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FDA grants priority review to NDA for copanlisib
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for copanlisib, an intravenous PI3K inhibitor.
The NDA is for copanlisib as a treatment for patients with relapsed or refractory follicular lymphoma (FL) who have received at least 2 prior therapies.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The application for copanlisib is supported by data from the CHRONOS-1 trial. This phase 2 trial enrolled 141 patients with relapsed/refractory, indolent non-Hodgkin lymphoma. Most of these patients had FL (n=104).
In all patients, copanlisib produced an objective response rate of 59.2%, with a complete response rate of 12%. The median duration of response exceeded 98 weeks.
In the FL subset, copanlisib produced an overall response rate of 58.7%, with a complete response rate of 14.4%. The median duration of response exceeded 52 weeks.
In the entire cohort, there were 3 deaths considered related to copanlisib.
The most common treatment-related adverse events were transient hyperglycemia (all grades: 49%/grade 3-4: 40%) and hypertension (all grades: 29%/grade 3: 23%).
“Patients with relapsed or refractory follicular lymphoma have a poor prognosis, and new treatment options which are well tolerated and effective are needed to prolong progression-free survival and improve quality of life for these patients,” said Martin Dreyling, MD, a professor at the University of Munich Hospital (Grosshadern) in Germany and lead investigator of the CHRONOS-1 study.
“Based on the CHRONOS-1 results, where copanlisib showed durable efficacy with a manageable and distinct safety profile, the compound may have the potential to address this unmet medical need.”
Data from CHRONOS-1 were presented at the AACR Annual Meeting 2017.
Data from the FL subset of the trial are scheduled to be presented at the 2017 ASCO Annual Meeting in June.
Copanlisib is being developed by Bayer. The compound has fast track and orphan drug designations from the FDA.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the NDA or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA. 
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for copanlisib, an intravenous PI3K inhibitor.
The NDA is for copanlisib as a treatment for patients with relapsed or refractory follicular lymphoma (FL) who have received at least 2 prior therapies.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The application for copanlisib is supported by data from the CHRONOS-1 trial. This phase 2 trial enrolled 141 patients with relapsed/refractory, indolent non-Hodgkin lymphoma. Most of these patients had FL (n=104).
In all patients, copanlisib produced an objective response rate of 59.2%, with a complete response rate of 12%. The median duration of response exceeded 98 weeks.
In the FL subset, copanlisib produced an overall response rate of 58.7%, with a complete response rate of 14.4%. The median duration of response exceeded 52 weeks.
In the entire cohort, there were 3 deaths considered related to copanlisib.
The most common treatment-related adverse events were transient hyperglycemia (all grades: 49%/grade 3-4: 40%) and hypertension (all grades: 29%/grade 3: 23%).
“Patients with relapsed or refractory follicular lymphoma have a poor prognosis, and new treatment options which are well tolerated and effective are needed to prolong progression-free survival and improve quality of life for these patients,” said Martin Dreyling, MD, a professor at the University of Munich Hospital (Grosshadern) in Germany and lead investigator of the CHRONOS-1 study.
“Based on the CHRONOS-1 results, where copanlisib showed durable efficacy with a manageable and distinct safety profile, the compound may have the potential to address this unmet medical need.”
Data from CHRONOS-1 were presented at the AACR Annual Meeting 2017.
Data from the FL subset of the trial are scheduled to be presented at the 2017 ASCO Annual Meeting in June.
Copanlisib is being developed by Bayer. The compound has fast track and orphan drug designations from the FDA.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the NDA or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for copanlisib, an intravenous PI3K inhibitor.
The NDA is for copanlisib as a treatment for patients with relapsed or refractory follicular lymphoma (FL) who have received at least 2 prior therapies.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The application for copanlisib is supported by data from the CHRONOS-1 trial. This phase 2 trial enrolled 141 patients with relapsed/refractory, indolent non-Hodgkin lymphoma. Most of these patients had FL (n=104).
In all patients, copanlisib produced an objective response rate of 59.2%, with a complete response rate of 12%. The median duration of response exceeded 98 weeks.
In the FL subset, copanlisib produced an overall response rate of 58.7%, with a complete response rate of 14.4%. The median duration of response exceeded 52 weeks.
In the entire cohort, there were 3 deaths considered related to copanlisib.
The most common treatment-related adverse events were transient hyperglycemia (all grades: 49%/grade 3-4: 40%) and hypertension (all grades: 29%/grade 3: 23%).
“Patients with relapsed or refractory follicular lymphoma have a poor prognosis, and new treatment options which are well tolerated and effective are needed to prolong progression-free survival and improve quality of life for these patients,” said Martin Dreyling, MD, a professor at the University of Munich Hospital (Grosshadern) in Germany and lead investigator of the CHRONOS-1 study.
“Based on the CHRONOS-1 results, where copanlisib showed durable efficacy with a manageable and distinct safety profile, the compound may have the potential to address this unmet medical need.”
Data from CHRONOS-1 were presented at the AACR Annual Meeting 2017.
Data from the FL subset of the trial are scheduled to be presented at the 2017 ASCO Annual Meeting in June.
Copanlisib is being developed by Bayer. The compound has fast track and orphan drug designations from the FDA.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the NDA or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Subcutaneous rituximab safe, effective for follicular lymphoma
Efficacy and safety profiles were similar for subcutaneous and standard IV rituximab when given as first-line therapy to adults with follicular lymphoma, based on results of a phase III clinical trial published online in Lancet Haematology.
Administering rituximab by IV infusion can take up to 6 hours to complete and requires continuous monitoring. Subcutaneous delivery takes approximately 6 minutes using a new rituximab formulation that is 12 times more concentrated to reduce the administered volume. The new formulation is expected to reduce the burden of treatment for patients, as well as for the health care system, said Andrew Davies, PhD, of the Cancer Research UK Centre, Southampton, and his associates.
They compared the two agents in an international open-label trial funded by Hoffmann-La Roche, maker of the subcutaneous formulation. Adult patients at 113 medical centers in 30 countries were randomly assigned to receive either IV (205 patients) or subcutaneous (205 patients) rituximab during induction therapy with six to eight cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CVP (cyclophosphamide, vincristine, and prednisone). They continued with rituximab as maintenance therapy every 2 months for 2 years. The median duration of treatment was 27 months, and median follow-up was 37 months.
The primary efficacy end point – overall (complete or partial) response rate at the end of induction, based on investigator assessment confirmed by an independent review panel of radiologists – was 84.9% with IV and 84.4% with subcutaneous rituximab, a nonsignificant difference. Similarly, the overall response rate at the end of maintenance therapy was not significantly different between the two groups, at 78.1% and 77.9%, respectively.
Progression-free survival (hazard ratio, 0.84) and event-free survival (HR, 0.91) also did not differ significantly between the two study groups, the investigators said (Lancet Haematol. 2017 doi: 10.1016/S2352.3026(17)30078-9).
The rates of adverse events, grade 3 or higher adverse events, and serious adverse events also were similar for IV and subcutaneous formulations of rituximab. “Administration-related reactions were more common in the subcutaneous group but were predominantly mild-to-moderate local injection-site reactions, such as mild pain, swelling and erythema, reflecting the expected change in safety profile when switching to the subcutaneous route of administration,” Dr. Davies and his associates said.
These results indicate that subcutaneous administration of rituximab along with chemotherapy doesn’t compromise the agent’s antilymphoma activity, they added.
Efficacy and safety profiles were similar for subcutaneous and standard IV rituximab when given as first-line therapy to adults with follicular lymphoma, based on results of a phase III clinical trial published online in Lancet Haematology.
Administering rituximab by IV infusion can take up to 6 hours to complete and requires continuous monitoring. Subcutaneous delivery takes approximately 6 minutes using a new rituximab formulation that is 12 times more concentrated to reduce the administered volume. The new formulation is expected to reduce the burden of treatment for patients, as well as for the health care system, said Andrew Davies, PhD, of the Cancer Research UK Centre, Southampton, and his associates.
They compared the two agents in an international open-label trial funded by Hoffmann-La Roche, maker of the subcutaneous formulation. Adult patients at 113 medical centers in 30 countries were randomly assigned to receive either IV (205 patients) or subcutaneous (205 patients) rituximab during induction therapy with six to eight cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CVP (cyclophosphamide, vincristine, and prednisone). They continued with rituximab as maintenance therapy every 2 months for 2 years. The median duration of treatment was 27 months, and median follow-up was 37 months.
The primary efficacy end point – overall (complete or partial) response rate at the end of induction, based on investigator assessment confirmed by an independent review panel of radiologists – was 84.9% with IV and 84.4% with subcutaneous rituximab, a nonsignificant difference. Similarly, the overall response rate at the end of maintenance therapy was not significantly different between the two groups, at 78.1% and 77.9%, respectively.
Progression-free survival (hazard ratio, 0.84) and event-free survival (HR, 0.91) also did not differ significantly between the two study groups, the investigators said (Lancet Haematol. 2017 doi: 10.1016/S2352.3026(17)30078-9).
The rates of adverse events, grade 3 or higher adverse events, and serious adverse events also were similar for IV and subcutaneous formulations of rituximab. “Administration-related reactions were more common in the subcutaneous group but were predominantly mild-to-moderate local injection-site reactions, such as mild pain, swelling and erythema, reflecting the expected change in safety profile when switching to the subcutaneous route of administration,” Dr. Davies and his associates said.
These results indicate that subcutaneous administration of rituximab along with chemotherapy doesn’t compromise the agent’s antilymphoma activity, they added.
Efficacy and safety profiles were similar for subcutaneous and standard IV rituximab when given as first-line therapy to adults with follicular lymphoma, based on results of a phase III clinical trial published online in Lancet Haematology.
Administering rituximab by IV infusion can take up to 6 hours to complete and requires continuous monitoring. Subcutaneous delivery takes approximately 6 minutes using a new rituximab formulation that is 12 times more concentrated to reduce the administered volume. The new formulation is expected to reduce the burden of treatment for patients, as well as for the health care system, said Andrew Davies, PhD, of the Cancer Research UK Centre, Southampton, and his associates.
They compared the two agents in an international open-label trial funded by Hoffmann-La Roche, maker of the subcutaneous formulation. Adult patients at 113 medical centers in 30 countries were randomly assigned to receive either IV (205 patients) or subcutaneous (205 patients) rituximab during induction therapy with six to eight cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CVP (cyclophosphamide, vincristine, and prednisone). They continued with rituximab as maintenance therapy every 2 months for 2 years. The median duration of treatment was 27 months, and median follow-up was 37 months.
The primary efficacy end point – overall (complete or partial) response rate at the end of induction, based on investigator assessment confirmed by an independent review panel of radiologists – was 84.9% with IV and 84.4% with subcutaneous rituximab, a nonsignificant difference. Similarly, the overall response rate at the end of maintenance therapy was not significantly different between the two groups, at 78.1% and 77.9%, respectively.
Progression-free survival (hazard ratio, 0.84) and event-free survival (HR, 0.91) also did not differ significantly between the two study groups, the investigators said (Lancet Haematol. 2017 doi: 10.1016/S2352.3026(17)30078-9).
The rates of adverse events, grade 3 or higher adverse events, and serious adverse events also were similar for IV and subcutaneous formulations of rituximab. “Administration-related reactions were more common in the subcutaneous group but were predominantly mild-to-moderate local injection-site reactions, such as mild pain, swelling and erythema, reflecting the expected change in safety profile when switching to the subcutaneous route of administration,” Dr. Davies and his associates said.
These results indicate that subcutaneous administration of rituximab along with chemotherapy doesn’t compromise the agent’s antilymphoma activity, they added.
FROM LANCET HAEMATOLOGY
Key clinical point: Subcutaneous rituximab had efficacy and safety profiles similar to those of standard IV rituximab when given as first-line therapy to adults with follicular lymphoma.
Major finding: The primary efficacy end point – overall response rate at the end of induction – was 84.9% with IV and 84.4% with subcutaneous rituximab.
Data source: An international randomized controlled phase III trial involving 410 adults followed for 3 years.
Disclosures: This trial was funded by Hoffmann-La Roche, maker of the subcutaneous formulation of rituximab. The pharmaceutical company also was involved in the design and conduct of the trial, collection and interpretation of the data, and writing of the results. Dr. Davies reported ties to Hoffmann-La Roche and numerous other drug companies.
Drug receives fast track designation for follicular lymphoma
The US Food and Drug Administration (FDA) has granted fast track designation to the EZH2 inhibitor tazemetostat as a treatment for relapsed or refractory follicular lymphoma, with or without EZH2-activating mutations.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review.
In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat also has fast track designation from the FDA as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2-activating mutations.
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat can produce durable responses in patients with advanced non-Hodgkin lymphomas, including follicular lymphoma and DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Tazemetostat is currently under investigation in a phase 2 trial of adults with relapsed or refractory DLBCL or follicular lymphoma.
Interim efficacy and safety data from this study are scheduled to be presented at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, on June 14, 2017, at 2:00 pm CET.
Tazemetostat is being developed by Epizyme, Inc.
The US Food and Drug Administration (FDA) has granted fast track designation to the EZH2 inhibitor tazemetostat as a treatment for relapsed or refractory follicular lymphoma, with or without EZH2-activating mutations.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review.
In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat also has fast track designation from the FDA as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2-activating mutations.
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat can produce durable responses in patients with advanced non-Hodgkin lymphomas, including follicular lymphoma and DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Tazemetostat is currently under investigation in a phase 2 trial of adults with relapsed or refractory DLBCL or follicular lymphoma.
Interim efficacy and safety data from this study are scheduled to be presented at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, on June 14, 2017, at 2:00 pm CET.
Tazemetostat is being developed by Epizyme, Inc.
The US Food and Drug Administration (FDA) has granted fast track designation to the EZH2 inhibitor tazemetostat as a treatment for relapsed or refractory follicular lymphoma, with or without EZH2-activating mutations.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review.
In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat also has fast track designation from the FDA as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2-activating mutations.
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat can produce durable responses in patients with advanced non-Hodgkin lymphomas, including follicular lymphoma and DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Tazemetostat is currently under investigation in a phase 2 trial of adults with relapsed or refractory DLBCL or follicular lymphoma.
Interim efficacy and safety data from this study are scheduled to be presented at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, on June 14, 2017, at 2:00 pm CET.
Tazemetostat is being developed by Epizyme, Inc.
In mantle cell lymphoma, triple therapy proves too toxic
Combined idelalisib, lenalidomide, and rituximab proved excessively toxic for the treatment of relapsed and refractory mantle cell and follicular lymphoma in two phase I trials conducted by the Alliance for Clinical Trials in Oncology.
The unexpected outcome, which led to early study termination, underscores the need for caution as new treatment combinations are proposed, Sonali M. Smith, MD, of the University of Chicago and her colleagues said in The Lancet Haematology.
In four of the first eight patients enrolled in the mantle cell lymphoma (A051201) and follicular lymphoma (A051202) phase I trials between July 9, 2013, and Sept. 30, 2014, unexpected dose-limiting toxicities occurred, including grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash.
The adverse events occurred between 9 and 20 days after treatment initiation and coincided with rituximab infusions, the researchers said. No treatment-related deaths occurred (Lancet Haematol. 2017 Apr;4:e176-82).
Overall, 8 of 11 patients were removed from treatment because of an adverse event, and 3 of those required intensive care unit level of care.
Although rituximab was removed in both trials, two of the remaining three patients in the studies, including three with mantle cell lymphoma and eight with follicular lymphoma, experienced grade 3 rashes, and one had grade 3 AST elevations. In those with mantle cell lymphoma, the most common grade 3-4 adverse events were ALT elevations and rash. In those with follicular lymphoma, the most common grade 3-4 adverse events were neutropenia and rash.
“Given the inability to deliver treatment due to toxicity, both studies were permanently closed,” the researchers wrote, noting that the primary endpoint of safety and tolerability was not met.
The trials had the overall goal of developing targeted regimens to replace cytotoxic therapy.
“Both ... trials were designed to capitalize on the clinical synergy of lenalidomide and rituximab observed in previous trials by adding the highly specific PI3K delta inhibitor, idelalisib, for patients with relapsed mantle cell lymphoma and follicular lymphoma,” they said.
Previously available data implied that lenalidomide plus rituximab would be a safe backbone for therapy, and there was clinical rationale for adding idelalisib to that combination, they explained.
“Overall, our brief experience underscores the limited knowledge regarding drug interactions and off-target effects and serves as a cautionary note in developing biological agents in combination and against ad-hoc combinations outside of carefully monitored clinical trials,” they said.
The researchers noted that the nature of the toxicities observed in these trials supports an immune-activated state characterized by excessive inflammation.
“A more detailed assessment of effect on cytokines, T-cell subsets, natural killer cells, and clinical features predictive of toxicity and response should be included in any further testing of these classes of agents, and they should never be combined outside of a carefully designed and diligently monitored clinical trial setting,” they concluded.
The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.
The findings by Dr. Smith and her colleagues add to several other reported studies that involved unexpected toxicities with various combinations of targeted agents in lymphoid malignancies.
Combinations of B-cell receptor signaling inhibitors can lead to immune dysregulation, which can be acute and severe when combined with immunomodulatory agents.
While the study of rational targeted combinations continues to hold immense potential in both untreated and relapsed/refractory disease, the combination must be thoroughly studied in the context of carefully and conservatively designed clinical trials.
Given the unpredictable nature of adverse events, the use of novel combinations outside of a clinical trial should be strongly discouraged.
Patrick M. Reagan, MD , and Paul M. Barr, MD , are with the James P. Wilmot Cancer Institute, University of Rochester, New York. Dr. Reagan reported having no disclosures. Dr. Barr has consulted for Gilead, Pharmacyclics, AbbVie, and Celgene. They made their remarks in an editorial that accompanied the article.
The findings by Dr. Smith and her colleagues add to several other reported studies that involved unexpected toxicities with various combinations of targeted agents in lymphoid malignancies.
Combinations of B-cell receptor signaling inhibitors can lead to immune dysregulation, which can be acute and severe when combined with immunomodulatory agents.
While the study of rational targeted combinations continues to hold immense potential in both untreated and relapsed/refractory disease, the combination must be thoroughly studied in the context of carefully and conservatively designed clinical trials.
Given the unpredictable nature of adverse events, the use of novel combinations outside of a clinical trial should be strongly discouraged.
Patrick M. Reagan, MD , and Paul M. Barr, MD , are with the James P. Wilmot Cancer Institute, University of Rochester, New York. Dr. Reagan reported having no disclosures. Dr. Barr has consulted for Gilead, Pharmacyclics, AbbVie, and Celgene. They made their remarks in an editorial that accompanied the article.
The findings by Dr. Smith and her colleagues add to several other reported studies that involved unexpected toxicities with various combinations of targeted agents in lymphoid malignancies.
Combinations of B-cell receptor signaling inhibitors can lead to immune dysregulation, which can be acute and severe when combined with immunomodulatory agents.
While the study of rational targeted combinations continues to hold immense potential in both untreated and relapsed/refractory disease, the combination must be thoroughly studied in the context of carefully and conservatively designed clinical trials.
Given the unpredictable nature of adverse events, the use of novel combinations outside of a clinical trial should be strongly discouraged.
Patrick M. Reagan, MD , and Paul M. Barr, MD , are with the James P. Wilmot Cancer Institute, University of Rochester, New York. Dr. Reagan reported having no disclosures. Dr. Barr has consulted for Gilead, Pharmacyclics, AbbVie, and Celgene. They made their remarks in an editorial that accompanied the article.
Combined idelalisib, lenalidomide, and rituximab proved excessively toxic for the treatment of relapsed and refractory mantle cell and follicular lymphoma in two phase I trials conducted by the Alliance for Clinical Trials in Oncology.
The unexpected outcome, which led to early study termination, underscores the need for caution as new treatment combinations are proposed, Sonali M. Smith, MD, of the University of Chicago and her colleagues said in The Lancet Haematology.
In four of the first eight patients enrolled in the mantle cell lymphoma (A051201) and follicular lymphoma (A051202) phase I trials between July 9, 2013, and Sept. 30, 2014, unexpected dose-limiting toxicities occurred, including grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash.
The adverse events occurred between 9 and 20 days after treatment initiation and coincided with rituximab infusions, the researchers said. No treatment-related deaths occurred (Lancet Haematol. 2017 Apr;4:e176-82).
Overall, 8 of 11 patients were removed from treatment because of an adverse event, and 3 of those required intensive care unit level of care.
Although rituximab was removed in both trials, two of the remaining three patients in the studies, including three with mantle cell lymphoma and eight with follicular lymphoma, experienced grade 3 rashes, and one had grade 3 AST elevations. In those with mantle cell lymphoma, the most common grade 3-4 adverse events were ALT elevations and rash. In those with follicular lymphoma, the most common grade 3-4 adverse events were neutropenia and rash.
“Given the inability to deliver treatment due to toxicity, both studies were permanently closed,” the researchers wrote, noting that the primary endpoint of safety and tolerability was not met.
The trials had the overall goal of developing targeted regimens to replace cytotoxic therapy.
“Both ... trials were designed to capitalize on the clinical synergy of lenalidomide and rituximab observed in previous trials by adding the highly specific PI3K delta inhibitor, idelalisib, for patients with relapsed mantle cell lymphoma and follicular lymphoma,” they said.
Previously available data implied that lenalidomide plus rituximab would be a safe backbone for therapy, and there was clinical rationale for adding idelalisib to that combination, they explained.
“Overall, our brief experience underscores the limited knowledge regarding drug interactions and off-target effects and serves as a cautionary note in developing biological agents in combination and against ad-hoc combinations outside of carefully monitored clinical trials,” they said.
The researchers noted that the nature of the toxicities observed in these trials supports an immune-activated state characterized by excessive inflammation.
“A more detailed assessment of effect on cytokines, T-cell subsets, natural killer cells, and clinical features predictive of toxicity and response should be included in any further testing of these classes of agents, and they should never be combined outside of a carefully designed and diligently monitored clinical trial setting,” they concluded.
The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.
Combined idelalisib, lenalidomide, and rituximab proved excessively toxic for the treatment of relapsed and refractory mantle cell and follicular lymphoma in two phase I trials conducted by the Alliance for Clinical Trials in Oncology.
The unexpected outcome, which led to early study termination, underscores the need for caution as new treatment combinations are proposed, Sonali M. Smith, MD, of the University of Chicago and her colleagues said in The Lancet Haematology.
In four of the first eight patients enrolled in the mantle cell lymphoma (A051201) and follicular lymphoma (A051202) phase I trials between July 9, 2013, and Sept. 30, 2014, unexpected dose-limiting toxicities occurred, including grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash.
The adverse events occurred between 9 and 20 days after treatment initiation and coincided with rituximab infusions, the researchers said. No treatment-related deaths occurred (Lancet Haematol. 2017 Apr;4:e176-82).
Overall, 8 of 11 patients were removed from treatment because of an adverse event, and 3 of those required intensive care unit level of care.
Although rituximab was removed in both trials, two of the remaining three patients in the studies, including three with mantle cell lymphoma and eight with follicular lymphoma, experienced grade 3 rashes, and one had grade 3 AST elevations. In those with mantle cell lymphoma, the most common grade 3-4 adverse events were ALT elevations and rash. In those with follicular lymphoma, the most common grade 3-4 adverse events were neutropenia and rash.
“Given the inability to deliver treatment due to toxicity, both studies were permanently closed,” the researchers wrote, noting that the primary endpoint of safety and tolerability was not met.
The trials had the overall goal of developing targeted regimens to replace cytotoxic therapy.
“Both ... trials were designed to capitalize on the clinical synergy of lenalidomide and rituximab observed in previous trials by adding the highly specific PI3K delta inhibitor, idelalisib, for patients with relapsed mantle cell lymphoma and follicular lymphoma,” they said.
Previously available data implied that lenalidomide plus rituximab would be a safe backbone for therapy, and there was clinical rationale for adding idelalisib to that combination, they explained.
“Overall, our brief experience underscores the limited knowledge regarding drug interactions and off-target effects and serves as a cautionary note in developing biological agents in combination and against ad-hoc combinations outside of carefully monitored clinical trials,” they said.
The researchers noted that the nature of the toxicities observed in these trials supports an immune-activated state characterized by excessive inflammation.
“A more detailed assessment of effect on cytokines, T-cell subsets, natural killer cells, and clinical features predictive of toxicity and response should be included in any further testing of these classes of agents, and they should never be combined outside of a carefully designed and diligently monitored clinical trial setting,” they concluded.
The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.
Key clinical point:
Major finding: Of 11 patients, 8 were removed from treatment because of an adverse event, and 3 of those required intensive care unit–level care.
Data source: Two phase I trials involving 11 patients.
Disclosures: The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.
CHMP recommends approval for rituximab biosimilar
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for a biosimilar rituximab product called Rixathon.
The recommended authorization for Rixathon encompasses all the same indications as the reference medicine, MabThera, which includes non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA).
The CHMP’s recommendation for Rixathon has been forwarded to the European Commission, which normally decides whether it will grant marketing authorization for a product within 67 days from the time the CHMP adopts its opinion.
The active substance of Rixathon is rituximab, a monoclonal antibody that binds specifically to the transmembrane protein CD20, which is found on both malignant and normal B cells.
In NHL and CLL, this promotes destruction of malignant B cells and controls tumor growth. In RA, GPA, and MPA, it reduces B cells involved in their pathogenesis.
The reference product for Rixathon is Mabthera, which was authorized for use in the European Union in June 1998.
The CHMP says studies have shown Rixathon to have comparable quality, safety, and efficacy to Mabthera.1, 2, 3
The applicant for Rixathon is Sandoz GmbH.
If authorized by the European Commission, Rixathon will be available for the following indications.
NHL
Rixathon is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV follicular lymphoma (FL).
Rixathon maintenance therapy is indicated for the treatment of FL patients responding to induction therapy.
Rixathon monotherapy is indicated for the treatment of patients with stage III-IV FL who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.
Rixathon is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.
CLL
Rixathon in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory CLL.
The CHMP noted that limited efficacy and safety data are available for patients previously treated with monoclonal antibodies, including rituximab, or patients who are refractory to previous rituximab plus chemotherapy.
RA, GPA, and MPA
Rixathon in combination with methotrexate is indicated for the treatment of adults with severe, active RA who have had an inadequate response to or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.
Rixathon in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active GPA or MPA.
1. Visser J et al. Physicochemical and Functional Comparability Between the Proposed Biosimilar Rituximab GP2013 and Originator Rituximab. BioDrugs. 2013;27:495-507.
2. Da Silva A et al. Target-directed development and preclinical characterization of the proposed biosimilar rituximab GP2013. Leuk Lymphoma. 2014;55:1609-1617.
3. Jurczak W et al. A Phase III Efficacy and Safety Study of the Proposed Rituximab Biosimilar GP2013 Versus Rituximab in Patients with Previously Untreated Advanced Follicular Lymphoma. ASH Annual Meeting 2016.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for a biosimilar rituximab product called Rixathon.
The recommended authorization for Rixathon encompasses all the same indications as the reference medicine, MabThera, which includes non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA).
The CHMP’s recommendation for Rixathon has been forwarded to the European Commission, which normally decides whether it will grant marketing authorization for a product within 67 days from the time the CHMP adopts its opinion.
The active substance of Rixathon is rituximab, a monoclonal antibody that binds specifically to the transmembrane protein CD20, which is found on both malignant and normal B cells.
In NHL and CLL, this promotes destruction of malignant B cells and controls tumor growth. In RA, GPA, and MPA, it reduces B cells involved in their pathogenesis.
The reference product for Rixathon is Mabthera, which was authorized for use in the European Union in June 1998.
The CHMP says studies have shown Rixathon to have comparable quality, safety, and efficacy to Mabthera.1, 2, 3
The applicant for Rixathon is Sandoz GmbH.
If authorized by the European Commission, Rixathon will be available for the following indications.
NHL
Rixathon is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV follicular lymphoma (FL).
Rixathon maintenance therapy is indicated for the treatment of FL patients responding to induction therapy.
Rixathon monotherapy is indicated for the treatment of patients with stage III-IV FL who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.
Rixathon is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.
CLL
Rixathon in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory CLL.
The CHMP noted that limited efficacy and safety data are available for patients previously treated with monoclonal antibodies, including rituximab, or patients who are refractory to previous rituximab plus chemotherapy.
RA, GPA, and MPA
Rixathon in combination with methotrexate is indicated for the treatment of adults with severe, active RA who have had an inadequate response to or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.
Rixathon in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active GPA or MPA.
1. Visser J et al. Physicochemical and Functional Comparability Between the Proposed Biosimilar Rituximab GP2013 and Originator Rituximab. BioDrugs. 2013;27:495-507.
2. Da Silva A et al. Target-directed development and preclinical characterization of the proposed biosimilar rituximab GP2013. Leuk Lymphoma. 2014;55:1609-1617.
3. Jurczak W et al. A Phase III Efficacy and Safety Study of the Proposed Rituximab Biosimilar GP2013 Versus Rituximab in Patients with Previously Untreated Advanced Follicular Lymphoma. ASH Annual Meeting 2016.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for a biosimilar rituximab product called Rixathon.
The recommended authorization for Rixathon encompasses all the same indications as the reference medicine, MabThera, which includes non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA).
The CHMP’s recommendation for Rixathon has been forwarded to the European Commission, which normally decides whether it will grant marketing authorization for a product within 67 days from the time the CHMP adopts its opinion.
The active substance of Rixathon is rituximab, a monoclonal antibody that binds specifically to the transmembrane protein CD20, which is found on both malignant and normal B cells.
In NHL and CLL, this promotes destruction of malignant B cells and controls tumor growth. In RA, GPA, and MPA, it reduces B cells involved in their pathogenesis.
The reference product for Rixathon is Mabthera, which was authorized for use in the European Union in June 1998.
The CHMP says studies have shown Rixathon to have comparable quality, safety, and efficacy to Mabthera.1, 2, 3
The applicant for Rixathon is Sandoz GmbH.
If authorized by the European Commission, Rixathon will be available for the following indications.
NHL
Rixathon is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV follicular lymphoma (FL).
Rixathon maintenance therapy is indicated for the treatment of FL patients responding to induction therapy.
Rixathon monotherapy is indicated for the treatment of patients with stage III-IV FL who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.
Rixathon is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.
CLL
Rixathon in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory CLL.
The CHMP noted that limited efficacy and safety data are available for patients previously treated with monoclonal antibodies, including rituximab, or patients who are refractory to previous rituximab plus chemotherapy.
RA, GPA, and MPA
Rixathon in combination with methotrexate is indicated for the treatment of adults with severe, active RA who have had an inadequate response to or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.
Rixathon in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active GPA or MPA.
1. Visser J et al. Physicochemical and Functional Comparability Between the Proposed Biosimilar Rituximab GP2013 and Originator Rituximab. BioDrugs. 2013;27:495-507.
2. Da Silva A et al. Target-directed development and preclinical characterization of the proposed biosimilar rituximab GP2013. Leuk Lymphoma. 2014;55:1609-1617.
3. Jurczak W et al. A Phase III Efficacy and Safety Study of the Proposed Rituximab Biosimilar GP2013 Versus Rituximab in Patients with Previously Untreated Advanced Follicular Lymphoma. ASH Annual Meeting 2016.
Thousands expected to get CAR T-cells by 2018
NEW YORK – Should the first chimeric antigen receptor (CAR) T-cell treatment receive Food and Drug Administration approval for refractory, aggressive non-Hodgkin lymphoma, possibly before the end of 2017, several thousand U.S. patients will be potential candidates for the treatment, Jeremy S. Abramson, MD, predicted at a conference held by Imedex.
Dr. Abramson has led studies using a CAR T cell that differs from the one furthest along in development. He based his predicted timetable for an approved biologics license of the process, with which he can engineer patient-specific T cells that are under development by Kite Pharma, on the “remarkable” level of complete responses the intervention produced in a pivotal phase II study.
“Seeing a complete response rate of close to 40% that is sustained for more than 3 months and a complete response rate of close to a third at 6 months is light years beyond what is now available for patients” with these chemotherapy refractory B-cell lymphomas, said Dr. Abramson, clinical director of the Center for Lymphoma at Massachusetts General Hospital in Boston. “This is the first treatment to show a significant impact on large B-cell lymphoma, and that makes me optimistic” that the FDA will grant license approval later in 2017, he said in an interview.
Dr. Abramson acknowledged that some patients developed grade 3 or 4 cytokine-release syndrome and neurologic events, but the events were reversible and manageable if treated with the immunosuppressant tocilizumab (Actemra) or a corticosteroid.
At the end of March, Kite reported the completion of its FDA application, and, on April 2, the ZUMA-1 investigators presented an updated report on their results, with a 36% complete response rate across all enrolled patients at 6 month follow-up and a 39% complete response rate in all patients out to a median follow-up of 8.7 months.
Annually, in U.S. practice, perhaps 3,000 new patients with diffuse large B-cell lymphoma would meet the enrollment criteria for ZUMA-1, Dr. Abramson estimated. Once axicabtagene ciloleucel becomes commercially available in the United States, several thousand U.S. patients might initially seek the treatment.
Dr. Abramson has been a consultant to Kite Pharma and to AbbVie, Genentech, Gilead, and Seattle Genetics.
[email protected]
On Twitter @mitchelzoler
NEW YORK – Should the first chimeric antigen receptor (CAR) T-cell treatment receive Food and Drug Administration approval for refractory, aggressive non-Hodgkin lymphoma, possibly before the end of 2017, several thousand U.S. patients will be potential candidates for the treatment, Jeremy S. Abramson, MD, predicted at a conference held by Imedex.
Dr. Abramson has led studies using a CAR T cell that differs from the one furthest along in development. He based his predicted timetable for an approved biologics license of the process, with which he can engineer patient-specific T cells that are under development by Kite Pharma, on the “remarkable” level of complete responses the intervention produced in a pivotal phase II study.
“Seeing a complete response rate of close to 40% that is sustained for more than 3 months and a complete response rate of close to a third at 6 months is light years beyond what is now available for patients” with these chemotherapy refractory B-cell lymphomas, said Dr. Abramson, clinical director of the Center for Lymphoma at Massachusetts General Hospital in Boston. “This is the first treatment to show a significant impact on large B-cell lymphoma, and that makes me optimistic” that the FDA will grant license approval later in 2017, he said in an interview.
Dr. Abramson acknowledged that some patients developed grade 3 or 4 cytokine-release syndrome and neurologic events, but the events were reversible and manageable if treated with the immunosuppressant tocilizumab (Actemra) or a corticosteroid.
At the end of March, Kite reported the completion of its FDA application, and, on April 2, the ZUMA-1 investigators presented an updated report on their results, with a 36% complete response rate across all enrolled patients at 6 month follow-up and a 39% complete response rate in all patients out to a median follow-up of 8.7 months.
Annually, in U.S. practice, perhaps 3,000 new patients with diffuse large B-cell lymphoma would meet the enrollment criteria for ZUMA-1, Dr. Abramson estimated. Once axicabtagene ciloleucel becomes commercially available in the United States, several thousand U.S. patients might initially seek the treatment.
Dr. Abramson has been a consultant to Kite Pharma and to AbbVie, Genentech, Gilead, and Seattle Genetics.
[email protected]
On Twitter @mitchelzoler
NEW YORK – Should the first chimeric antigen receptor (CAR) T-cell treatment receive Food and Drug Administration approval for refractory, aggressive non-Hodgkin lymphoma, possibly before the end of 2017, several thousand U.S. patients will be potential candidates for the treatment, Jeremy S. Abramson, MD, predicted at a conference held by Imedex.
Dr. Abramson has led studies using a CAR T cell that differs from the one furthest along in development. He based his predicted timetable for an approved biologics license of the process, with which he can engineer patient-specific T cells that are under development by Kite Pharma, on the “remarkable” level of complete responses the intervention produced in a pivotal phase II study.
“Seeing a complete response rate of close to 40% that is sustained for more than 3 months and a complete response rate of close to a third at 6 months is light years beyond what is now available for patients” with these chemotherapy refractory B-cell lymphomas, said Dr. Abramson, clinical director of the Center for Lymphoma at Massachusetts General Hospital in Boston. “This is the first treatment to show a significant impact on large B-cell lymphoma, and that makes me optimistic” that the FDA will grant license approval later in 2017, he said in an interview.
Dr. Abramson acknowledged that some patients developed grade 3 or 4 cytokine-release syndrome and neurologic events, but the events were reversible and manageable if treated with the immunosuppressant tocilizumab (Actemra) or a corticosteroid.
At the end of March, Kite reported the completion of its FDA application, and, on April 2, the ZUMA-1 investigators presented an updated report on their results, with a 36% complete response rate across all enrolled patients at 6 month follow-up and a 39% complete response rate in all patients out to a median follow-up of 8.7 months.
Annually, in U.S. practice, perhaps 3,000 new patients with diffuse large B-cell lymphoma would meet the enrollment criteria for ZUMA-1, Dr. Abramson estimated. Once axicabtagene ciloleucel becomes commercially available in the United States, several thousand U.S. patients might initially seek the treatment.
Dr. Abramson has been a consultant to Kite Pharma and to AbbVie, Genentech, Gilead, and Seattle Genetics.
[email protected]
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM A MEETING ON HEMATOLOGIC MALIGNANCIES
Obinutuzumab vs. rituximab weighed as follicular lymphoma therapy
NEW YORK – Does obinutuzumab have a leg up over rituximab for treating follicular lymphoma?
A strict reading of the efficacy records of the two anti-CD20 antibodies when they went head-to-head suggests that obinutuzumab (Gazyva) edged out rituximab (Rituxan), but a broader view leaves the door open for rituximab as a still viable option depending on a patient’s status and priorities, experts said at the conference held by Imedex.
While conceding that quality of life correlates with progression-free survival (PFS), he stressed that it also correlates with treatment toxicities, treatment duration, and disease-related side effects.
Trial results have indicated that patients with newly diagnosed follicular lymphoma are reasonably treated with rituximab alone, or with rituximab plus bendamustine, without need for maintenance therapy, Dr. Leonard said.
In contrast, GALLIUM, a phase III trial that compared rituximab against obinutuzumab, used a maintenance phase of monotherapy with each of these two drugs following an induction phase when each of the drugs was combined with chemotherapy.
“If you use this approach [tested in GALLIUM] you need to use maintenance therapy,” and it was in GALLIUM that the most dramatic efficacy advantage for obinutuzumab over rituximab appeared, in the form of longer PFS although, so far, without demonstrated advantage in overall survival. The GALLIUM results, reported in December 2016 at the American Society of Hematology meeting, showed a 3-year PFS rate of 80% among patients treated with obinutuzumab and 73% among those treated with rituximab, a hazard ratio of 0.66 in favor of obinutuzumab that was statistically significant (P = .001) for the study’s primary endpoint (Blood. 2016 Dec 4;abstract 6).
“If you follow this study, you commit the patient to maintenance. We need to talk with patients about the pros and cons of maintenance, the pros and cons of chemotherapy, and the pros and cons of single agent therapy” with one of these anti-CD20 antibodies, Dr. Leonard said. “Right now, I think it’s unclear which antibody is best,” he concluded
To further buttress the case for obinutuzumab, he also cited the higher response rate among relapsed patients when single-agent obinutuzumab went against single-agent rituximab (J Clin Oncol. 2015 Oct 20:33[30]:3467-74), and the overall survival advantage that obinutuzumab gave patients when combined with bendamustine in patients refractory to rituximab (Blood. 2016 Dec 5; abstract 615).
Agreeing that the design of GALLIUM focused on combining an anti-CD20 antibody with chemotherapy, Dr. Friedberg acknowledged that, as initial therapy, “using rituximab monotherapy is very reasonable for many patients. I divide [follicular lymphoma] patients into those who are very symptomatic” (for example, those with hydronephrosis) “and need chemotherapy, and those who are not that symptomatic for whom single-agent rituximab is very reasonable,” he said in an interview.
Tumor aggressiveness is another way to identify patients who need chemotherapy plus an antibody, he added. “If the patient is not symptomatic, I generally first observe them, and if the growth is slow, you can sometimes intervene with rituximab alone, but, if the growth is fast, you also need chemotherapy,” Dr. Friedberg said.
Cost may soon become another consideration now that the U.S. patent on rituximab has expired leading to the ongoing development of several biosimilar versions of the antibody. If biosimilar formulations of rituximab soon appear on the U.S. market and if they result in a significant drop in drug price, it would introduce yet another significant variable. “Presuming biosimilar rituximab lowers the cost, that would be another important treatment decision,” he said.
Dr. Friedberg has been a consultant to Bayer. Dr. Leonard has been a consultant to 13 drug companies. Neither disclosed a relationship with the companies that market obinutuzumab or rituximab.
[email protected]
On Twitter @mitchelzoler
NEW YORK – Does obinutuzumab have a leg up over rituximab for treating follicular lymphoma?
A strict reading of the efficacy records of the two anti-CD20 antibodies when they went head-to-head suggests that obinutuzumab (Gazyva) edged out rituximab (Rituxan), but a broader view leaves the door open for rituximab as a still viable option depending on a patient’s status and priorities, experts said at the conference held by Imedex.
While conceding that quality of life correlates with progression-free survival (PFS), he stressed that it also correlates with treatment toxicities, treatment duration, and disease-related side effects.
Trial results have indicated that patients with newly diagnosed follicular lymphoma are reasonably treated with rituximab alone, or with rituximab plus bendamustine, without need for maintenance therapy, Dr. Leonard said.
In contrast, GALLIUM, a phase III trial that compared rituximab against obinutuzumab, used a maintenance phase of monotherapy with each of these two drugs following an induction phase when each of the drugs was combined with chemotherapy.
“If you use this approach [tested in GALLIUM] you need to use maintenance therapy,” and it was in GALLIUM that the most dramatic efficacy advantage for obinutuzumab over rituximab appeared, in the form of longer PFS although, so far, without demonstrated advantage in overall survival. The GALLIUM results, reported in December 2016 at the American Society of Hematology meeting, showed a 3-year PFS rate of 80% among patients treated with obinutuzumab and 73% among those treated with rituximab, a hazard ratio of 0.66 in favor of obinutuzumab that was statistically significant (P = .001) for the study’s primary endpoint (Blood. 2016 Dec 4;abstract 6).
“If you follow this study, you commit the patient to maintenance. We need to talk with patients about the pros and cons of maintenance, the pros and cons of chemotherapy, and the pros and cons of single agent therapy” with one of these anti-CD20 antibodies, Dr. Leonard said. “Right now, I think it’s unclear which antibody is best,” he concluded
To further buttress the case for obinutuzumab, he also cited the higher response rate among relapsed patients when single-agent obinutuzumab went against single-agent rituximab (J Clin Oncol. 2015 Oct 20:33[30]:3467-74), and the overall survival advantage that obinutuzumab gave patients when combined with bendamustine in patients refractory to rituximab (Blood. 2016 Dec 5; abstract 615).
Agreeing that the design of GALLIUM focused on combining an anti-CD20 antibody with chemotherapy, Dr. Friedberg acknowledged that, as initial therapy, “using rituximab monotherapy is very reasonable for many patients. I divide [follicular lymphoma] patients into those who are very symptomatic” (for example, those with hydronephrosis) “and need chemotherapy, and those who are not that symptomatic for whom single-agent rituximab is very reasonable,” he said in an interview.
Tumor aggressiveness is another way to identify patients who need chemotherapy plus an antibody, he added. “If the patient is not symptomatic, I generally first observe them, and if the growth is slow, you can sometimes intervene with rituximab alone, but, if the growth is fast, you also need chemotherapy,” Dr. Friedberg said.
Cost may soon become another consideration now that the U.S. patent on rituximab has expired leading to the ongoing development of several biosimilar versions of the antibody. If biosimilar formulations of rituximab soon appear on the U.S. market and if they result in a significant drop in drug price, it would introduce yet another significant variable. “Presuming biosimilar rituximab lowers the cost, that would be another important treatment decision,” he said.
Dr. Friedberg has been a consultant to Bayer. Dr. Leonard has been a consultant to 13 drug companies. Neither disclosed a relationship with the companies that market obinutuzumab or rituximab.
[email protected]
On Twitter @mitchelzoler
NEW YORK – Does obinutuzumab have a leg up over rituximab for treating follicular lymphoma?
A strict reading of the efficacy records of the two anti-CD20 antibodies when they went head-to-head suggests that obinutuzumab (Gazyva) edged out rituximab (Rituxan), but a broader view leaves the door open for rituximab as a still viable option depending on a patient’s status and priorities, experts said at the conference held by Imedex.
While conceding that quality of life correlates with progression-free survival (PFS), he stressed that it also correlates with treatment toxicities, treatment duration, and disease-related side effects.
Trial results have indicated that patients with newly diagnosed follicular lymphoma are reasonably treated with rituximab alone, or with rituximab plus bendamustine, without need for maintenance therapy, Dr. Leonard said.
In contrast, GALLIUM, a phase III trial that compared rituximab against obinutuzumab, used a maintenance phase of monotherapy with each of these two drugs following an induction phase when each of the drugs was combined with chemotherapy.
“If you use this approach [tested in GALLIUM] you need to use maintenance therapy,” and it was in GALLIUM that the most dramatic efficacy advantage for obinutuzumab over rituximab appeared, in the form of longer PFS although, so far, without demonstrated advantage in overall survival. The GALLIUM results, reported in December 2016 at the American Society of Hematology meeting, showed a 3-year PFS rate of 80% among patients treated with obinutuzumab and 73% among those treated with rituximab, a hazard ratio of 0.66 in favor of obinutuzumab that was statistically significant (P = .001) for the study’s primary endpoint (Blood. 2016 Dec 4;abstract 6).
“If you follow this study, you commit the patient to maintenance. We need to talk with patients about the pros and cons of maintenance, the pros and cons of chemotherapy, and the pros and cons of single agent therapy” with one of these anti-CD20 antibodies, Dr. Leonard said. “Right now, I think it’s unclear which antibody is best,” he concluded
To further buttress the case for obinutuzumab, he also cited the higher response rate among relapsed patients when single-agent obinutuzumab went against single-agent rituximab (J Clin Oncol. 2015 Oct 20:33[30]:3467-74), and the overall survival advantage that obinutuzumab gave patients when combined with bendamustine in patients refractory to rituximab (Blood. 2016 Dec 5; abstract 615).
Agreeing that the design of GALLIUM focused on combining an anti-CD20 antibody with chemotherapy, Dr. Friedberg acknowledged that, as initial therapy, “using rituximab monotherapy is very reasonable for many patients. I divide [follicular lymphoma] patients into those who are very symptomatic” (for example, those with hydronephrosis) “and need chemotherapy, and those who are not that symptomatic for whom single-agent rituximab is very reasonable,” he said in an interview.
Tumor aggressiveness is another way to identify patients who need chemotherapy plus an antibody, he added. “If the patient is not symptomatic, I generally first observe them, and if the growth is slow, you can sometimes intervene with rituximab alone, but, if the growth is fast, you also need chemotherapy,” Dr. Friedberg said.
Cost may soon become another consideration now that the U.S. patent on rituximab has expired leading to the ongoing development of several biosimilar versions of the antibody. If biosimilar formulations of rituximab soon appear on the U.S. market and if they result in a significant drop in drug price, it would introduce yet another significant variable. “Presuming biosimilar rituximab lowers the cost, that would be another important treatment decision,” he said.
Dr. Friedberg has been a consultant to Bayer. Dr. Leonard has been a consultant to 13 drug companies. Neither disclosed a relationship with the companies that market obinutuzumab or rituximab.
[email protected]
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM A MEETING ON HEMATOLOGIC MALIGNANCIES
Inhibitor exhibits activity against hematologic malignancies
A dual kinase inhibitor is active against a range of hematologic malignancies, according to preclinical research.
Investigators found that ASN002, a SYK/JAK inhibitor, exhibited “potent” antiproliferative activity in leukemia, lymphoma, and myeloma cell lines.
ASN002 also inhibited tumor growth in mouse models of these malignancies and proved active against ibrutinib-resistant diffuse large B-cell lymphoma (DLBCL).
The investigators presented these results at the AACR Annual Meeting 2017 (abstract 4204).
The work was conducted by employees of Asana BioSciences, the company developing ASN002.
The investigators tested ASN002 in 178 cell lines and found the drug exhibited “strong antiproliferative activity” in a range of hematologic cancer cell lines, including:
- Leukemia—HEL31, HL60, Jurkat, MOLM-13, and MOLM-16
- Lymphoma—KARPAS-299, OCI-LY10, OCI-LY-19, Pfeiffer, Raji, Ramos, SU-DHL-1, SU-DHL-6, and SU-DHL-10
- Myeloma—H929, JJN3, OPM2, and U266.
In addition, ASN002 was active against ibrutinib-resistant clones derived from the DLBCL cell line SU-DHL-6.
In a SU-DHL-6 xenograft model, the combination of ASN002 and ibrutinib was more effective than either compound alone.
The investigators also found that ASN002 alone demonstrated “strong tumor growth inhibition” in mouse models of DLBCL (Pfeiffer and SU-DHL-6), myeloma (H929), and erythroleukemia (HEL).
The team pointed out that ASN002 is currently under investigation in a phase 1/2 study of patients with B-cell lymphomas (DLBCL, mantle cell lymphoma, and follicular lymphoma) as well as solid tumors.
The investigators said that, to date, ASN002 has been well tolerated and has shown encouraging early evidence of clinical activity and symptomatic benefit in the lymphoma patients.
A dual kinase inhibitor is active against a range of hematologic malignancies, according to preclinical research.
Investigators found that ASN002, a SYK/JAK inhibitor, exhibited “potent” antiproliferative activity in leukemia, lymphoma, and myeloma cell lines.
ASN002 also inhibited tumor growth in mouse models of these malignancies and proved active against ibrutinib-resistant diffuse large B-cell lymphoma (DLBCL).
The investigators presented these results at the AACR Annual Meeting 2017 (abstract 4204).
The work was conducted by employees of Asana BioSciences, the company developing ASN002.
The investigators tested ASN002 in 178 cell lines and found the drug exhibited “strong antiproliferative activity” in a range of hematologic cancer cell lines, including:
- Leukemia—HEL31, HL60, Jurkat, MOLM-13, and MOLM-16
- Lymphoma—KARPAS-299, OCI-LY10, OCI-LY-19, Pfeiffer, Raji, Ramos, SU-DHL-1, SU-DHL-6, and SU-DHL-10
- Myeloma—H929, JJN3, OPM2, and U266.
In addition, ASN002 was active against ibrutinib-resistant clones derived from the DLBCL cell line SU-DHL-6.
In a SU-DHL-6 xenograft model, the combination of ASN002 and ibrutinib was more effective than either compound alone.
The investigators also found that ASN002 alone demonstrated “strong tumor growth inhibition” in mouse models of DLBCL (Pfeiffer and SU-DHL-6), myeloma (H929), and erythroleukemia (HEL).
The team pointed out that ASN002 is currently under investigation in a phase 1/2 study of patients with B-cell lymphomas (DLBCL, mantle cell lymphoma, and follicular lymphoma) as well as solid tumors.
The investigators said that, to date, ASN002 has been well tolerated and has shown encouraging early evidence of clinical activity and symptomatic benefit in the lymphoma patients.
A dual kinase inhibitor is active against a range of hematologic malignancies, according to preclinical research.
Investigators found that ASN002, a SYK/JAK inhibitor, exhibited “potent” antiproliferative activity in leukemia, lymphoma, and myeloma cell lines.
ASN002 also inhibited tumor growth in mouse models of these malignancies and proved active against ibrutinib-resistant diffuse large B-cell lymphoma (DLBCL).
The investigators presented these results at the AACR Annual Meeting 2017 (abstract 4204).
The work was conducted by employees of Asana BioSciences, the company developing ASN002.
The investigators tested ASN002 in 178 cell lines and found the drug exhibited “strong antiproliferative activity” in a range of hematologic cancer cell lines, including:
- Leukemia—HEL31, HL60, Jurkat, MOLM-13, and MOLM-16
- Lymphoma—KARPAS-299, OCI-LY10, OCI-LY-19, Pfeiffer, Raji, Ramos, SU-DHL-1, SU-DHL-6, and SU-DHL-10
- Myeloma—H929, JJN3, OPM2, and U266.
In addition, ASN002 was active against ibrutinib-resistant clones derived from the DLBCL cell line SU-DHL-6.
In a SU-DHL-6 xenograft model, the combination of ASN002 and ibrutinib was more effective than either compound alone.
The investigators also found that ASN002 alone demonstrated “strong tumor growth inhibition” in mouse models of DLBCL (Pfeiffer and SU-DHL-6), myeloma (H929), and erythroleukemia (HEL).
The team pointed out that ASN002 is currently under investigation in a phase 1/2 study of patients with B-cell lymphomas (DLBCL, mantle cell lymphoma, and follicular lymphoma) as well as solid tumors.
The investigators said that, to date, ASN002 has been well tolerated and has shown encouraging early evidence of clinical activity and symptomatic benefit in the lymphoma patients.
Reduced-intensity conditioning may not preserve fertility in young girls after bone marrow transplant
ORLANDO – Girls who undergo reduced-intensity conditioning for a bone marrow transplant may face fertility problems in the future, even if they experience an outwardly normal puberty.
In the first-ever study to compare high- and low-intensity chemotherapeutic conditioning regimens among young girls, significantly more who underwent the reduced-intensity regimen had normal estradiol, luteinizing hormone, and follicle-stimulating hormone compared with those who had high-intensity conditioning. But anti-Müllerian hormone was low or absent in almost all the girls, no matter which conditioning regimen they had, Jonathan C. Howell, MD, PhD, said at the annual meeting of the Endocrine Society.
While not a perfect predictor of future fertility, anti-Müllerian hormone is a good indicator of ovarian follicular reserve, said Dr. Howell, a pediatric endocrinologist at Cincinnati Children’s Hospital Medical Center.
Dr. Howell and his colleagues, Holly R. Hoefgen, MD, Kasiani C. Myers, MD, and Helen Oquendo-Del Toro, MD, all of Cincinnati Children’s Hospital Medical Center, are following 49 females aged 1-40 years who had preconditioning chemotherapy in advance of hematopoietic stem cell transplantation.
At the meeting, Dr. Howell reported data on 23 girls who were in puberty during their treatment (mean age 12 years). The mean follow-up was 4 years, but this varied widely, from 1 to 13 years. Most (16) had high-intensity myeloablation; the remainder had reduced-intensity conditioning. Diagnoses varied between the groups. Among those with high-intensity conditioning, malignancy and bone marrow failure were the most common indications (seven patients each); one patient had an immunodeficiency, and the cause was unknown for another.
Among those who had the reduced-intensity regimen, five had an immunodeficiency and two had bone marrow failure.
The discrepancy in diagnoses between the groups isn’t surprising, Dr. Howell said. “Diagnosis can dictate which treatment patients receive. People with malignancies or a prior history of leukemia or lymphoma often receive the high-intensity conditioning. You want to wipe out every single malignant cell.”
Reduced-intensity conditioning may be an option for patients with other problems such as bone marrow failure, immunodeficiencies, or genetic or metabolic problems. The less-intense regimen does confer some benefits, Dr. Howell noted. “The short-term need for intensive medical therapy while getting the stem cells is less. The medical benefit of these less-intense regimens is certainly there, but the long-term endocrine impact has yet to be defined.”
Most of the girls in the high-intensity regimen group (64%) had high follicle stimulating hormone and luteinizing hormone, suggesting primary ovarian failure; 71% of them also had low estradiol levels. However, all of these hormones were normal in the reduced-intensity group. But regardless of conditioning treatment, anti-Müllerian hormone was abnormally low in nearly all of the patients (87%). Only one girl with myeloablative conditioning and two girls with reduced intensity condition had normal anti-Müllerian levels. “This tells us that fertility potential may not be preserved, despite [their] getting the reduced-intensity conditioning,” Dr. Howell said.
The story here is only beginning to unfold, he said. “Fertility is defined as the ability to conceive a child, and that’s not something we have looked at yet. We would like to know the long-term outcomes of fertility in these patients, and whether they can conceive when they’re ready to start a family. Our goal is to follow these young women into their 20s and 30s, and to see if that’s an opportunity they are able to experience.”
The study is a cooperative project involving the hospital’s divisions of Pediatric and Adolescent Gynecology, Bone Marrow Transplantation and Immunology, and Endocrinology.
Neither Dr. Howell nor any of his colleagues had any financial disclosures.
Fertility preservation talks: The earlier, the better
A talk about fertility preservation can be the first step into a new future for families of children with a cancer diagnosis.
“Talking about your baby having a baby can be the farthest thing from your mind,” when you’re the parent of a child about to undergo cancer treatment, said Dr. Hoefgen. “But we know from survivors that this can be a very important issue in the future. We simply start by telling parents, ‘This will be important to your child at some point, and we want to talk about it now, while there is still something we may be able to do about it.’ ”
Dr. Hoefgen, a staff member at the hospital’s Comprehensive Fertility Care and Preservation Program, said parents “sometimes find it weird” to be talking about unborn grandchildren when they’re consumed with making critical decisions for their own child. But by asking them to consider that child’s long-term future, the discussion offers its own message of hope.
The talks always begin with a basic discussion of how cancer treatments can affect the reproductive organs. The hospital has a series of short animated videos that are very helpful in relaying the information. Another video in that series describes the different methods of fertility preservation: mature oocyte or sperm harvesting, or, for younger patients, removing and freezing ovarian and testicular tissue. Parents and children can watch them together, get grounding in the basics, and be prepared for a productive conversation.
Talks always include the team oncologist, who creates a specialized risk assessment for each patient. The group discusses each preservation method, the risks and benefits, and the cost. But the talks are exploratory, too, helping both clinicians and families understand what’s most important to them, she said.
“Common things that we typically talk about are genetics, religion, and ethics – which may mean different things to different families.”
Dr. Hoefgen and her team reach out to more than 95% of families that face a pediatric cancer diagnosis. After the in-depth discussions, she said, about 20% decide to investigate some form of fertility preservation.
“The most important thing is having the conversation early, while we still have options,” she said.
Dr. Hoefgen had no financial disclosures.
ORLANDO – Girls who undergo reduced-intensity conditioning for a bone marrow transplant may face fertility problems in the future, even if they experience an outwardly normal puberty.
In the first-ever study to compare high- and low-intensity chemotherapeutic conditioning regimens among young girls, significantly more who underwent the reduced-intensity regimen had normal estradiol, luteinizing hormone, and follicle-stimulating hormone compared with those who had high-intensity conditioning. But anti-Müllerian hormone was low or absent in almost all the girls, no matter which conditioning regimen they had, Jonathan C. Howell, MD, PhD, said at the annual meeting of the Endocrine Society.
While not a perfect predictor of future fertility, anti-Müllerian hormone is a good indicator of ovarian follicular reserve, said Dr. Howell, a pediatric endocrinologist at Cincinnati Children’s Hospital Medical Center.
Dr. Howell and his colleagues, Holly R. Hoefgen, MD, Kasiani C. Myers, MD, and Helen Oquendo-Del Toro, MD, all of Cincinnati Children’s Hospital Medical Center, are following 49 females aged 1-40 years who had preconditioning chemotherapy in advance of hematopoietic stem cell transplantation.
At the meeting, Dr. Howell reported data on 23 girls who were in puberty during their treatment (mean age 12 years). The mean follow-up was 4 years, but this varied widely, from 1 to 13 years. Most (16) had high-intensity myeloablation; the remainder had reduced-intensity conditioning. Diagnoses varied between the groups. Among those with high-intensity conditioning, malignancy and bone marrow failure were the most common indications (seven patients each); one patient had an immunodeficiency, and the cause was unknown for another.
Among those who had the reduced-intensity regimen, five had an immunodeficiency and two had bone marrow failure.
The discrepancy in diagnoses between the groups isn’t surprising, Dr. Howell said. “Diagnosis can dictate which treatment patients receive. People with malignancies or a prior history of leukemia or lymphoma often receive the high-intensity conditioning. You want to wipe out every single malignant cell.”
Reduced-intensity conditioning may be an option for patients with other problems such as bone marrow failure, immunodeficiencies, or genetic or metabolic problems. The less-intense regimen does confer some benefits, Dr. Howell noted. “The short-term need for intensive medical therapy while getting the stem cells is less. The medical benefit of these less-intense regimens is certainly there, but the long-term endocrine impact has yet to be defined.”
Most of the girls in the high-intensity regimen group (64%) had high follicle stimulating hormone and luteinizing hormone, suggesting primary ovarian failure; 71% of them also had low estradiol levels. However, all of these hormones were normal in the reduced-intensity group. But regardless of conditioning treatment, anti-Müllerian hormone was abnormally low in nearly all of the patients (87%). Only one girl with myeloablative conditioning and two girls with reduced intensity condition had normal anti-Müllerian levels. “This tells us that fertility potential may not be preserved, despite [their] getting the reduced-intensity conditioning,” Dr. Howell said.
The story here is only beginning to unfold, he said. “Fertility is defined as the ability to conceive a child, and that’s not something we have looked at yet. We would like to know the long-term outcomes of fertility in these patients, and whether they can conceive when they’re ready to start a family. Our goal is to follow these young women into their 20s and 30s, and to see if that’s an opportunity they are able to experience.”
The study is a cooperative project involving the hospital’s divisions of Pediatric and Adolescent Gynecology, Bone Marrow Transplantation and Immunology, and Endocrinology.
Neither Dr. Howell nor any of his colleagues had any financial disclosures.
Fertility preservation talks: The earlier, the better
A talk about fertility preservation can be the first step into a new future for families of children with a cancer diagnosis.
“Talking about your baby having a baby can be the farthest thing from your mind,” when you’re the parent of a child about to undergo cancer treatment, said Dr. Hoefgen. “But we know from survivors that this can be a very important issue in the future. We simply start by telling parents, ‘This will be important to your child at some point, and we want to talk about it now, while there is still something we may be able to do about it.’ ”
Dr. Hoefgen, a staff member at the hospital’s Comprehensive Fertility Care and Preservation Program, said parents “sometimes find it weird” to be talking about unborn grandchildren when they’re consumed with making critical decisions for their own child. But by asking them to consider that child’s long-term future, the discussion offers its own message of hope.
The talks always begin with a basic discussion of how cancer treatments can affect the reproductive organs. The hospital has a series of short animated videos that are very helpful in relaying the information. Another video in that series describes the different methods of fertility preservation: mature oocyte or sperm harvesting, or, for younger patients, removing and freezing ovarian and testicular tissue. Parents and children can watch them together, get grounding in the basics, and be prepared for a productive conversation.
Talks always include the team oncologist, who creates a specialized risk assessment for each patient. The group discusses each preservation method, the risks and benefits, and the cost. But the talks are exploratory, too, helping both clinicians and families understand what’s most important to them, she said.
“Common things that we typically talk about are genetics, religion, and ethics – which may mean different things to different families.”
Dr. Hoefgen and her team reach out to more than 95% of families that face a pediatric cancer diagnosis. After the in-depth discussions, she said, about 20% decide to investigate some form of fertility preservation.
“The most important thing is having the conversation early, while we still have options,” she said.
Dr. Hoefgen had no financial disclosures.
ORLANDO – Girls who undergo reduced-intensity conditioning for a bone marrow transplant may face fertility problems in the future, even if they experience an outwardly normal puberty.
In the first-ever study to compare high- and low-intensity chemotherapeutic conditioning regimens among young girls, significantly more who underwent the reduced-intensity regimen had normal estradiol, luteinizing hormone, and follicle-stimulating hormone compared with those who had high-intensity conditioning. But anti-Müllerian hormone was low or absent in almost all the girls, no matter which conditioning regimen they had, Jonathan C. Howell, MD, PhD, said at the annual meeting of the Endocrine Society.
While not a perfect predictor of future fertility, anti-Müllerian hormone is a good indicator of ovarian follicular reserve, said Dr. Howell, a pediatric endocrinologist at Cincinnati Children’s Hospital Medical Center.
Dr. Howell and his colleagues, Holly R. Hoefgen, MD, Kasiani C. Myers, MD, and Helen Oquendo-Del Toro, MD, all of Cincinnati Children’s Hospital Medical Center, are following 49 females aged 1-40 years who had preconditioning chemotherapy in advance of hematopoietic stem cell transplantation.
At the meeting, Dr. Howell reported data on 23 girls who were in puberty during their treatment (mean age 12 years). The mean follow-up was 4 years, but this varied widely, from 1 to 13 years. Most (16) had high-intensity myeloablation; the remainder had reduced-intensity conditioning. Diagnoses varied between the groups. Among those with high-intensity conditioning, malignancy and bone marrow failure were the most common indications (seven patients each); one patient had an immunodeficiency, and the cause was unknown for another.
Among those who had the reduced-intensity regimen, five had an immunodeficiency and two had bone marrow failure.
The discrepancy in diagnoses between the groups isn’t surprising, Dr. Howell said. “Diagnosis can dictate which treatment patients receive. People with malignancies or a prior history of leukemia or lymphoma often receive the high-intensity conditioning. You want to wipe out every single malignant cell.”
Reduced-intensity conditioning may be an option for patients with other problems such as bone marrow failure, immunodeficiencies, or genetic or metabolic problems. The less-intense regimen does confer some benefits, Dr. Howell noted. “The short-term need for intensive medical therapy while getting the stem cells is less. The medical benefit of these less-intense regimens is certainly there, but the long-term endocrine impact has yet to be defined.”
Most of the girls in the high-intensity regimen group (64%) had high follicle stimulating hormone and luteinizing hormone, suggesting primary ovarian failure; 71% of them also had low estradiol levels. However, all of these hormones were normal in the reduced-intensity group. But regardless of conditioning treatment, anti-Müllerian hormone was abnormally low in nearly all of the patients (87%). Only one girl with myeloablative conditioning and two girls with reduced intensity condition had normal anti-Müllerian levels. “This tells us that fertility potential may not be preserved, despite [their] getting the reduced-intensity conditioning,” Dr. Howell said.
The story here is only beginning to unfold, he said. “Fertility is defined as the ability to conceive a child, and that’s not something we have looked at yet. We would like to know the long-term outcomes of fertility in these patients, and whether they can conceive when they’re ready to start a family. Our goal is to follow these young women into their 20s and 30s, and to see if that’s an opportunity they are able to experience.”
The study is a cooperative project involving the hospital’s divisions of Pediatric and Adolescent Gynecology, Bone Marrow Transplantation and Immunology, and Endocrinology.
Neither Dr. Howell nor any of his colleagues had any financial disclosures.
Fertility preservation talks: The earlier, the better
A talk about fertility preservation can be the first step into a new future for families of children with a cancer diagnosis.
“Talking about your baby having a baby can be the farthest thing from your mind,” when you’re the parent of a child about to undergo cancer treatment, said Dr. Hoefgen. “But we know from survivors that this can be a very important issue in the future. We simply start by telling parents, ‘This will be important to your child at some point, and we want to talk about it now, while there is still something we may be able to do about it.’ ”
Dr. Hoefgen, a staff member at the hospital’s Comprehensive Fertility Care and Preservation Program, said parents “sometimes find it weird” to be talking about unborn grandchildren when they’re consumed with making critical decisions for their own child. But by asking them to consider that child’s long-term future, the discussion offers its own message of hope.
The talks always begin with a basic discussion of how cancer treatments can affect the reproductive organs. The hospital has a series of short animated videos that are very helpful in relaying the information. Another video in that series describes the different methods of fertility preservation: mature oocyte or sperm harvesting, or, for younger patients, removing and freezing ovarian and testicular tissue. Parents and children can watch them together, get grounding in the basics, and be prepared for a productive conversation.
Talks always include the team oncologist, who creates a specialized risk assessment for each patient. The group discusses each preservation method, the risks and benefits, and the cost. But the talks are exploratory, too, helping both clinicians and families understand what’s most important to them, she said.
“Common things that we typically talk about are genetics, religion, and ethics – which may mean different things to different families.”
Dr. Hoefgen and her team reach out to more than 95% of families that face a pediatric cancer diagnosis. After the in-depth discussions, she said, about 20% decide to investigate some form of fertility preservation.
“The most important thing is having the conversation early, while we still have options,” she said.
Dr. Hoefgen had no financial disclosures.
AT ENDO 2017
Key clinical point:
Major finding: Anti-Müllerian hormone was abnormally low or absent in all treated girls, whether they had reduced-intensity or high-intensity conditioning.
Data source: The prospective study is following 49 females aged 1-40 years.
Disclosures: Neither Dr. Howell nor any of his colleagues had any financial disclosures.
MAGNIFY in relapsed/refractory mantle cell lymphoma
MAGNIFY is a phase IIIB randomized trial actively recruiting patients with relapsed/refractory mantle cell lymphoma, based on studies posted at ClinicalTrials.gov.
MAGNIFY (NCT01996865) is a study of lenalidomide (CC-5013) plus rituximab maintenance therapy, followed by lenalidomide single-agent maintenance therapy, versus rituximab. Sponsored by Celgene, the maker of lenalidomide (Revlimid), the trial’s primary outcome measure is progression-free survival at up to 8 years.
The MAGNIFY trial includes patients with grades 1-3b or transformed follicular lymphoma, marginal zone lymphoma, or mantle cell lymphoma who had received at least one prior therapy and had stage I-IV measurable disease. About 500 patients are planned to enroll in 12 cycles of R2 induction, and slightly more than 300 patients are projected to be randomized after induction to the two maintenance arms. Induction includes oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle; plus intravenous rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles).
Patients will then be randomized to maintenance lenalidomide 10 mg/day, given on days 1-21 per 28-day cycle for cycles 13-30; plus rituximab 375 mg/m2, given on day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (R2, Arm A), or rituximab alone (same schedule, Arm B). Patients receiving R2 maintenance after 18 cycles may continue maintenance lenalidomide monotherapy at 10 mg/day, days 1-21 per 28-day cycle, at the discretion of the patient and/or investigator, until disease progression as tolerated.
The primary endpoint is progression-free survival. Secondary endpoints include safety, overall survival, response rates, duration of response, and quality of life. Patients will be followed for at least 5 years after the last patient-initiated induction therapy. Enrollment in MAGNIFY began in March 2014; as of January 2016, 133 patients are enrolled, according to the study page at ClinicalTrials.gov.
MAGNIFY is a phase IIIB randomized trial actively recruiting patients with relapsed/refractory mantle cell lymphoma, based on studies posted at ClinicalTrials.gov.
MAGNIFY (NCT01996865) is a study of lenalidomide (CC-5013) plus rituximab maintenance therapy, followed by lenalidomide single-agent maintenance therapy, versus rituximab. Sponsored by Celgene, the maker of lenalidomide (Revlimid), the trial’s primary outcome measure is progression-free survival at up to 8 years.
The MAGNIFY trial includes patients with grades 1-3b or transformed follicular lymphoma, marginal zone lymphoma, or mantle cell lymphoma who had received at least one prior therapy and had stage I-IV measurable disease. About 500 patients are planned to enroll in 12 cycles of R2 induction, and slightly more than 300 patients are projected to be randomized after induction to the two maintenance arms. Induction includes oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle; plus intravenous rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles).
Patients will then be randomized to maintenance lenalidomide 10 mg/day, given on days 1-21 per 28-day cycle for cycles 13-30; plus rituximab 375 mg/m2, given on day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (R2, Arm A), or rituximab alone (same schedule, Arm B). Patients receiving R2 maintenance after 18 cycles may continue maintenance lenalidomide monotherapy at 10 mg/day, days 1-21 per 28-day cycle, at the discretion of the patient and/or investigator, until disease progression as tolerated.
The primary endpoint is progression-free survival. Secondary endpoints include safety, overall survival, response rates, duration of response, and quality of life. Patients will be followed for at least 5 years after the last patient-initiated induction therapy. Enrollment in MAGNIFY began in March 2014; as of January 2016, 133 patients are enrolled, according to the study page at ClinicalTrials.gov.
MAGNIFY is a phase IIIB randomized trial actively recruiting patients with relapsed/refractory mantle cell lymphoma, based on studies posted at ClinicalTrials.gov.
MAGNIFY (NCT01996865) is a study of lenalidomide (CC-5013) plus rituximab maintenance therapy, followed by lenalidomide single-agent maintenance therapy, versus rituximab. Sponsored by Celgene, the maker of lenalidomide (Revlimid), the trial’s primary outcome measure is progression-free survival at up to 8 years.
The MAGNIFY trial includes patients with grades 1-3b or transformed follicular lymphoma, marginal zone lymphoma, or mantle cell lymphoma who had received at least one prior therapy and had stage I-IV measurable disease. About 500 patients are planned to enroll in 12 cycles of R2 induction, and slightly more than 300 patients are projected to be randomized after induction to the two maintenance arms. Induction includes oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle; plus intravenous rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles).
Patients will then be randomized to maintenance lenalidomide 10 mg/day, given on days 1-21 per 28-day cycle for cycles 13-30; plus rituximab 375 mg/m2, given on day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (R2, Arm A), or rituximab alone (same schedule, Arm B). Patients receiving R2 maintenance after 18 cycles may continue maintenance lenalidomide monotherapy at 10 mg/day, days 1-21 per 28-day cycle, at the discretion of the patient and/or investigator, until disease progression as tolerated.
The primary endpoint is progression-free survival. Secondary endpoints include safety, overall survival, response rates, duration of response, and quality of life. Patients will be followed for at least 5 years after the last patient-initiated induction therapy. Enrollment in MAGNIFY began in March 2014; as of January 2016, 133 patients are enrolled, according to the study page at ClinicalTrials.gov.