median duration of MR4 before TKI stop was 4.7 years (range, 1.0-13.3).
Most patients had received imatinib (n=710) as first-line TKI treatment, though some received nilotinib (n=35) or dasatinib (n=14). The type of first-line TKI was unknown in 1 patient. Second-line TKI treatment included imatinib (n=7), nilotinib (n=47), and dasatinib (n=57).
Relapse, survival, and safety
Six months after stopping TKI treatment, the cumulative incidence of molecular relapse was 37%. It was 43% at 12 months, 47% at 24 months, and 50% at 36 months.
In all, 347 patients had a molecular relapse. Seventy-two patients had BCR/ABL >1%, and 11 lost their complete cytogenetic response. None of the patients progressed to accelerated phase or blast crisis.
Among patients who restarted TKI treatment, the median time to restart was 4.1 months. Fourteen patients restarted treatment without a loss of major molecular response.
Dr Richter noted that the study is still ongoing, but, thus far, more than 80% of patients who restarted TKI therapy have achieved MR4 again.
The molecular relapse-free survival was 62% at 6 months after TKI stop, 56% at 12 months, 52% at 24 months, and 49% at 36 months.
There were 9 on-trial deaths, none of which were related to CML. Five patients died while in remission.
Previous studies revealed a TKI withdrawal syndrome that consists of (mostly transient) musculoskeletal pain or discomfort. In this study, 30.9% of patients (n=235) reported musculoskeletal symptoms, 226 with grade 1-2 events and 9 with grade 3 events.
Prognostic factors
The researchers performed prognostic modeling in 448 patients who previously received imatinib. Univariate analysis revealed no significant association between molecular relapse-free survival at 6 months and age, gender, depth of molecular response, Sokal score, EURO score, EUTOS score, or ELTS score.
However, TKI treatment duration and MR4 duration were both significantly (P<0.001) associated with major molecular response status at 6 months.
The odds ratio for treatment duration was 1.16 (95% CI, 1.08-1.25), which means that an additional year of imatinib treatment increases a patient’s odds of staying in major molecular response at 6 months by 16%.
The odds ratio for MR4 duration was also 1.16 (95% CI, 1.076-1.253), which means that an additional year in MR4 before TKI stop increases a patient’s odds of staying in major molecular response at 6 months by 16%.
Dr Richter noted that treatment duration and MR4 duration were highly correlated, which prevented a significant multiple model including both variables. He said the researchers will conduct further analyses to overcome the correlation between the 2 variables and determine an optimal cutoff for MR4 duration.
The team also plans to collect more data on pretreatment with interferon, as there is reason to suspect it has an influence on major molecular response duration after TKI discontinuation.
*Data in the abstract differ from data presented at the meeting.
COPENHAGEN—Results of a large study suggest that stopping treatment with tyrosine kinase inhibitors (TKIs) can be safe for patients with chronic myeloid leukemia (CML) in deep molecular response (MR4).
Six months after patients stopped receiving a TKI, the relapse-free survival was 62%. At 12 months, it was 56%.
Havinga longer duration of TKI treatment and a longer duration of deep molecular response were both associated with a higher likelihood of relapse-free survival.
These results, from the EURO-SKI trial, were presented at the 21st Congress of the European Hematology Association (abstract S145*) by Johan Richter, MD, PhD, of Skåne University Hospital in Lund, Sweden.
The goal of the EURO-SKI study was to define prognostic markers to increase the proportion of patients in durable deep molecular response after stopping TKI treatment.
The trial included 760 adults with chronic phase CML who were on TKI treatment for at least 3 years. Patients were either on their first TKI or on their second TKI due to toxicity with their first. (None had failed TKI treatment.)
Patients had been in MR4 (BCR/ABL <0.01%) for at least a year, which was confirmed by 3 consecutive polymerase chain reaction (PCR) results during the last 12 months. The final MR4 confirmation was performed in a EUTOS standardized laboratory.
After the final MR4 confirmation, patients stopped TKI treatment. They underwent real-time quantitative PCR (RQ-PCR) every 4 weeks for the first 6 months and every 6 weeks for the next 6 months. In years 2 and 3, they underwent RQ-PCR every third month.
The patients had a median age at diagnosis of 52 (range, 11.2-85.5) and a median age at TKI stop of 60.3 (range, 19.5-89.9). The median duration of TKI therapy was 7.6 years (range, 3.0-14.2), and the median duration of MR4 before TKI stop was 4.7 years (range, 1.0-13.3).
Most patients had received imatinib (n=710) as first-line TKI treatment, though some received nilotinib (n=35) or dasatinib (n=14). The type of first-line TKI was unknown in 1 patient. Second-line TKI treatment included imatinib (n=7), nilotinib (n=47), and dasatinib (n=57).
Relapse, survival, and safety
Six months after stopping TKI treatment, the cumulative incidence of molecular relapse was 37%. It was 43% at 12 months, 47% at 24 months, and 50% at 36 months.
In all, 347 patients had a molecular relapse. Seventy-two patients had BCR/ABL >1%, and 11 lost their complete cytogenetic response. None of the patients progressed to accelerated phase or blast crisis.
Among patients who restarted TKI treatment, the median time to restart was 4.1 months. Fourteen patients restarted treatment without a loss of major molecular response.
Dr Richter noted that the study is still ongoing, but, thus far, more than 80% of patients who restarted TKI therapy have achieved MR4 again.
The molecular relapse-free survival was 62% at 6 months after TKI stop, 56% at 12 months, 52% at 24 months, and 49% at 36 months.
There were 9 on-trial deaths, none of which were related to CML. Five patients died while in remission.
Previous studies revealed a TKI withdrawal syndrome that consists of (mostly transient) musculoskeletal pain or discomfort. In this study, 30.9% of patients (n=235) reported musculoskeletal symptoms, 226 with grade 1-2 events and 9 with grade 3 events.
Prognostic factors
The researchers performed prognostic modeling in 448 patients who previously received imatinib. Univariate analysis revealed no significant association between molecular relapse-free survival at 6 months and age, gender, depth of molecular response, Sokal score, EURO score, EUTOS score, or ELTS score.
However, TKI treatment duration and MR4 duration were both significantly (P<0.001) associated with major molecular response status at 6 months.
The odds ratio for treatment duration was 1.16 (95% CI, 1.08-1.25), which means that an additional year of imatinib treatment increases a patient’s odds of staying in major molecular response at 6 months by 16%.
The odds ratio for MR4 duration was also 1.16 (95% CI, 1.076-1.253), which means that an additional year in MR4 before TKI stop increases a patient’s odds of staying in major molecular response at 6 months by 16%.
Dr Richter noted that treatment duration and MR4 duration were highly correlated, which prevented a significant multiple model including both variables. He said the researchers will conduct further analyses to overcome the correlation between the 2 variables and determine an optimal cutoff for MR4 duration.
The team also plans to collect more data on pretreatment with interferon, as there is reason to suspect it has an influence on major molecular response duration after TKI discontinuation.
*Data in the abstract differ from data presented at the meeting.
A new approach to treat AML?
Preclinical research suggests that activating the STING pathway may be a feasible approach for treating acute myeloid leukemia (AML).
The STING protein has been shown to play a crucial role in the immune system’s ability to “sense” cancer by recognizing and responding to DNA from tumor cells.
In past studies, researchers injected compounds that activate the STING pathway directly into solid tumors in mice, and this produced potent anti-tumor immune responses.
In a new study, researchers injected substances that mimic tumor-cell DNA into the bloodstream and found they could stimulate STING to provoke a life-extending immune response in mice with AML.
“Delivery of these substances into the blood led to massive immune responses,” said study author Justin Kline, MD, of the University of Chicago in Illinois.
“I’ve worked extensively with animal models of this disease, and have never seen responses like this.”
This research, published in Cell Reports, is the first demonstration that activating the STING pathway could be effective in hematologic malignancies.
STING (short for STimulator of INterferon Genes) plays a role in detecting threats, such as viral infections or cancer. STING is activated when DNA turns up in the wrong place, inside the cell but outside the nucleus.
When it encounters such misplaced DNA, STING induces the production of interferon-beta and other chemical signals that recruit certain components of the immune system to manage the threat, such as leukemia-specific killer T cells.
In this study, the researchers found that mice with established AML were rarely able to launch an effective immune response against the disease.
But when the team exposed the mice to DMXAA (5,6-dimethylxanthenone-4-acetic acid), a molecule that activates STING, the immune system responded aggressively, culminating in the activation of highly potent, cancer-cell killing T cells.
This response prolonged survival and, in some cases, cured the mice of their leukemia. About 60% of DMXAA-treated mice survived long-term. They were even able to protect themselves when “re-challenged” with AML cells.
Because of significant differences between mice and humans, DMXAA does not activate the human STING pathway, but researchers have found that several cyclic dinucleotides—signaling molecules produced by bacteria—have a comparable effect in stimulating the STING pathway.
This leads to an immune response that begins with the production of type I interferons and proceeds to later, more powerful stages, ultimately including leukemia-specific T cells.
“Our results provide strong rationale for the clinical translation of STING agonists as immune therapy for leukemia and possibly other hematologic
malignancies,” said study author Emily Curran, MD, of the University of Chicago.
However, Dr Kline noted that this approach is “not without risk.” He said it can induce “a lot of inflammation, fever, even shock.” Such a stimulated immune system can be “too effective,” especially when the therapy is given through the blood stream, rather than injected into a solid tumor.
“I think drug makers will want to focus on intra-tumoral injection studies before they are ready to bet on systemic infusion,” Dr Kline said. “But this is an important first step.”
Preclinical research suggests that activating the STING pathway may be a feasible approach for treating acute myeloid leukemia (AML).
The STING protein has been shown to play a crucial role in the immune system’s ability to “sense” cancer by recognizing and responding to DNA from tumor cells.
In past studies, researchers injected compounds that activate the STING pathway directly into solid tumors in mice, and this produced potent anti-tumor immune responses.
In a new study, researchers injected substances that mimic tumor-cell DNA into the bloodstream and found they could stimulate STING to provoke a life-extending immune response in mice with AML.
“Delivery of these substances into the blood led to massive immune responses,” said study author Justin Kline, MD, of the University of Chicago in Illinois.
“I’ve worked extensively with animal models of this disease, and have never seen responses like this.”
This research, published in Cell Reports, is the first demonstration that activating the STING pathway could be effective in hematologic malignancies.
STING (short for STimulator of INterferon Genes) plays a role in detecting threats, such as viral infections or cancer. STING is activated when DNA turns up in the wrong place, inside the cell but outside the nucleus.
When it encounters such misplaced DNA, STING induces the production of interferon-beta and other chemical signals that recruit certain components of the immune system to manage the threat, such as leukemia-specific killer T cells.
In this study, the researchers found that mice with established AML were rarely able to launch an effective immune response against the disease.
But when the team exposed the mice to DMXAA (5,6-dimethylxanthenone-4-acetic acid), a molecule that activates STING, the immune system responded aggressively, culminating in the activation of highly potent, cancer-cell killing T cells.
This response prolonged survival and, in some cases, cured the mice of their leukemia. About 60% of DMXAA-treated mice survived long-term. They were even able to protect themselves when “re-challenged” with AML cells.
Because of significant differences between mice and humans, DMXAA does not activate the human STING pathway, but researchers have found that several cyclic dinucleotides—signaling molecules produced by bacteria—have a comparable effect in stimulating the STING pathway.
This leads to an immune response that begins with the production of type I interferons and proceeds to later, more powerful stages, ultimately including leukemia-specific T cells.
“Our results provide strong rationale for the clinical translation of STING agonists as immune therapy for leukemia and possibly other hematologic
malignancies,” said study author Emily Curran, MD, of the University of Chicago.
However, Dr Kline noted that this approach is “not without risk.” He said it can induce “a lot of inflammation, fever, even shock.” Such a stimulated immune system can be “too effective,” especially when the therapy is given through the blood stream, rather than injected into a solid tumor.
“I think drug makers will want to focus on intra-tumoral injection studies before they are ready to bet on systemic infusion,” Dr Kline said. “But this is an important first step.”
Preclinical research suggests that activating the STING pathway may be a feasible approach for treating acute myeloid leukemia (AML).
The STING protein has been shown to play a crucial role in the immune system’s ability to “sense” cancer by recognizing and responding to DNA from tumor cells.
In past studies, researchers injected compounds that activate the STING pathway directly into solid tumors in mice, and this produced potent anti-tumor immune responses.
In a new study, researchers injected substances that mimic tumor-cell DNA into the bloodstream and found they could stimulate STING to provoke a life-extending immune response in mice with AML.
“Delivery of these substances into the blood led to massive immune responses,” said study author Justin Kline, MD, of the University of Chicago in Illinois.
“I’ve worked extensively with animal models of this disease, and have never seen responses like this.”
This research, published in Cell Reports, is the first demonstration that activating the STING pathway could be effective in hematologic malignancies.
STING (short for STimulator of INterferon Genes) plays a role in detecting threats, such as viral infections or cancer. STING is activated when DNA turns up in the wrong place, inside the cell but outside the nucleus.
When it encounters such misplaced DNA, STING induces the production of interferon-beta and other chemical signals that recruit certain components of the immune system to manage the threat, such as leukemia-specific killer T cells.
In this study, the researchers found that mice with established AML were rarely able to launch an effective immune response against the disease.
But when the team exposed the mice to DMXAA (5,6-dimethylxanthenone-4-acetic acid), a molecule that activates STING, the immune system responded aggressively, culminating in the activation of highly potent, cancer-cell killing T cells.
This response prolonged survival and, in some cases, cured the mice of their leukemia. About 60% of DMXAA-treated mice survived long-term. They were even able to protect themselves when “re-challenged” with AML cells.
Because of significant differences between mice and humans, DMXAA does not activate the human STING pathway, but researchers have found that several cyclic dinucleotides—signaling molecules produced by bacteria—have a comparable effect in stimulating the STING pathway.
This leads to an immune response that begins with the production of type I interferons and proceeds to later, more powerful stages, ultimately including leukemia-specific T cells.
“Our results provide strong rationale for the clinical translation of STING agonists as immune therapy for leukemia and possibly other hematologic
malignancies,” said study author Emily Curran, MD, of the University of Chicago.
However, Dr Kline noted that this approach is “not without risk.” He said it can induce “a lot of inflammation, fever, even shock.” Such a stimulated immune system can be “too effective,” especially when the therapy is given through the blood stream, rather than injected into a solid tumor.
“I think drug makers will want to focus on intra-tumoral injection studies before they are ready to bet on systemic infusion,” Dr Kline said. “But this is an important first step.”
Ibrutinib at below standard dose may achieve good survival in CLL
Ibrutinib given at doses lower than the standard dose of 420 mg/day was associated with comparable overall survival and progression-free survival as the standard dose in patients with chronic lymphocytic leukemia (CLL), based on the results of a multicenter, retrospective study submitted as a poster at the annual meeting of the American Society of Clinical Oncology.
The initial findings indicate patients who experience toxicity on the 420 mg/day dosage can still do well on a slightly lower dose of ibrutinib, reported Colleen Timlin, Pharm.D., of the Hospital of the University of Pennsylvania, Philadelphia, and her associates.
At a median follow-up of 13.5 months, the median progression-free survival was 37.4 months in the standard dose group and the median progression-free survival had not been reached in the reduced-dose group. The median overall survival had not been reached in either group. The hazard ratio in the reduced-dose group was 1.2 for progression-free survival and 0.6 for overall survival; neither difference was statistically significant. Best overall response rate was 85% in the standard-dose group and 84% in the reduced-dose group.
The study included 197 patients, 37 of whom were shifted to reduced doses of ibrutinib within 3 months of initiating therapy at the recommended 420 mg/day dosage. For reduced-dose patients, the median ibrutinib dose was 4.3 mg/kg per day. The most common reasons for reducing the ibrutinib dose were gastrointestinal toxicity, bleeding, rash, cardiotoxicity, and renal insufficiency, the researchers said.
Most of the patients treated with doses less than 420 mg/day still maintained a dose of greater than 2.5 mg/kg per day, which assured adequate Bruton’s tyrosine kinase occupancy. The 420 mg/day dosage noted in the labeling was established, based on achievement of greater than 90% Bruton’s tyrosine kinase occupancy. Fewer patients achieve greater than 90% occupancy at lower doses, but lower doses may not translate into inferior outcomes.
Weight-based dosing should be considered in future studies and pharmacoeconomic analyses. Comparative analyses of toxicity profiles stratified by ibrutinib dose are underway, according to Dr. Timlin and her colleagues.
Dr. Timlin had no relevant disclosures. Several of her colleagues had multiple financial disclosures.
On Twitter @maryjodales
Ibrutinib given at doses lower than the standard dose of 420 mg/day was associated with comparable overall survival and progression-free survival as the standard dose in patients with chronic lymphocytic leukemia (CLL), based on the results of a multicenter, retrospective study submitted as a poster at the annual meeting of the American Society of Clinical Oncology.
The initial findings indicate patients who experience toxicity on the 420 mg/day dosage can still do well on a slightly lower dose of ibrutinib, reported Colleen Timlin, Pharm.D., of the Hospital of the University of Pennsylvania, Philadelphia, and her associates.
At a median follow-up of 13.5 months, the median progression-free survival was 37.4 months in the standard dose group and the median progression-free survival had not been reached in the reduced-dose group. The median overall survival had not been reached in either group. The hazard ratio in the reduced-dose group was 1.2 for progression-free survival and 0.6 for overall survival; neither difference was statistically significant. Best overall response rate was 85% in the standard-dose group and 84% in the reduced-dose group.
The study included 197 patients, 37 of whom were shifted to reduced doses of ibrutinib within 3 months of initiating therapy at the recommended 420 mg/day dosage. For reduced-dose patients, the median ibrutinib dose was 4.3 mg/kg per day. The most common reasons for reducing the ibrutinib dose were gastrointestinal toxicity, bleeding, rash, cardiotoxicity, and renal insufficiency, the researchers said.
Most of the patients treated with doses less than 420 mg/day still maintained a dose of greater than 2.5 mg/kg per day, which assured adequate Bruton’s tyrosine kinase occupancy. The 420 mg/day dosage noted in the labeling was established, based on achievement of greater than 90% Bruton’s tyrosine kinase occupancy. Fewer patients achieve greater than 90% occupancy at lower doses, but lower doses may not translate into inferior outcomes.
Weight-based dosing should be considered in future studies and pharmacoeconomic analyses. Comparative analyses of toxicity profiles stratified by ibrutinib dose are underway, according to Dr. Timlin and her colleagues.
Dr. Timlin had no relevant disclosures. Several of her colleagues had multiple financial disclosures.
On Twitter @maryjodales
Ibrutinib given at doses lower than the standard dose of 420 mg/day was associated with comparable overall survival and progression-free survival as the standard dose in patients with chronic lymphocytic leukemia (CLL), based on the results of a multicenter, retrospective study submitted as a poster at the annual meeting of the American Society of Clinical Oncology.
The initial findings indicate patients who experience toxicity on the 420 mg/day dosage can still do well on a slightly lower dose of ibrutinib, reported Colleen Timlin, Pharm.D., of the Hospital of the University of Pennsylvania, Philadelphia, and her associates.
At a median follow-up of 13.5 months, the median progression-free survival was 37.4 months in the standard dose group and the median progression-free survival had not been reached in the reduced-dose group. The median overall survival had not been reached in either group. The hazard ratio in the reduced-dose group was 1.2 for progression-free survival and 0.6 for overall survival; neither difference was statistically significant. Best overall response rate was 85% in the standard-dose group and 84% in the reduced-dose group.
The study included 197 patients, 37 of whom were shifted to reduced doses of ibrutinib within 3 months of initiating therapy at the recommended 420 mg/day dosage. For reduced-dose patients, the median ibrutinib dose was 4.3 mg/kg per day. The most common reasons for reducing the ibrutinib dose were gastrointestinal toxicity, bleeding, rash, cardiotoxicity, and renal insufficiency, the researchers said.
Most of the patients treated with doses less than 420 mg/day still maintained a dose of greater than 2.5 mg/kg per day, which assured adequate Bruton’s tyrosine kinase occupancy. The 420 mg/day dosage noted in the labeling was established, based on achievement of greater than 90% Bruton’s tyrosine kinase occupancy. Fewer patients achieve greater than 90% occupancy at lower doses, but lower doses may not translate into inferior outcomes.
Weight-based dosing should be considered in future studies and pharmacoeconomic analyses. Comparative analyses of toxicity profiles stratified by ibrutinib dose are underway, according to Dr. Timlin and her colleagues.
Dr. Timlin had no relevant disclosures. Several of her colleagues had multiple financial disclosures.
On Twitter @maryjodales
Key clinical point: Ibrutinib given at doses lower than the standard dose of 420 mg/day may achieve comparable overall survival and progression-free survival.
Major finding: At a median follow-up of 13.5 months, the median progression-free survival was 37.4 months in the standard dose group, and the median progression-free survival had not been reached in the reduced-dose group.
Data source: A multicenter, retrospective study of 197 patients.
Disclosures: Dr. Timlin had no relevant disclosures. Several of her colleagues had multiple financial disclosures.
Study provides clues to AML survival after chemotherapy
Preclinical research suggests that some leukemia cells harvest energy resources from normal cells during chemotherapy, and this helps the leukemia cells survive and thrive after treatment.
Investigators found that acute myeloid leukemia (AML) cells are capable of stealing mitochondria from stromal cells, and these stolen mitochondria give an energy boost to surviving AML cells, which helps fuel the leukemia’s resurgence after chemotherapy.
“There are multiple mechanisms for resistance to chemotherapy, and it will be important to target them all in order to eliminate all leukemic cells,” said Jean-François Peyron, PhD, of the Centre Méditerranéen de Médecine Moléculaire (C3M) in Nice, France.
“Targeting this protective mitochondrial transfer could represent a new strategy to improve the efficacy of the current treatments for acute myeloid leukemia.”
Dr Peyron and his colleagues described their discovery of the mitochondrial transfer in Blood.
The team conducted their experiments using cell cultures and mouse models of AML. They found that nearly all AML cells died when exposed to chemotherapy drugs, but some survived. And these cells issued a “mayday” signal that “tricked” nearby non-cancerous cells into yielding their mitochondria to the AML cells, thus strengthening the leukemia cells.
“Mitochondria produce the energy that is vital for cell functions,” explained study author Emmanuel Griessinger, PhD, also of C3M.
“Through the uptake of mitochondria, chemotherapy-injured acute myeloid leukemia cells recover new energy to survive.”
The AML cells were found to increase their mitochondria mass by an average of 14%. This increase led to a 1.5-fold increase in energy production and significantly better survival rates. That is, the leukemia cells that had a high level of mitochondria were also more resistant to the chemotherapy.
The investigators observed the phenomenon in several types of leukemia cells, most notably leukemia-initiating cells. The team said this finding may explain why it can be difficult to treat AML and other cancers.
They also believe these findings offer new hope for developing better treatments for AML. If researchers can find a way to interfere with the transfer of mitochondria, that could reduce the risk of relapse.
The study may also shed light on other cancer types. Similar mechanisms may be at play in other hematologic malignancies and even solid tumors, according to the investigators.
For now, the team’s next step for this research is to identify the mechanism underlying the transfer of mitochondria in AML.
Preclinical research suggests that some leukemia cells harvest energy resources from normal cells during chemotherapy, and this helps the leukemia cells survive and thrive after treatment.
Investigators found that acute myeloid leukemia (AML) cells are capable of stealing mitochondria from stromal cells, and these stolen mitochondria give an energy boost to surviving AML cells, which helps fuel the leukemia’s resurgence after chemotherapy.
“There are multiple mechanisms for resistance to chemotherapy, and it will be important to target them all in order to eliminate all leukemic cells,” said Jean-François Peyron, PhD, of the Centre Méditerranéen de Médecine Moléculaire (C3M) in Nice, France.
“Targeting this protective mitochondrial transfer could represent a new strategy to improve the efficacy of the current treatments for acute myeloid leukemia.”
Dr Peyron and his colleagues described their discovery of the mitochondrial transfer in Blood.
The team conducted their experiments using cell cultures and mouse models of AML. They found that nearly all AML cells died when exposed to chemotherapy drugs, but some survived. And these cells issued a “mayday” signal that “tricked” nearby non-cancerous cells into yielding their mitochondria to the AML cells, thus strengthening the leukemia cells.
“Mitochondria produce the energy that is vital for cell functions,” explained study author Emmanuel Griessinger, PhD, also of C3M.
“Through the uptake of mitochondria, chemotherapy-injured acute myeloid leukemia cells recover new energy to survive.”
The AML cells were found to increase their mitochondria mass by an average of 14%. This increase led to a 1.5-fold increase in energy production and significantly better survival rates. That is, the leukemia cells that had a high level of mitochondria were also more resistant to the chemotherapy.
The investigators observed the phenomenon in several types of leukemia cells, most notably leukemia-initiating cells. The team said this finding may explain why it can be difficult to treat AML and other cancers.
They also believe these findings offer new hope for developing better treatments for AML. If researchers can find a way to interfere with the transfer of mitochondria, that could reduce the risk of relapse.
The study may also shed light on other cancer types. Similar mechanisms may be at play in other hematologic malignancies and even solid tumors, according to the investigators.
For now, the team’s next step for this research is to identify the mechanism underlying the transfer of mitochondria in AML.
Preclinical research suggests that some leukemia cells harvest energy resources from normal cells during chemotherapy, and this helps the leukemia cells survive and thrive after treatment.
Investigators found that acute myeloid leukemia (AML) cells are capable of stealing mitochondria from stromal cells, and these stolen mitochondria give an energy boost to surviving AML cells, which helps fuel the leukemia’s resurgence after chemotherapy.
“There are multiple mechanisms for resistance to chemotherapy, and it will be important to target them all in order to eliminate all leukemic cells,” said Jean-François Peyron, PhD, of the Centre Méditerranéen de Médecine Moléculaire (C3M) in Nice, France.
“Targeting this protective mitochondrial transfer could represent a new strategy to improve the efficacy of the current treatments for acute myeloid leukemia.”
Dr Peyron and his colleagues described their discovery of the mitochondrial transfer in Blood.
The team conducted their experiments using cell cultures and mouse models of AML. They found that nearly all AML cells died when exposed to chemotherapy drugs, but some survived. And these cells issued a “mayday” signal that “tricked” nearby non-cancerous cells into yielding their mitochondria to the AML cells, thus strengthening the leukemia cells.
“Mitochondria produce the energy that is vital for cell functions,” explained study author Emmanuel Griessinger, PhD, also of C3M.
“Through the uptake of mitochondria, chemotherapy-injured acute myeloid leukemia cells recover new energy to survive.”
The AML cells were found to increase their mitochondria mass by an average of 14%. This increase led to a 1.5-fold increase in energy production and significantly better survival rates. That is, the leukemia cells that had a high level of mitochondria were also more resistant to the chemotherapy.
The investigators observed the phenomenon in several types of leukemia cells, most notably leukemia-initiating cells. The team said this finding may explain why it can be difficult to treat AML and other cancers.
They also believe these findings offer new hope for developing better treatments for AML. If researchers can find a way to interfere with the transfer of mitochondria, that could reduce the risk of relapse.
The study may also shed light on other cancer types. Similar mechanisms may be at play in other hematologic malignancies and even solid tumors, according to the investigators.
For now, the team’s next step for this research is to identify the mechanism underlying the transfer of mitochondria in AML.
FDA reports shortage of doxorubicin for injection, initiates importation
A critical shortage of doxorubicin hydrochloride 50 mg powder for injection has been reported to the Food and Drug Administration.
Doxorubicin is approved to treat acute lymphoblastic leukemia, acute myeloid leukemia, breast cancer, gastric cancer, ovarian cancer, neuroblastoma, and other cancer types.
To increase availability, the pharmaceutical company Hospira (a Pfizer company) is coordinating with the FDA to import the drug from Ahmedabad, India, where it is manufactured by Zydus Hospira Oncology Private Ltd. at an FDA-inspected facility that is in compliance with current good manufacturing practice requirements.
“It is important to note that there are substantive differences in the format and content of the labeling between the U.S.-approved doxorubicin hydrochloride for injection, USP and the Hospira Limited’s doxorubicin hydrochloride 50 mg powder for injection,” Hospira reported in a letter to health care providers.
To place an order or to get questions answered, contact Hospira directly by calling customer care at 1-877-946-7747 (Mondays-Fridays, 7 a.m.-6 p.m. Central time).
For clinical inquiries, contact Hospira Medical Communications at 1-800-615-0187 or email medcom@hospira.com.
According to the letter, adverse events or quality problems associated with use of this product should be reported by calling Hospira Global Complaint Management by phone, 1-800-441-4100; by sending an email to ProductComplaintsPP@hospira.com; or by submitting a report online to Medwatch.
On Twitter @jessnicolecraig
A critical shortage of doxorubicin hydrochloride 50 mg powder for injection has been reported to the Food and Drug Administration.
Doxorubicin is approved to treat acute lymphoblastic leukemia, acute myeloid leukemia, breast cancer, gastric cancer, ovarian cancer, neuroblastoma, and other cancer types.
To increase availability, the pharmaceutical company Hospira (a Pfizer company) is coordinating with the FDA to import the drug from Ahmedabad, India, where it is manufactured by Zydus Hospira Oncology Private Ltd. at an FDA-inspected facility that is in compliance with current good manufacturing practice requirements.
“It is important to note that there are substantive differences in the format and content of the labeling between the U.S.-approved doxorubicin hydrochloride for injection, USP and the Hospira Limited’s doxorubicin hydrochloride 50 mg powder for injection,” Hospira reported in a letter to health care providers.
To place an order or to get questions answered, contact Hospira directly by calling customer care at 1-877-946-7747 (Mondays-Fridays, 7 a.m.-6 p.m. Central time).
For clinical inquiries, contact Hospira Medical Communications at 1-800-615-0187 or email medcom@hospira.com.
According to the letter, adverse events or quality problems associated with use of this product should be reported by calling Hospira Global Complaint Management by phone, 1-800-441-4100; by sending an email to ProductComplaintsPP@hospira.com; or by submitting a report online to Medwatch.
On Twitter @jessnicolecraig
A critical shortage of doxorubicin hydrochloride 50 mg powder for injection has been reported to the Food and Drug Administration.
Doxorubicin is approved to treat acute lymphoblastic leukemia, acute myeloid leukemia, breast cancer, gastric cancer, ovarian cancer, neuroblastoma, and other cancer types.
To increase availability, the pharmaceutical company Hospira (a Pfizer company) is coordinating with the FDA to import the drug from Ahmedabad, India, where it is manufactured by Zydus Hospira Oncology Private Ltd. at an FDA-inspected facility that is in compliance with current good manufacturing practice requirements.
“It is important to note that there are substantive differences in the format and content of the labeling between the U.S.-approved doxorubicin hydrochloride for injection, USP and the Hospira Limited’s doxorubicin hydrochloride 50 mg powder for injection,” Hospira reported in a letter to health care providers.
To place an order or to get questions answered, contact Hospira directly by calling customer care at 1-877-946-7747 (Mondays-Fridays, 7 a.m.-6 p.m. Central time).
For clinical inquiries, contact Hospira Medical Communications at 1-800-615-0187 or email medcom@hospira.com.
According to the letter, adverse events or quality problems associated with use of this product should be reported by calling Hospira Global Complaint Management by phone, 1-800-441-4100; by sending an email to ProductComplaintsPP@hospira.com; or by submitting a report online to Medwatch.
On Twitter @jessnicolecraig
How CML cells respond to stress
Image by Difu Wu
Researchers have used a tiny force probe to compare how healthy hematopoietic cells and cancerous ones respond to stress.
They found that cells harvested from the bone marrow of 5 patients with chronic myeloid leukemia (CML) appeared much stiffer than comparable samples taken from 5 healthy volunteers.
In addition, the researchers were able to identify areas of localized brittle failure events in the CML cells.
“What makes this work so exciting to us is not simply seeing a difference between the stiffness of healthy and cancerous cells but observing that the cancerous cells also lost their dynamic ductility and behaved as more breakable objects,” said study author Françoise Argoul, PhD, of the French National Centre for Research (CNRS) in Lyon, France.
Dr Argoul and her colleagues described this work in Physical Biology.
The researchers believe the mechanical signatures obtained by squeezing or deforming cells could potentially assist physicians in determining the presence of CML and other hematologic malignancies.
The mechanical data might also provide clues as to how long the cells have been affected by the cancer.
“We would like to construct a hematopoietic cancer cell chart where the loss of cell mechanical functions could be graded, depending on the leukemia and its stage of evolution,” Dr Argoul said.
Thinking about how the technique might be applied in a hospital setting, she added that biopsy needles could, in principle, be adapted to allow local sensing of internal soft tissue structures.
However, before the researchers can even progress to testing cells inside the body and preparing for clinical trials, they must first build up sufficient information from their measurements on isolated cells under a range of conditions in the lab.
Image by Difu Wu
Researchers have used a tiny force probe to compare how healthy hematopoietic cells and cancerous ones respond to stress.
They found that cells harvested from the bone marrow of 5 patients with chronic myeloid leukemia (CML) appeared much stiffer than comparable samples taken from 5 healthy volunteers.
In addition, the researchers were able to identify areas of localized brittle failure events in the CML cells.
“What makes this work so exciting to us is not simply seeing a difference between the stiffness of healthy and cancerous cells but observing that the cancerous cells also lost their dynamic ductility and behaved as more breakable objects,” said study author Françoise Argoul, PhD, of the French National Centre for Research (CNRS) in Lyon, France.
Dr Argoul and her colleagues described this work in Physical Biology.
The researchers believe the mechanical signatures obtained by squeezing or deforming cells could potentially assist physicians in determining the presence of CML and other hematologic malignancies.
The mechanical data might also provide clues as to how long the cells have been affected by the cancer.
“We would like to construct a hematopoietic cancer cell chart where the loss of cell mechanical functions could be graded, depending on the leukemia and its stage of evolution,” Dr Argoul said.
Thinking about how the technique might be applied in a hospital setting, she added that biopsy needles could, in principle, be adapted to allow local sensing of internal soft tissue structures.
However, before the researchers can even progress to testing cells inside the body and preparing for clinical trials, they must first build up sufficient information from their measurements on isolated cells under a range of conditions in the lab.
Image by Difu Wu
Researchers have used a tiny force probe to compare how healthy hematopoietic cells and cancerous ones respond to stress.
They found that cells harvested from the bone marrow of 5 patients with chronic myeloid leukemia (CML) appeared much stiffer than comparable samples taken from 5 healthy volunteers.
In addition, the researchers were able to identify areas of localized brittle failure events in the CML cells.
“What makes this work so exciting to us is not simply seeing a difference between the stiffness of healthy and cancerous cells but observing that the cancerous cells also lost their dynamic ductility and behaved as more breakable objects,” said study author Françoise Argoul, PhD, of the French National Centre for Research (CNRS) in Lyon, France.
Dr Argoul and her colleagues described this work in Physical Biology.
The researchers believe the mechanical signatures obtained by squeezing or deforming cells could potentially assist physicians in determining the presence of CML and other hematologic malignancies.
The mechanical data might also provide clues as to how long the cells have been affected by the cancer.
“We would like to construct a hematopoietic cancer cell chart where the loss of cell mechanical functions could be graded, depending on the leukemia and its stage of evolution,” Dr Argoul said.
Thinking about how the technique might be applied in a hospital setting, she added that biopsy needles could, in principle, be adapted to allow local sensing of internal soft tissue structures.
However, before the researchers can even progress to testing cells inside the body and preparing for clinical trials, they must first build up sufficient information from their measurements on isolated cells under a range of conditions in the lab.
Better ways to drive CAR T-cell therapy
© ASCO/Brian Powers
CHICAGO—Treatment dose and schedule, as well as a patient’s tumor burden, influence the outcome of therapy with chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASCO Annual Meeting.
One presentation suggested the dose and schedule of CTL019 can impact both complete response (CR) rates and the incidence of cytokine release syndrome (CRS).
Another presentation indicated that disease burden may determine the risk of toxicity and correlate with the efficacy of JCAR015.
CTL019
Noelle Frey, MD, of the University of Pennsylvania in Philadelphia, presented results observed with CTL019 in 30 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated on 2 trials (NCT02030847 and NCT01029366) as abstract 7002.*
Dr Frey noted that CAR T-cell therapies, including CTL019, have led to “unprecedented remission rates of between 70% and 90%.” However, immune activation that leads to high response rates also confers significant treatment-related toxicity—namely, CRS.
She reported that, in the 2 trials of adult ALL patients, a high dose of CTL019 led to a 100% response rate and a 100% CRS rate. Splitting the dose over 3 days led to an 86% response rate and a 66% CRS rate. A single low dose reduced efficacy to 33% and CRS to 66%.
Three of 6 patients who received a single high dose developed CRS and died within weeks. All of these patients had infections or sepsis that likely led to their deaths, Dr Frey said. She suggested clinicians aggressively monitor infections and treat with antimicrobials prior to CAR T-cell therapy.
“The infusion dose and schedule of CTL019 correlate with toxicity and response,” she observed. “A fractionated dosing scheme allows for real-time intra-patient dose modification in response to toxicity and the maintenance of high response rates. Concurrent sepsis and CRS confers a poor outcome.”
Dr Frey said future studies will determine the optimal approach to minimize toxicity while maintaining high efficacy. A fractionated dosing scheme is only one way to mitigate CRS. Other attractive approaches include inverse dosing based on disease burden and varying the timing of anti-cytokine-directed therapy.
JCAR015
Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, reported data from a phase 1 clinical trial (NCT01044069) of JCAR015 in 51 adults with relapsed/refractory ALL as abstract 7003.*
Treatment with JCAR015 led to high CR rates and minimal residual disease (MRD)-negativity, regardless of the amount of disease at baseline. However, outcomes were superior among patients with minimal disease at baseline.
For patients with morphologic disease, 77% achieved a CR by 20 days after treatment, and 90% were MRD-negative.
For those with minimal disease, 90% achieved a CR by 25 days after treatment, and 78% were MRD-negative. These patients experienced significantly less CRS and neurotoxicity than patients with morphologic disease.
“High CR and MRD-negativity rates were observed regardless of pre-T-cell burden,” Dr Park noted. “We observed durable responses and survivals in a subset of patients with no subsequent allotransplant in both morphological and minimal disease cohorts.”
*Data in the abstracts differ from the presentations.
© ASCO/Brian Powers
CHICAGO—Treatment dose and schedule, as well as a patient’s tumor burden, influence the outcome of therapy with chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASCO Annual Meeting.
One presentation suggested the dose and schedule of CTL019 can impact both complete response (CR) rates and the incidence of cytokine release syndrome (CRS).
Another presentation indicated that disease burden may determine the risk of toxicity and correlate with the efficacy of JCAR015.
CTL019
Noelle Frey, MD, of the University of Pennsylvania in Philadelphia, presented results observed with CTL019 in 30 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated on 2 trials (NCT02030847 and NCT01029366) as abstract 7002.*
Dr Frey noted that CAR T-cell therapies, including CTL019, have led to “unprecedented remission rates of between 70% and 90%.” However, immune activation that leads to high response rates also confers significant treatment-related toxicity—namely, CRS.
She reported that, in the 2 trials of adult ALL patients, a high dose of CTL019 led to a 100% response rate and a 100% CRS rate. Splitting the dose over 3 days led to an 86% response rate and a 66% CRS rate. A single low dose reduced efficacy to 33% and CRS to 66%.
Three of 6 patients who received a single high dose developed CRS and died within weeks. All of these patients had infections or sepsis that likely led to their deaths, Dr Frey said. She suggested clinicians aggressively monitor infections and treat with antimicrobials prior to CAR T-cell therapy.
“The infusion dose and schedule of CTL019 correlate with toxicity and response,” she observed. “A fractionated dosing scheme allows for real-time intra-patient dose modification in response to toxicity and the maintenance of high response rates. Concurrent sepsis and CRS confers a poor outcome.”
Dr Frey said future studies will determine the optimal approach to minimize toxicity while maintaining high efficacy. A fractionated dosing scheme is only one way to mitigate CRS. Other attractive approaches include inverse dosing based on disease burden and varying the timing of anti-cytokine-directed therapy.
JCAR015
Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, reported data from a phase 1 clinical trial (NCT01044069) of JCAR015 in 51 adults with relapsed/refractory ALL as abstract 7003.*
Treatment with JCAR015 led to high CR rates and minimal residual disease (MRD)-negativity, regardless of the amount of disease at baseline. However, outcomes were superior among patients with minimal disease at baseline.
For patients with morphologic disease, 77% achieved a CR by 20 days after treatment, and 90% were MRD-negative.
For those with minimal disease, 90% achieved a CR by 25 days after treatment, and 78% were MRD-negative. These patients experienced significantly less CRS and neurotoxicity than patients with morphologic disease.
“High CR and MRD-negativity rates were observed regardless of pre-T-cell burden,” Dr Park noted. “We observed durable responses and survivals in a subset of patients with no subsequent allotransplant in both morphological and minimal disease cohorts.”
*Data in the abstracts differ from the presentations.
© ASCO/Brian Powers
CHICAGO—Treatment dose and schedule, as well as a patient’s tumor burden, influence the outcome of therapy with chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASCO Annual Meeting.
One presentation suggested the dose and schedule of CTL019 can impact both complete response (CR) rates and the incidence of cytokine release syndrome (CRS).
Another presentation indicated that disease burden may determine the risk of toxicity and correlate with the efficacy of JCAR015.
CTL019
Noelle Frey, MD, of the University of Pennsylvania in Philadelphia, presented results observed with CTL019 in 30 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated on 2 trials (NCT02030847 and NCT01029366) as abstract 7002.*
Dr Frey noted that CAR T-cell therapies, including CTL019, have led to “unprecedented remission rates of between 70% and 90%.” However, immune activation that leads to high response rates also confers significant treatment-related toxicity—namely, CRS.
She reported that, in the 2 trials of adult ALL patients, a high dose of CTL019 led to a 100% response rate and a 100% CRS rate. Splitting the dose over 3 days led to an 86% response rate and a 66% CRS rate. A single low dose reduced efficacy to 33% and CRS to 66%.
Three of 6 patients who received a single high dose developed CRS and died within weeks. All of these patients had infections or sepsis that likely led to their deaths, Dr Frey said. She suggested clinicians aggressively monitor infections and treat with antimicrobials prior to CAR T-cell therapy.
“The infusion dose and schedule of CTL019 correlate with toxicity and response,” she observed. “A fractionated dosing scheme allows for real-time intra-patient dose modification in response to toxicity and the maintenance of high response rates. Concurrent sepsis and CRS confers a poor outcome.”
Dr Frey said future studies will determine the optimal approach to minimize toxicity while maintaining high efficacy. A fractionated dosing scheme is only one way to mitigate CRS. Other attractive approaches include inverse dosing based on disease burden and varying the timing of anti-cytokine-directed therapy.
JCAR015
Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, reported data from a phase 1 clinical trial (NCT01044069) of JCAR015 in 51 adults with relapsed/refractory ALL as abstract 7003.*
Treatment with JCAR015 led to high CR rates and minimal residual disease (MRD)-negativity, regardless of the amount of disease at baseline. However, outcomes were superior among patients with minimal disease at baseline.
For patients with morphologic disease, 77% achieved a CR by 20 days after treatment, and 90% were MRD-negative.
For those with minimal disease, 90% achieved a CR by 25 days after treatment, and 78% were MRD-negative. These patients experienced significantly less CRS and neurotoxicity than patients with morphologic disease.
“High CR and MRD-negativity rates were observed regardless of pre-T-cell burden,” Dr Park noted. “We observed durable responses and survivals in a subset of patients with no subsequent allotransplant in both morphological and minimal disease cohorts.”
*Data in the abstracts differ from the presentations.
No kidding: Adults fare better with pediatric ALL regimen
COPENHAGEN – A study from seven Nordic and Baltic countries adds to the growing body of evidence that young adults with acute lymphoblastic leukemia do better when they are treated like children – that is, with a standard pediatric chemotherapy regimen.
In a study of 221 patients from the age of 18 to 45 with acute lymphoblastic leukemia (ALL) treated with a pediatric regimen and followed for a median of 4 years, the event-free survival rate was 73%, compared with 42% for historical controls, reported Dr. Nina Toft from Herlev (Denmark) University Hospital.
“We have improved the survival for ALL patients 18 to 45 years, and we show that the cure rates are close to those of children. If you compare an adult in the standard-risk group with a child in the standard-risk group, there’s no difference,” she said at a briefing at the annual congress of the European Hematology Association (EHA).
The findings support those from an earlier study reported at the 2014 annual meeting of the American Society of Hematology. That study, conducted by Dr. Wendy Stock of the University of Chicago Medical Center and her colleagues showed that among 296 adolescents and young adults with ALL treated with an intensive pediatric chemotherapy combination regimen rather than a less-intensive adult regimen, the rate of overall survival (OS) at 2 years was 78%, and the event-free survival (EFS) rate was 66%.
In the current study, Dr. Toft and her colleagues looked at event-free survival among 1,509 children and adults (up to age 45) diagnosed with Philadelphia chromosome-negative ALL from July 2008 through December 2014.
The patients were treated in Sweden, Norway, Iceland, Finland Denmark, Lithuania, and Estonia, and all received the Nordic Society for Pediatric Hematology and Oncology (NOPHO)–ALL 2008 protocol, consisting of induction with prednisolone, vincristine, doxorubicin, and pegylated (PEG) asparaginase; consolidation for patients with standard- and intermediate-risk disease, with mercaptopurine, vincristine, PEG asparaginase, and methotrexate; and additional intensive combination chemotherapy for patients with high-risk disease, followed by maintenance with mercaptopurine and/or methotrexate, PEG asparaginase, vincristine, and dexamethasone.
Of the 1,509 patients, 1,022 were children from 1 to 9 years, 266 were preteens/adolescents (10-17 years), and 221 were adults up to age 45.
All patients were stratified by clinical, cytogenetic, and other factors into one of four risk groups: standard, intermediate, high risk, or high risk in first remission after a hematopoietic stem cell transplant, and all were treated with the NOPHO-ALL 2008 protocol.
The investigators found that in general older patients had higher-risk disease. Nonetheless, treatment intervals and severe toxicities, with the exception of osteonecrosis and thrombosis, were “almost identical” between adults and children, Dr. Toft said.
After a median of 4 years of follow-up, 16 patients, 3 of whom were adults, had died during the induction phase, and 50 patients (12 adults) had died in first remission.
There were a total of 123 relapses (36 among adults), and 1 adult and 12 children were diagnosed with a second malignancy.
Overall 5-year EFS rates were 88% for patients aged 1-9 years, 79% for those 10-17 years, and 73% for those 18-45, and these differences were significant (P less than .001). However, when EFS was stratified by risk group, EFS rates were lower only for adults with intermediate-risk disease (78% vs. 90% for 1- to 9-year-olds and 82% for 10- to 17-year-olds, P = .002).
Although the investigators did not formally report overall survival data, it was approximately 95% among all children in the cohort, and approximately 76% among the adults, Dr. Toft said in response to a reporter.
“What we need now is further cooperation, because we need to unite and get more patients so that we can show new developments faster. We also need to find new risk criteria, because of the intermediate-risk group; something is missing for the adults. We need more cytogenetics, we need something to define the patients as high risk or not,” Dr. Toft said.
“We also need new drugs, because with this method we’ve reached the limit of toxicity,” she added.
The study was sponsored by health authorities in the participating countries. Dr. Toft reported no relevant financial disclosures.
COPENHAGEN – A study from seven Nordic and Baltic countries adds to the growing body of evidence that young adults with acute lymphoblastic leukemia do better when they are treated like children – that is, with a standard pediatric chemotherapy regimen.
In a study of 221 patients from the age of 18 to 45 with acute lymphoblastic leukemia (ALL) treated with a pediatric regimen and followed for a median of 4 years, the event-free survival rate was 73%, compared with 42% for historical controls, reported Dr. Nina Toft from Herlev (Denmark) University Hospital.
“We have improved the survival for ALL patients 18 to 45 years, and we show that the cure rates are close to those of children. If you compare an adult in the standard-risk group with a child in the standard-risk group, there’s no difference,” she said at a briefing at the annual congress of the European Hematology Association (EHA).
The findings support those from an earlier study reported at the 2014 annual meeting of the American Society of Hematology. That study, conducted by Dr. Wendy Stock of the University of Chicago Medical Center and her colleagues showed that among 296 adolescents and young adults with ALL treated with an intensive pediatric chemotherapy combination regimen rather than a less-intensive adult regimen, the rate of overall survival (OS) at 2 years was 78%, and the event-free survival (EFS) rate was 66%.
In the current study, Dr. Toft and her colleagues looked at event-free survival among 1,509 children and adults (up to age 45) diagnosed with Philadelphia chromosome-negative ALL from July 2008 through December 2014.
The patients were treated in Sweden, Norway, Iceland, Finland Denmark, Lithuania, and Estonia, and all received the Nordic Society for Pediatric Hematology and Oncology (NOPHO)–ALL 2008 protocol, consisting of induction with prednisolone, vincristine, doxorubicin, and pegylated (PEG) asparaginase; consolidation for patients with standard- and intermediate-risk disease, with mercaptopurine, vincristine, PEG asparaginase, and methotrexate; and additional intensive combination chemotherapy for patients with high-risk disease, followed by maintenance with mercaptopurine and/or methotrexate, PEG asparaginase, vincristine, and dexamethasone.
Of the 1,509 patients, 1,022 were children from 1 to 9 years, 266 were preteens/adolescents (10-17 years), and 221 were adults up to age 45.
All patients were stratified by clinical, cytogenetic, and other factors into one of four risk groups: standard, intermediate, high risk, or high risk in first remission after a hematopoietic stem cell transplant, and all were treated with the NOPHO-ALL 2008 protocol.
The investigators found that in general older patients had higher-risk disease. Nonetheless, treatment intervals and severe toxicities, with the exception of osteonecrosis and thrombosis, were “almost identical” between adults and children, Dr. Toft said.
After a median of 4 years of follow-up, 16 patients, 3 of whom were adults, had died during the induction phase, and 50 patients (12 adults) had died in first remission.
There were a total of 123 relapses (36 among adults), and 1 adult and 12 children were diagnosed with a second malignancy.
Overall 5-year EFS rates were 88% for patients aged 1-9 years, 79% for those 10-17 years, and 73% for those 18-45, and these differences were significant (P less than .001). However, when EFS was stratified by risk group, EFS rates were lower only for adults with intermediate-risk disease (78% vs. 90% for 1- to 9-year-olds and 82% for 10- to 17-year-olds, P = .002).
Although the investigators did not formally report overall survival data, it was approximately 95% among all children in the cohort, and approximately 76% among the adults, Dr. Toft said in response to a reporter.
“What we need now is further cooperation, because we need to unite and get more patients so that we can show new developments faster. We also need to find new risk criteria, because of the intermediate-risk group; something is missing for the adults. We need more cytogenetics, we need something to define the patients as high risk or not,” Dr. Toft said.
“We also need new drugs, because with this method we’ve reached the limit of toxicity,” she added.
The study was sponsored by health authorities in the participating countries. Dr. Toft reported no relevant financial disclosures.
COPENHAGEN – A study from seven Nordic and Baltic countries adds to the growing body of evidence that young adults with acute lymphoblastic leukemia do better when they are treated like children – that is, with a standard pediatric chemotherapy regimen.
In a study of 221 patients from the age of 18 to 45 with acute lymphoblastic leukemia (ALL) treated with a pediatric regimen and followed for a median of 4 years, the event-free survival rate was 73%, compared with 42% for historical controls, reported Dr. Nina Toft from Herlev (Denmark) University Hospital.
“We have improved the survival for ALL patients 18 to 45 years, and we show that the cure rates are close to those of children. If you compare an adult in the standard-risk group with a child in the standard-risk group, there’s no difference,” she said at a briefing at the annual congress of the European Hematology Association (EHA).
The findings support those from an earlier study reported at the 2014 annual meeting of the American Society of Hematology. That study, conducted by Dr. Wendy Stock of the University of Chicago Medical Center and her colleagues showed that among 296 adolescents and young adults with ALL treated with an intensive pediatric chemotherapy combination regimen rather than a less-intensive adult regimen, the rate of overall survival (OS) at 2 years was 78%, and the event-free survival (EFS) rate was 66%.
In the current study, Dr. Toft and her colleagues looked at event-free survival among 1,509 children and adults (up to age 45) diagnosed with Philadelphia chromosome-negative ALL from July 2008 through December 2014.
The patients were treated in Sweden, Norway, Iceland, Finland Denmark, Lithuania, and Estonia, and all received the Nordic Society for Pediatric Hematology and Oncology (NOPHO)–ALL 2008 protocol, consisting of induction with prednisolone, vincristine, doxorubicin, and pegylated (PEG) asparaginase; consolidation for patients with standard- and intermediate-risk disease, with mercaptopurine, vincristine, PEG asparaginase, and methotrexate; and additional intensive combination chemotherapy for patients with high-risk disease, followed by maintenance with mercaptopurine and/or methotrexate, PEG asparaginase, vincristine, and dexamethasone.
Of the 1,509 patients, 1,022 were children from 1 to 9 years, 266 were preteens/adolescents (10-17 years), and 221 were adults up to age 45.
All patients were stratified by clinical, cytogenetic, and other factors into one of four risk groups: standard, intermediate, high risk, or high risk in first remission after a hematopoietic stem cell transplant, and all were treated with the NOPHO-ALL 2008 protocol.
The investigators found that in general older patients had higher-risk disease. Nonetheless, treatment intervals and severe toxicities, with the exception of osteonecrosis and thrombosis, were “almost identical” between adults and children, Dr. Toft said.
After a median of 4 years of follow-up, 16 patients, 3 of whom were adults, had died during the induction phase, and 50 patients (12 adults) had died in first remission.
There were a total of 123 relapses (36 among adults), and 1 adult and 12 children were diagnosed with a second malignancy.
Overall 5-year EFS rates were 88% for patients aged 1-9 years, 79% for those 10-17 years, and 73% for those 18-45, and these differences were significant (P less than .001). However, when EFS was stratified by risk group, EFS rates were lower only for adults with intermediate-risk disease (78% vs. 90% for 1- to 9-year-olds and 82% for 10- to 17-year-olds, P = .002).
Although the investigators did not formally report overall survival data, it was approximately 95% among all children in the cohort, and approximately 76% among the adults, Dr. Toft said in response to a reporter.
“What we need now is further cooperation, because we need to unite and get more patients so that we can show new developments faster. We also need to find new risk criteria, because of the intermediate-risk group; something is missing for the adults. We need more cytogenetics, we need something to define the patients as high risk or not,” Dr. Toft said.
“We also need new drugs, because with this method we’ve reached the limit of toxicity,” she added.
The study was sponsored by health authorities in the participating countries. Dr. Toft reported no relevant financial disclosures.
AT THE EHA CONGRESS
Key clinical point: Younger adults with acute lymphoblastic leukemia have better outcomes when treated with more intensive chemotherapy regimens designed for children with ALL.
Major finding: No significant differences were found in event-free survival between children and adults, except for a slightly lower EFS among adults with intermediate risk.
Data source: A prospective study of 1,509 children and adults with ALL in seven Nordic and Baltic countries.
Disclosures: The study was sponsored by health authorities in the participating countries. Dr. Toft reported no relevant financial disclosures.
Immunotherapy ‘outcompetes’ chemo in rel/ref B-ALL
COPENHAGEN—Interim results from the phase 3 TOWER trial suggest blinatumomab can prolong overall survival (OS) when compared to standard care in adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).
The median OS for patients treated with blinatumomab was nearly double the median OS of patients who received standard chemotherapy (investigator’s choice of 4 different regimens).
Based on these results, Amgen, the company sponsoring the trial, decided to stop it early.
“This was the first study to show that immunotherapy can outcompete chemotherapy,” said Max S. Topp, MD, of University Hospital of Wuerzburg in Germany.
Dr Topp presented results from this study at the 21st Congress of the European Hematology Association (abstract S149).
Patients and treatment
The TOWER trial enrolled and randomized 405 patients with Ph-negative, relapsed/refractory B-ALL, and 376 of them ultimately received treatment.
The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):
- FLAG (fludarabine, high-dose cytarabine, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
- A high-dose cytarabine-based regimen (n=19, 17%)
- A high-dose methotrexate-based regimen (n=22, 20%)
- A clofarabine-based regimen (n=19, 17%).
Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.
If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.
Patient characteristics were similar between the treatment arms. The median age was 37 in both arms (overall range, 18-80). About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.
More than 30% of patients in both arms had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT), and about 20% were primary refractory. Roughly 30% of blinatumomab-treated patients were refractory to salvage therapy, as were more than 20% of chemotherapy-treated patients.
Response and survival
During induction, in the intent-to-treat population (n=271 in the blinatumomab arm and 134 in the chemotherapy arm), the overall response rate was 44% in the blinatumomab arm and 25% in the chemotherapy arm (P<0.001). The complete response rates were 34% and 16%, respectively.
Among patients who received their assigned treatment (n=267 in the blinatumomab arm and 109 in the chemotherapy arm), the overall response rates were 45% and 30%, respectively (P=0.007).
In the intent-to-treat population, the median OS was 7.7 months (95% CI, 5.6-9.6) in the blinatumomab arm and 4 months (95% CI, 2.9-5.3) in the chemotherapy arm (hazard ratio=0.71, P=0.012). The survival curves were similar in the as-treated population.
Dr Topp noted that the improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.
Dr Topp and his colleagues also considered the effect post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).
When the researchers censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).
Safety
In the as-treated population, 99% of patients in both arms experienced adverse events (AEs).
The incidence of grade 3 AEs was 37% in the blinatumomab arm and 30% in the chemotherapy arm. The incidence of grade 4 AEs was 31% and 44%, respectively. The incidence of grade 5 AEs was 19% and 17%, respectively.
Grade 3 or higher AEs of interest, according to Dr Topp, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), neurologic events (9% and 8%, respectively), and cytokine release syndrome (5% and 0%, respectively).
Seven patients—5 in the blinatumomab arm and 2 in the chemotherapy arm—who did not undergo allo-HSCT died during the study without documented relapse.
COPENHAGEN—Interim results from the phase 3 TOWER trial suggest blinatumomab can prolong overall survival (OS) when compared to standard care in adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).
The median OS for patients treated with blinatumomab was nearly double the median OS of patients who received standard chemotherapy (investigator’s choice of 4 different regimens).
Based on these results, Amgen, the company sponsoring the trial, decided to stop it early.
“This was the first study to show that immunotherapy can outcompete chemotherapy,” said Max S. Topp, MD, of University Hospital of Wuerzburg in Germany.
Dr Topp presented results from this study at the 21st Congress of the European Hematology Association (abstract S149).
Patients and treatment
The TOWER trial enrolled and randomized 405 patients with Ph-negative, relapsed/refractory B-ALL, and 376 of them ultimately received treatment.
The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):
- FLAG (fludarabine, high-dose cytarabine, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
- A high-dose cytarabine-based regimen (n=19, 17%)
- A high-dose methotrexate-based regimen (n=22, 20%)
- A clofarabine-based regimen (n=19, 17%).
Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.
If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.
Patient characteristics were similar between the treatment arms. The median age was 37 in both arms (overall range, 18-80). About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.
More than 30% of patients in both arms had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT), and about 20% were primary refractory. Roughly 30% of blinatumomab-treated patients were refractory to salvage therapy, as were more than 20% of chemotherapy-treated patients.
Response and survival
During induction, in the intent-to-treat population (n=271 in the blinatumomab arm and 134 in the chemotherapy arm), the overall response rate was 44% in the blinatumomab arm and 25% in the chemotherapy arm (P<0.001). The complete response rates were 34% and 16%, respectively.
Among patients who received their assigned treatment (n=267 in the blinatumomab arm and 109 in the chemotherapy arm), the overall response rates were 45% and 30%, respectively (P=0.007).
In the intent-to-treat population, the median OS was 7.7 months (95% CI, 5.6-9.6) in the blinatumomab arm and 4 months (95% CI, 2.9-5.3) in the chemotherapy arm (hazard ratio=0.71, P=0.012). The survival curves were similar in the as-treated population.
Dr Topp noted that the improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.
Dr Topp and his colleagues also considered the effect post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).
When the researchers censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).
Safety
In the as-treated population, 99% of patients in both arms experienced adverse events (AEs).
The incidence of grade 3 AEs was 37% in the blinatumomab arm and 30% in the chemotherapy arm. The incidence of grade 4 AEs was 31% and 44%, respectively. The incidence of grade 5 AEs was 19% and 17%, respectively.
Grade 3 or higher AEs of interest, according to Dr Topp, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), neurologic events (9% and 8%, respectively), and cytokine release syndrome (5% and 0%, respectively).
Seven patients—5 in the blinatumomab arm and 2 in the chemotherapy arm—who did not undergo allo-HSCT died during the study without documented relapse.
COPENHAGEN—Interim results from the phase 3 TOWER trial suggest blinatumomab can prolong overall survival (OS) when compared to standard care in adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).
The median OS for patients treated with blinatumomab was nearly double the median OS of patients who received standard chemotherapy (investigator’s choice of 4 different regimens).
Based on these results, Amgen, the company sponsoring the trial, decided to stop it early.
“This was the first study to show that immunotherapy can outcompete chemotherapy,” said Max S. Topp, MD, of University Hospital of Wuerzburg in Germany.
Dr Topp presented results from this study at the 21st Congress of the European Hematology Association (abstract S149).
Patients and treatment
The TOWER trial enrolled and randomized 405 patients with Ph-negative, relapsed/refractory B-ALL, and 376 of them ultimately received treatment.
The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):
- FLAG (fludarabine, high-dose cytarabine, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
- A high-dose cytarabine-based regimen (n=19, 17%)
- A high-dose methotrexate-based regimen (n=22, 20%)
- A clofarabine-based regimen (n=19, 17%).
Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.
If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.
Patient characteristics were similar between the treatment arms. The median age was 37 in both arms (overall range, 18-80). About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.
More than 30% of patients in both arms had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT), and about 20% were primary refractory. Roughly 30% of blinatumomab-treated patients were refractory to salvage therapy, as were more than 20% of chemotherapy-treated patients.
Response and survival
During induction, in the intent-to-treat population (n=271 in the blinatumomab arm and 134 in the chemotherapy arm), the overall response rate was 44% in the blinatumomab arm and 25% in the chemotherapy arm (P<0.001). The complete response rates were 34% and 16%, respectively.
Among patients who received their assigned treatment (n=267 in the blinatumomab arm and 109 in the chemotherapy arm), the overall response rates were 45% and 30%, respectively (P=0.007).
In the intent-to-treat population, the median OS was 7.7 months (95% CI, 5.6-9.6) in the blinatumomab arm and 4 months (95% CI, 2.9-5.3) in the chemotherapy arm (hazard ratio=0.71, P=0.012). The survival curves were similar in the as-treated population.
Dr Topp noted that the improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.
Dr Topp and his colleagues also considered the effect post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).
When the researchers censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).
Safety
In the as-treated population, 99% of patients in both arms experienced adverse events (AEs).
The incidence of grade 3 AEs was 37% in the blinatumomab arm and 30% in the chemotherapy arm. The incidence of grade 4 AEs was 31% and 44%, respectively. The incidence of grade 5 AEs was 19% and 17%, respectively.
Grade 3 or higher AEs of interest, according to Dr Topp, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), neurologic events (9% and 8%, respectively), and cytokine release syndrome (5% and 0%, respectively).
Seven patients—5 in the blinatumomab arm and 2 in the chemotherapy arm—who did not undergo allo-HSCT died during the study without documented relapse.
ESA benefits lower-risk MDS patients
COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.
In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.
The ESA also significantly improved erythroid response.
In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.
Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.
Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.
So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.
The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).
During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.
At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.
Patient characteristics
Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.
In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).
In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.
Dosing
During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.
Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.
Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.
Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).
During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.
Efficacy
During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).
During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.
During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.
All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.
During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.
Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).
For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.
Safety
During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.
The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.
The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.
One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.
AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).
During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.
The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.
The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.
COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.
In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.
The ESA also significantly improved erythroid response.
In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.
Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.
Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.
So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.
The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).
During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.
At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.
Patient characteristics
Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.
In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).
In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.
Dosing
During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.
Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.
Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.
Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).
During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.
Efficacy
During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).
During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.
During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.
All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.
During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.
Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).
For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.
Safety
During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.
The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.
The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.
One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.
AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).
During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.
The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.
The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.
COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.
In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.
The ESA also significantly improved erythroid response.
In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.
Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.
Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.
So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.
The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).
During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.
At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.
Patient characteristics
Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.
In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).
In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.
Dosing
During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.
Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.
Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.
Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).
During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.
Efficacy
During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).
During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.
During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.
All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.
During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.
Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).
For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.
Safety
During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.
The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.
The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.
One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.
AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).
During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.
The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.
The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.