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VIDEO: Are chemo-free regimens possible for CLL?
MILAN – The Food and Drug Administration has given full approval for ibrutinib for patients with chronic lymphocytic leukemia who have received at least one prior therapy and for those who have a deletion in chromosome 17 (17p deletion) and may or may not have received previous treatment.
At the annual congress of the European Hematology Association, Dr. Peter Hillmen discusses the results he presented from RESONATE, the study used to convert conditional, accelerated approval to full approval. The study evaluated daily ibrutinib monotherapy versus the anti-CD20 antibody ofatumumab, for patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
Dr. Hillmen, professor of experimental hematology at the University of Leeds, England, also outlines some of the research in the works to evaluate ibrutinib as frontline therapy for patients with CLL and the possibility of chemotherapy-free regimens. He disclosed a consultancy role and honoraria from Pharmacyclics.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MILAN – The Food and Drug Administration has given full approval for ibrutinib for patients with chronic lymphocytic leukemia who have received at least one prior therapy and for those who have a deletion in chromosome 17 (17p deletion) and may or may not have received previous treatment.
At the annual congress of the European Hematology Association, Dr. Peter Hillmen discusses the results he presented from RESONATE, the study used to convert conditional, accelerated approval to full approval. The study evaluated daily ibrutinib monotherapy versus the anti-CD20 antibody ofatumumab, for patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
Dr. Hillmen, professor of experimental hematology at the University of Leeds, England, also outlines some of the research in the works to evaluate ibrutinib as frontline therapy for patients with CLL and the possibility of chemotherapy-free regimens. He disclosed a consultancy role and honoraria from Pharmacyclics.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MILAN – The Food and Drug Administration has given full approval for ibrutinib for patients with chronic lymphocytic leukemia who have received at least one prior therapy and for those who have a deletion in chromosome 17 (17p deletion) and may or may not have received previous treatment.
At the annual congress of the European Hematology Association, Dr. Peter Hillmen discusses the results he presented from RESONATE, the study used to convert conditional, accelerated approval to full approval. The study evaluated daily ibrutinib monotherapy versus the anti-CD20 antibody ofatumumab, for patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
Dr. Hillmen, professor of experimental hematology at the University of Leeds, England, also outlines some of the research in the works to evaluate ibrutinib as frontline therapy for patients with CLL and the possibility of chemotherapy-free regimens. He disclosed a consultancy role and honoraria from Pharmacyclics.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE EHA CONGRESS
VIDEO: ABT-199 alone and in combination shows promise against advanced CLL
MILAN – Dr. Andrew W. Roberts discusses the high response rates that have occurred with the Bcl-2 inhibitor ABT-199, alone and in combination, against refractory or relapsed chronic lymphocytic leukemia.
Drug-induced tumor lysis syndrome in some patients appears to have been avoided with a new modified dosing regimen, said Dr. Roberts, who presented phase Ib study results of ABT-199 in combination with rituximab at the annual congress of the European Hematology Association. In the interview, Dr. Roberts of the Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia, describes the study results and future plans for ABT-199 research.
On Twitter @nikolaideslaura
MILAN – Dr. Andrew W. Roberts discusses the high response rates that have occurred with the Bcl-2 inhibitor ABT-199, alone and in combination, against refractory or relapsed chronic lymphocytic leukemia.
Drug-induced tumor lysis syndrome in some patients appears to have been avoided with a new modified dosing regimen, said Dr. Roberts, who presented phase Ib study results of ABT-199 in combination with rituximab at the annual congress of the European Hematology Association. In the interview, Dr. Roberts of the Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia, describes the study results and future plans for ABT-199 research.
On Twitter @nikolaideslaura
MILAN – Dr. Andrew W. Roberts discusses the high response rates that have occurred with the Bcl-2 inhibitor ABT-199, alone and in combination, against refractory or relapsed chronic lymphocytic leukemia.
Drug-induced tumor lysis syndrome in some patients appears to have been avoided with a new modified dosing regimen, said Dr. Roberts, who presented phase Ib study results of ABT-199 in combination with rituximab at the annual congress of the European Hematology Association. In the interview, Dr. Roberts of the Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia, describes the study results and future plans for ABT-199 research.
On Twitter @nikolaideslaura
AT THE EHA CONGRESS
FDA gives full approval to ibrutinib for CLL
The Food and Drug Administration has given full approval for ibrutinib (Imbruvica) for patients with chronic lymphocytic leukemia who have received at least one prior therapy and for those who have a deletion in chromosome 17 (17p deletion) and may or may not have received previous treatment.
The drug received conditional, accelerated approval from the FDA in February for CLL. The agency said that new trial results that looked at overall survival and progression-free survival confirmed the drug’s benefit. Ibrutinib’s label will be updated to show that it has a confirmed survival benefit.
The FDA also designated ibrutinib as a breakthrough therapy for CLL with 17p deletion.
"Imbruvica is the fourth drug approved to treat CLL that received a breakthrough therapy designation, reflecting the promise of the breakthrough therapy designation program and demonstrating the FDA’s commitment to working cooperatively with companies to expedite the development, review, and approval of these important new drugs," said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement.
"This FDA approval for Imbruvica is a major step toward chemo-free treatment in CLL," said Dr. John Byrd, director of the hematology division at the Ohio State University Comprehensive Cancer Center, Columbus, in a statement issued by Pharmacyclics, the Sunnyvale, Calif.–based company that is comarketing the drug with Janssen Biotech.
"I continue to be awed by the duration of my patients’ responses to Imbruvica and am grateful Imbruvica now is available to a broader group of CLL patients," said Dr. Byrd, who was a lead investigator for the main trial evaluating ibrutinib, RESONATE.
Three other drugs for CLL have also received breakthrough designations: obinutuzumab (Gazyva), ofatumumab (Arzerra), and most recently, idelalisib (Zydelig), earlier in July.
CLL is a non-Hodgkin’s lymphoma that primarily affects older individuals. The National Cancer Institute estimates that 15,720 Americans will be diagnosed and 4,600 will die from CLL in 2014, the FDA said.
In RESONATE, 391 previously treated patients received either ibrutinib or ofatumumab. Of those, 127 patients had a 17p deletion. The trial was stopped early because overall, patients receiving ibrutinib had a 78% reduction in the risk of disease progression or death, and a 57% reduction in risk of death. For the patients with 17p, there was a 75% reduction in the risk of disease progression or death.
This is the third FDA approval for ibrutinib. In addition to the accelerated approval for CLL in February, the drug was approved for mantle cell lymphoma in November 2013.
Dr. Byrd has served as an unpaid adviser to both Pharmacyclics and Janssen. He reported no financial interest in either company.
On Twitter @aliciaault
The Food and Drug Administration has given full approval for ibrutinib (Imbruvica) for patients with chronic lymphocytic leukemia who have received at least one prior therapy and for those who have a deletion in chromosome 17 (17p deletion) and may or may not have received previous treatment.
The drug received conditional, accelerated approval from the FDA in February for CLL. The agency said that new trial results that looked at overall survival and progression-free survival confirmed the drug’s benefit. Ibrutinib’s label will be updated to show that it has a confirmed survival benefit.
The FDA also designated ibrutinib as a breakthrough therapy for CLL with 17p deletion.
"Imbruvica is the fourth drug approved to treat CLL that received a breakthrough therapy designation, reflecting the promise of the breakthrough therapy designation program and demonstrating the FDA’s commitment to working cooperatively with companies to expedite the development, review, and approval of these important new drugs," said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement.
"This FDA approval for Imbruvica is a major step toward chemo-free treatment in CLL," said Dr. John Byrd, director of the hematology division at the Ohio State University Comprehensive Cancer Center, Columbus, in a statement issued by Pharmacyclics, the Sunnyvale, Calif.–based company that is comarketing the drug with Janssen Biotech.
"I continue to be awed by the duration of my patients’ responses to Imbruvica and am grateful Imbruvica now is available to a broader group of CLL patients," said Dr. Byrd, who was a lead investigator for the main trial evaluating ibrutinib, RESONATE.
Three other drugs for CLL have also received breakthrough designations: obinutuzumab (Gazyva), ofatumumab (Arzerra), and most recently, idelalisib (Zydelig), earlier in July.
CLL is a non-Hodgkin’s lymphoma that primarily affects older individuals. The National Cancer Institute estimates that 15,720 Americans will be diagnosed and 4,600 will die from CLL in 2014, the FDA said.
In RESONATE, 391 previously treated patients received either ibrutinib or ofatumumab. Of those, 127 patients had a 17p deletion. The trial was stopped early because overall, patients receiving ibrutinib had a 78% reduction in the risk of disease progression or death, and a 57% reduction in risk of death. For the patients with 17p, there was a 75% reduction in the risk of disease progression or death.
This is the third FDA approval for ibrutinib. In addition to the accelerated approval for CLL in February, the drug was approved for mantle cell lymphoma in November 2013.
Dr. Byrd has served as an unpaid adviser to both Pharmacyclics and Janssen. He reported no financial interest in either company.
On Twitter @aliciaault
The Food and Drug Administration has given full approval for ibrutinib (Imbruvica) for patients with chronic lymphocytic leukemia who have received at least one prior therapy and for those who have a deletion in chromosome 17 (17p deletion) and may or may not have received previous treatment.
The drug received conditional, accelerated approval from the FDA in February for CLL. The agency said that new trial results that looked at overall survival and progression-free survival confirmed the drug’s benefit. Ibrutinib’s label will be updated to show that it has a confirmed survival benefit.
The FDA also designated ibrutinib as a breakthrough therapy for CLL with 17p deletion.
"Imbruvica is the fourth drug approved to treat CLL that received a breakthrough therapy designation, reflecting the promise of the breakthrough therapy designation program and demonstrating the FDA’s commitment to working cooperatively with companies to expedite the development, review, and approval of these important new drugs," said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement.
"This FDA approval for Imbruvica is a major step toward chemo-free treatment in CLL," said Dr. John Byrd, director of the hematology division at the Ohio State University Comprehensive Cancer Center, Columbus, in a statement issued by Pharmacyclics, the Sunnyvale, Calif.–based company that is comarketing the drug with Janssen Biotech.
"I continue to be awed by the duration of my patients’ responses to Imbruvica and am grateful Imbruvica now is available to a broader group of CLL patients," said Dr. Byrd, who was a lead investigator for the main trial evaluating ibrutinib, RESONATE.
Three other drugs for CLL have also received breakthrough designations: obinutuzumab (Gazyva), ofatumumab (Arzerra), and most recently, idelalisib (Zydelig), earlier in July.
CLL is a non-Hodgkin’s lymphoma that primarily affects older individuals. The National Cancer Institute estimates that 15,720 Americans will be diagnosed and 4,600 will die from CLL in 2014, the FDA said.
In RESONATE, 391 previously treated patients received either ibrutinib or ofatumumab. Of those, 127 patients had a 17p deletion. The trial was stopped early because overall, patients receiving ibrutinib had a 78% reduction in the risk of disease progression or death, and a 57% reduction in risk of death. For the patients with 17p, there was a 75% reduction in the risk of disease progression or death.
This is the third FDA approval for ibrutinib. In addition to the accelerated approval for CLL in February, the drug was approved for mantle cell lymphoma in November 2013.
Dr. Byrd has served as an unpaid adviser to both Pharmacyclics and Janssen. He reported no financial interest in either company.
On Twitter @aliciaault
ABT-199 rebounds in advanced CLL after tackling tumor lysis syndrome
MILAN – The investigational Bcl-2 inhibitor ABT-199 continues to impress with substantial activity as single-agent or combination therapy in relapsed or refractory chronic lymphocytic leukemia, following dose-scheduling modifications to address the risk of tumor lysis syndrome.
ABT-199 monotherapy
Updated data from all 105 CLL patients in the phase I trial show the overall response rate remains high at 77%, with 23% of patients achieving complete remission.
Seven of 11 complete responders assessed had no detectable minimal residual disease, Dr. John F. Seymour said at the annual congress of the European Hematology Association.
Overall response rates were sustained in the 75%-80% range for high-risk patients with deletion 17p, fludarabine-refractory, or immunoglobulin heavy-chain variable (IGHV)-unmutated CLL; and complete response rates in these subgroups also did not differ from the overall group at 22% to 29%.
Prior results from the first-in-human trial dazzled the leukemia community, but tumor lysis syndrome (TLS) complications, including two fatal events, temporarily halted ABT-199 clinical trials and gave the advantage to its closest competitor, the recently approved and more tolerable CLL drug ibrutinib (Imbruvica).
Use of a modified, ramp-up dosing scheme and aggressive TLS prophylaxis appear to have ameliorated the risk of TLS, with no further clinically significant or grade 3 or 4 events reported in the 49 patients treated with this schema, said Dr. Seymour, director of hematology and cancer medicine at the Peter MacCallum Cancer Centre, East Melbourne, Australia.
Rather than using a 3-week schedule and 50-mg starting dose, the safety expansion cohort received once-daily oral ABT-199 beginning at 20 mg, with weekly adjustments to 50 mg, 100 mg, 200 mg, and 400 mg over 5 weeks.
The 400-mg dose has been identified as the phase II dose, with 59% of patients free of progression at 18 months and beyond on this dose, he said.
As of April 2014, 37 of the 105 patients discontinued treatment, 22 due to progressive disease and 12 for adverse events; in addition, two proceeded to allogeneic hematopoietic cell transplantation, and one needed Coumadin, which is not permitted on protocol.
The median duration of response has not yet been reached for patients treated at doses of 400 mg or above, he said.
The most common treatment-emergent adverse events of any grade were diarrhea (40% of patients), neutropenia (36%), and nausea (35%).
Neutropenia was the only grade 3/4 event occurring in more than 10% of patients (33%), followed by anemia in 10%.
Combination ABT-199
Of substantial interest to many was a second phase Ib study presented in the same session, evaluating the role of ABT-199 with the anti-CD20 antibody rituximab (Rituxan) in relapsed or refractory CLL.
After a median time on study of just 7.5 months, the overall response rate was 84% among 25 evaluable patients, including 9 complete responses (36%) and 12 partial responses (48%), said Dr. Andrew W. Roberts, with the Royal Melbourne (Australia) Hospital and Walter and Eliza Hall Institute of Medical Research.
Six of eight complete responders tested were negative for minimal residual disease by flow cytometry.
Preliminary pharmacokinetic results suggest no apparent effect of rituximab on ABT-199 exposure, he said.
Three patients discontinued ABT-199 after achieving a complete remission, including one with fludarabine-refractory disease, and all remain in complete remission at 8.6, 8.8, and 11.6 months after cessation.
Dose modifications were also made in this study following a fatal TLS event in December 2012 after a first dose of ABT-199 at 50 mg. Under the modified step-up dosing, ABT-199 was started at 20 mg, escalating up to 600 mg daily over 5 weeks, with rituximab 375 mg/m2 added on day 1 of week 5 and rituximab 500 mg/m2 added on day 1 of months 2-6.
The combination was well tolerated, and no new safety concerns were identified, Dr. Roberts said. The most common grade 3/4 adverse events among 45 patients evaluable for safety were neutropenia in 47%, anemia in 16%, thrombocytopenia in 13%, and febrile neutropenia in 7%. Grade 3/4 neutropenia was more common at 600 mg, with the 400-mg dose selected for the ongoing safety expansion cohort. Two serious TLS events occurred, but both were prior to schedule modifications, he said.
One patient in the combination study and 13 in the monotherapy study received treatment for small lymphocytic lymphoma. Response rates and tolerability were similar between CLL and SLL patients in the monotherapy study, Dr. Roberts said in an interview.
During a press briefing at the meeting, Dr. Seymour said ABT-199 potentially could be combined with ibrutinib and that the combination was very potent in laboratory tests in both CLL and some forms of mantle cell lymphoma. Negotiations with the various companies involved are intricate, but there is agreement and commitment "to begin clinical trials of the combination later this year," he added.
ABT-199 is currently being evaluated in a phase II trial as monotherapy in deletion 17p relapsed CLL, as combination therapy with rituximab versus bendamustine plus rituximab in a phase III trial in relapsed/refractory CLL, and in combination trials with bendamustine/rituximab and obinutuzumab in relapsed/refractory CLL.
AbbVie and Genentech sponsored the trials. Dr. Seymour is a consultant and adviser for AbbVie, Genentech, and Roche. Dr. Roberts reported research funding from AbbVie and Genentech and milestone payments to his institution related to ABT-199.
MILAN – The investigational Bcl-2 inhibitor ABT-199 continues to impress with substantial activity as single-agent or combination therapy in relapsed or refractory chronic lymphocytic leukemia, following dose-scheduling modifications to address the risk of tumor lysis syndrome.
ABT-199 monotherapy
Updated data from all 105 CLL patients in the phase I trial show the overall response rate remains high at 77%, with 23% of patients achieving complete remission.
Seven of 11 complete responders assessed had no detectable minimal residual disease, Dr. John F. Seymour said at the annual congress of the European Hematology Association.
Overall response rates were sustained in the 75%-80% range for high-risk patients with deletion 17p, fludarabine-refractory, or immunoglobulin heavy-chain variable (IGHV)-unmutated CLL; and complete response rates in these subgroups also did not differ from the overall group at 22% to 29%.
Prior results from the first-in-human trial dazzled the leukemia community, but tumor lysis syndrome (TLS) complications, including two fatal events, temporarily halted ABT-199 clinical trials and gave the advantage to its closest competitor, the recently approved and more tolerable CLL drug ibrutinib (Imbruvica).
Use of a modified, ramp-up dosing scheme and aggressive TLS prophylaxis appear to have ameliorated the risk of TLS, with no further clinically significant or grade 3 or 4 events reported in the 49 patients treated with this schema, said Dr. Seymour, director of hematology and cancer medicine at the Peter MacCallum Cancer Centre, East Melbourne, Australia.
Rather than using a 3-week schedule and 50-mg starting dose, the safety expansion cohort received once-daily oral ABT-199 beginning at 20 mg, with weekly adjustments to 50 mg, 100 mg, 200 mg, and 400 mg over 5 weeks.
The 400-mg dose has been identified as the phase II dose, with 59% of patients free of progression at 18 months and beyond on this dose, he said.
As of April 2014, 37 of the 105 patients discontinued treatment, 22 due to progressive disease and 12 for adverse events; in addition, two proceeded to allogeneic hematopoietic cell transplantation, and one needed Coumadin, which is not permitted on protocol.
The median duration of response has not yet been reached for patients treated at doses of 400 mg or above, he said.
The most common treatment-emergent adverse events of any grade were diarrhea (40% of patients), neutropenia (36%), and nausea (35%).
Neutropenia was the only grade 3/4 event occurring in more than 10% of patients (33%), followed by anemia in 10%.
Combination ABT-199
Of substantial interest to many was a second phase Ib study presented in the same session, evaluating the role of ABT-199 with the anti-CD20 antibody rituximab (Rituxan) in relapsed or refractory CLL.
After a median time on study of just 7.5 months, the overall response rate was 84% among 25 evaluable patients, including 9 complete responses (36%) and 12 partial responses (48%), said Dr. Andrew W. Roberts, with the Royal Melbourne (Australia) Hospital and Walter and Eliza Hall Institute of Medical Research.
Six of eight complete responders tested were negative for minimal residual disease by flow cytometry.
Preliminary pharmacokinetic results suggest no apparent effect of rituximab on ABT-199 exposure, he said.
Three patients discontinued ABT-199 after achieving a complete remission, including one with fludarabine-refractory disease, and all remain in complete remission at 8.6, 8.8, and 11.6 months after cessation.
Dose modifications were also made in this study following a fatal TLS event in December 2012 after a first dose of ABT-199 at 50 mg. Under the modified step-up dosing, ABT-199 was started at 20 mg, escalating up to 600 mg daily over 5 weeks, with rituximab 375 mg/m2 added on day 1 of week 5 and rituximab 500 mg/m2 added on day 1 of months 2-6.
The combination was well tolerated, and no new safety concerns were identified, Dr. Roberts said. The most common grade 3/4 adverse events among 45 patients evaluable for safety were neutropenia in 47%, anemia in 16%, thrombocytopenia in 13%, and febrile neutropenia in 7%. Grade 3/4 neutropenia was more common at 600 mg, with the 400-mg dose selected for the ongoing safety expansion cohort. Two serious TLS events occurred, but both were prior to schedule modifications, he said.
One patient in the combination study and 13 in the monotherapy study received treatment for small lymphocytic lymphoma. Response rates and tolerability were similar between CLL and SLL patients in the monotherapy study, Dr. Roberts said in an interview.
During a press briefing at the meeting, Dr. Seymour said ABT-199 potentially could be combined with ibrutinib and that the combination was very potent in laboratory tests in both CLL and some forms of mantle cell lymphoma. Negotiations with the various companies involved are intricate, but there is agreement and commitment "to begin clinical trials of the combination later this year," he added.
ABT-199 is currently being evaluated in a phase II trial as monotherapy in deletion 17p relapsed CLL, as combination therapy with rituximab versus bendamustine plus rituximab in a phase III trial in relapsed/refractory CLL, and in combination trials with bendamustine/rituximab and obinutuzumab in relapsed/refractory CLL.
AbbVie and Genentech sponsored the trials. Dr. Seymour is a consultant and adviser for AbbVie, Genentech, and Roche. Dr. Roberts reported research funding from AbbVie and Genentech and milestone payments to his institution related to ABT-199.
MILAN – The investigational Bcl-2 inhibitor ABT-199 continues to impress with substantial activity as single-agent or combination therapy in relapsed or refractory chronic lymphocytic leukemia, following dose-scheduling modifications to address the risk of tumor lysis syndrome.
ABT-199 monotherapy
Updated data from all 105 CLL patients in the phase I trial show the overall response rate remains high at 77%, with 23% of patients achieving complete remission.
Seven of 11 complete responders assessed had no detectable minimal residual disease, Dr. John F. Seymour said at the annual congress of the European Hematology Association.
Overall response rates were sustained in the 75%-80% range for high-risk patients with deletion 17p, fludarabine-refractory, or immunoglobulin heavy-chain variable (IGHV)-unmutated CLL; and complete response rates in these subgroups also did not differ from the overall group at 22% to 29%.
Prior results from the first-in-human trial dazzled the leukemia community, but tumor lysis syndrome (TLS) complications, including two fatal events, temporarily halted ABT-199 clinical trials and gave the advantage to its closest competitor, the recently approved and more tolerable CLL drug ibrutinib (Imbruvica).
Use of a modified, ramp-up dosing scheme and aggressive TLS prophylaxis appear to have ameliorated the risk of TLS, with no further clinically significant or grade 3 or 4 events reported in the 49 patients treated with this schema, said Dr. Seymour, director of hematology and cancer medicine at the Peter MacCallum Cancer Centre, East Melbourne, Australia.
Rather than using a 3-week schedule and 50-mg starting dose, the safety expansion cohort received once-daily oral ABT-199 beginning at 20 mg, with weekly adjustments to 50 mg, 100 mg, 200 mg, and 400 mg over 5 weeks.
The 400-mg dose has been identified as the phase II dose, with 59% of patients free of progression at 18 months and beyond on this dose, he said.
As of April 2014, 37 of the 105 patients discontinued treatment, 22 due to progressive disease and 12 for adverse events; in addition, two proceeded to allogeneic hematopoietic cell transplantation, and one needed Coumadin, which is not permitted on protocol.
The median duration of response has not yet been reached for patients treated at doses of 400 mg or above, he said.
The most common treatment-emergent adverse events of any grade were diarrhea (40% of patients), neutropenia (36%), and nausea (35%).
Neutropenia was the only grade 3/4 event occurring in more than 10% of patients (33%), followed by anemia in 10%.
Combination ABT-199
Of substantial interest to many was a second phase Ib study presented in the same session, evaluating the role of ABT-199 with the anti-CD20 antibody rituximab (Rituxan) in relapsed or refractory CLL.
After a median time on study of just 7.5 months, the overall response rate was 84% among 25 evaluable patients, including 9 complete responses (36%) and 12 partial responses (48%), said Dr. Andrew W. Roberts, with the Royal Melbourne (Australia) Hospital and Walter and Eliza Hall Institute of Medical Research.
Six of eight complete responders tested were negative for minimal residual disease by flow cytometry.
Preliminary pharmacokinetic results suggest no apparent effect of rituximab on ABT-199 exposure, he said.
Three patients discontinued ABT-199 after achieving a complete remission, including one with fludarabine-refractory disease, and all remain in complete remission at 8.6, 8.8, and 11.6 months after cessation.
Dose modifications were also made in this study following a fatal TLS event in December 2012 after a first dose of ABT-199 at 50 mg. Under the modified step-up dosing, ABT-199 was started at 20 mg, escalating up to 600 mg daily over 5 weeks, with rituximab 375 mg/m2 added on day 1 of week 5 and rituximab 500 mg/m2 added on day 1 of months 2-6.
The combination was well tolerated, and no new safety concerns were identified, Dr. Roberts said. The most common grade 3/4 adverse events among 45 patients evaluable for safety were neutropenia in 47%, anemia in 16%, thrombocytopenia in 13%, and febrile neutropenia in 7%. Grade 3/4 neutropenia was more common at 600 mg, with the 400-mg dose selected for the ongoing safety expansion cohort. Two serious TLS events occurred, but both were prior to schedule modifications, he said.
One patient in the combination study and 13 in the monotherapy study received treatment for small lymphocytic lymphoma. Response rates and tolerability were similar between CLL and SLL patients in the monotherapy study, Dr. Roberts said in an interview.
During a press briefing at the meeting, Dr. Seymour said ABT-199 potentially could be combined with ibrutinib and that the combination was very potent in laboratory tests in both CLL and some forms of mantle cell lymphoma. Negotiations with the various companies involved are intricate, but there is agreement and commitment "to begin clinical trials of the combination later this year," he added.
ABT-199 is currently being evaluated in a phase II trial as monotherapy in deletion 17p relapsed CLL, as combination therapy with rituximab versus bendamustine plus rituximab in a phase III trial in relapsed/refractory CLL, and in combination trials with bendamustine/rituximab and obinutuzumab in relapsed/refractory CLL.
AbbVie and Genentech sponsored the trials. Dr. Seymour is a consultant and adviser for AbbVie, Genentech, and Roche. Dr. Roberts reported research funding from AbbVie and Genentech and milestone payments to his institution related to ABT-199.
AT THE EHA CONGRESS
Major finding: The overall response rate was 77% with ABT-199 monotherapy and 84% with the addition of rituximab in relapsed or refractory CLL.
Key clinical point: ABT-199 alone or as combination therapy with rituximab has substantial activity in relapsed/refractory CLL.
Data source: Two phase I trials in patients with CLL.
Disclosures: AbbVie and Genentech, codevelopers of ABT-199, sponsored the trials. Dr. Seymour is a consultant and adviser for AbbVie, Genentech, and Roche. Dr. Roberts reported research funding from AbbVie and Genentech and milestone payments to his institution related to ABT-199.
ONO-4059 delivered hit to relapsed/refractory CLL
MILAN – Monotherapy with the oral BTK inhibitor ONO-4059 showed good efficacy over a range of doses in relapsed or refractory and high-risk chronic lymphocytic leukemia, with a best overall response rate of 84% in a phase I trial.
Among 25 evaluable patients, 2 achieved complete responses with incomplete blood count recovery, 12 had partial responses, and 7 had partial responses with lymphocytosis.
One patient had stable disease and another progressive disease. Two patients withdrew due to adverse events.
ONO-4059 showed particularly good efficacy in patients with the deleterious 17p deletion (89%, or 8/9 patients) and in those refractory to their last therapy (91.6% or 11/12 patients), Dr. Franck Morschhauser, reported at the annual congress of the European Hematology Association.
ONO-4059 is a selective Bruton’s tyrosine kinase (BTK) inhibitor that has demonstrated greater than 90% inhibition of BTK at 12 hours in chronic lymphocytic leukemia (CLL) cells in vivo and antitumor activity in non-Hodgkin’s lymphoma.
In relapsed or refractory B-cell lymphoma, the same investigators reported a best overall response rate of 42% with ONO-4059 at doses of 40, 80, and 160 mg among 12 patients in a phase I study.
The current dose-escalation study evaluated the safety and tolerability of once-daily ONO-4059 at doses ranging from 20 to 600 mg for up to 2 years in patients with relapsed/refractory or high-risk CLL for whom no therapy of higher priority was available. Dose escalation was permitted upon completion of 6 months of treatment. The median duration of treatment was 11.5 cycles.
The 25 evaluable patients (median age, 67 years) had received a median of four prior therapies (range 2-9); 92% had prior exposure to rituximab (Rituxan) and 92% to fludarabine (Fludara); and 48% were refractory to their last therapy.
Lymph node reduction occurred early, between day 1 and 28 of the first cycle, and was accompanied by an improvement in hemoglobin and platelet counts within 3-4 months, said Dr. Morschhauser, head of the lymphoma unit, Centre Hospitalier Régional Universitaire–Claude Huriez Hospital, Lille, France.
"So far we do not have evidence that there is a dose-efficacy relationship, although there is quicker tumor shrinkage when you increase the dose," he said.
The majority of adverse events were grade 1 and 2, with a low incidence of diarrhea, fatigue, bruising, and rash and no dose-limiting toxicities, Dr. Morschhauser said. Five patients experienced grade 3/4 neutropenia: two grade 3 events at 20 and 40 mg and three grade 4 events at 20, 80, and 320 mg.
Eight ONO-4059–related serious adverse events were reported, including febrile neutropenia in the patient with grade 4 neutropenia at the 20-mg dose, pyrexia at 20 mg, rash at 80 mg, hepatitis E reactivation and neutropenia at 320 mg, lymphocytic infiltration of the right dorsal muscle and purpura at 400 mg, and spontaneous psoas hematoma at 500 mg. All events resolved, and four patients remain on study, he reported on behalf of lead author Dr. Christopher Fegan, clinical director of CLL, University Hospital of Wales, Cardiff.
The study was supported by Ono Pharmaceutical. The study authors reported no relevant financial disclosures.
MILAN – Monotherapy with the oral BTK inhibitor ONO-4059 showed good efficacy over a range of doses in relapsed or refractory and high-risk chronic lymphocytic leukemia, with a best overall response rate of 84% in a phase I trial.
Among 25 evaluable patients, 2 achieved complete responses with incomplete blood count recovery, 12 had partial responses, and 7 had partial responses with lymphocytosis.
One patient had stable disease and another progressive disease. Two patients withdrew due to adverse events.
ONO-4059 showed particularly good efficacy in patients with the deleterious 17p deletion (89%, or 8/9 patients) and in those refractory to their last therapy (91.6% or 11/12 patients), Dr. Franck Morschhauser, reported at the annual congress of the European Hematology Association.
ONO-4059 is a selective Bruton’s tyrosine kinase (BTK) inhibitor that has demonstrated greater than 90% inhibition of BTK at 12 hours in chronic lymphocytic leukemia (CLL) cells in vivo and antitumor activity in non-Hodgkin’s lymphoma.
In relapsed or refractory B-cell lymphoma, the same investigators reported a best overall response rate of 42% with ONO-4059 at doses of 40, 80, and 160 mg among 12 patients in a phase I study.
The current dose-escalation study evaluated the safety and tolerability of once-daily ONO-4059 at doses ranging from 20 to 600 mg for up to 2 years in patients with relapsed/refractory or high-risk CLL for whom no therapy of higher priority was available. Dose escalation was permitted upon completion of 6 months of treatment. The median duration of treatment was 11.5 cycles.
The 25 evaluable patients (median age, 67 years) had received a median of four prior therapies (range 2-9); 92% had prior exposure to rituximab (Rituxan) and 92% to fludarabine (Fludara); and 48% were refractory to their last therapy.
Lymph node reduction occurred early, between day 1 and 28 of the first cycle, and was accompanied by an improvement in hemoglobin and platelet counts within 3-4 months, said Dr. Morschhauser, head of the lymphoma unit, Centre Hospitalier Régional Universitaire–Claude Huriez Hospital, Lille, France.
"So far we do not have evidence that there is a dose-efficacy relationship, although there is quicker tumor shrinkage when you increase the dose," he said.
The majority of adverse events were grade 1 and 2, with a low incidence of diarrhea, fatigue, bruising, and rash and no dose-limiting toxicities, Dr. Morschhauser said. Five patients experienced grade 3/4 neutropenia: two grade 3 events at 20 and 40 mg and three grade 4 events at 20, 80, and 320 mg.
Eight ONO-4059–related serious adverse events were reported, including febrile neutropenia in the patient with grade 4 neutropenia at the 20-mg dose, pyrexia at 20 mg, rash at 80 mg, hepatitis E reactivation and neutropenia at 320 mg, lymphocytic infiltration of the right dorsal muscle and purpura at 400 mg, and spontaneous psoas hematoma at 500 mg. All events resolved, and four patients remain on study, he reported on behalf of lead author Dr. Christopher Fegan, clinical director of CLL, University Hospital of Wales, Cardiff.
The study was supported by Ono Pharmaceutical. The study authors reported no relevant financial disclosures.
MILAN – Monotherapy with the oral BTK inhibitor ONO-4059 showed good efficacy over a range of doses in relapsed or refractory and high-risk chronic lymphocytic leukemia, with a best overall response rate of 84% in a phase I trial.
Among 25 evaluable patients, 2 achieved complete responses with incomplete blood count recovery, 12 had partial responses, and 7 had partial responses with lymphocytosis.
One patient had stable disease and another progressive disease. Two patients withdrew due to adverse events.
ONO-4059 showed particularly good efficacy in patients with the deleterious 17p deletion (89%, or 8/9 patients) and in those refractory to their last therapy (91.6% or 11/12 patients), Dr. Franck Morschhauser, reported at the annual congress of the European Hematology Association.
ONO-4059 is a selective Bruton’s tyrosine kinase (BTK) inhibitor that has demonstrated greater than 90% inhibition of BTK at 12 hours in chronic lymphocytic leukemia (CLL) cells in vivo and antitumor activity in non-Hodgkin’s lymphoma.
In relapsed or refractory B-cell lymphoma, the same investigators reported a best overall response rate of 42% with ONO-4059 at doses of 40, 80, and 160 mg among 12 patients in a phase I study.
The current dose-escalation study evaluated the safety and tolerability of once-daily ONO-4059 at doses ranging from 20 to 600 mg for up to 2 years in patients with relapsed/refractory or high-risk CLL for whom no therapy of higher priority was available. Dose escalation was permitted upon completion of 6 months of treatment. The median duration of treatment was 11.5 cycles.
The 25 evaluable patients (median age, 67 years) had received a median of four prior therapies (range 2-9); 92% had prior exposure to rituximab (Rituxan) and 92% to fludarabine (Fludara); and 48% were refractory to their last therapy.
Lymph node reduction occurred early, between day 1 and 28 of the first cycle, and was accompanied by an improvement in hemoglobin and platelet counts within 3-4 months, said Dr. Morschhauser, head of the lymphoma unit, Centre Hospitalier Régional Universitaire–Claude Huriez Hospital, Lille, France.
"So far we do not have evidence that there is a dose-efficacy relationship, although there is quicker tumor shrinkage when you increase the dose," he said.
The majority of adverse events were grade 1 and 2, with a low incidence of diarrhea, fatigue, bruising, and rash and no dose-limiting toxicities, Dr. Morschhauser said. Five patients experienced grade 3/4 neutropenia: two grade 3 events at 20 and 40 mg and three grade 4 events at 20, 80, and 320 mg.
Eight ONO-4059–related serious adverse events were reported, including febrile neutropenia in the patient with grade 4 neutropenia at the 20-mg dose, pyrexia at 20 mg, rash at 80 mg, hepatitis E reactivation and neutropenia at 320 mg, lymphocytic infiltration of the right dorsal muscle and purpura at 400 mg, and spontaneous psoas hematoma at 500 mg. All events resolved, and four patients remain on study, he reported on behalf of lead author Dr. Christopher Fegan, clinical director of CLL, University Hospital of Wales, Cardiff.
The study was supported by Ono Pharmaceutical. The study authors reported no relevant financial disclosures.
AT THE EHA CONGRESS
Key clinical point: ONO-4059 induced responses in most patients with relapsed/refractory CLL, including those with a 17p deletion.
Major finding: The best response rate was 84% overall, 89% in 17p deletion patients, and 91.6% in refractory disease.
Data source: A phase I trial in 25 patients with relapsed/refractory or high-risk chronic lymphocytic leukemia.
Disclosures: The study was supported by Ono Pharmaceutical. The study authors reported no relevant financial disclosures.
Idelalisib efficacy remains rock steady in relapsed CLL
MILAN – The benefits of combining idelalisib with rituximab remained unchanged in heavily pretreated, relapsed chronic lymphocytic leukemia unsuitable for chemotherapy in the second interim analysis of a phase III trial and extension study.
With 63% of events reported in Study 116, the primary endpoint of progression-free survival was 5.5 months with rituximab (Rituxan) plus placebo and had not been reached with rituximab and idelalisib.
These data were identical to those observed in the first interim analysis, save for an almost imperceptible shift in the hazard ratio from 0.15 to 0.18, with the same P value of less than .0001.
In the poor-prognosis subsets of patients with the 17p deletion and/or TP53 mutations or unmutated immunoglobulin heavy chain variable disease, median progression-free survival had also yet to be reached with the combination, compared with medians of 4.0 months (HR, 0.16) and 5.5 months (HR, 0.14) with single-agent rituximab, Dr. Steven Coutre said at the annual congress of the European Hematology Association.
As previously reported by this publication, Study 116 was stopped early after the first interim analysis and 50% of events reported due to overwhelming efficacy. The results also prompted the Food & Drug Administration to grant idelalisib, an oral phosphoinositide 3–kinase-delta inhibitor, breakthrough therapy designation for relapsed chronic lymphocytic leukemia (CLL).
In the second interim analysis, the addition of idelalisib to rituximab significantly increased the overall response rate from 15% to 77% (Odds ratio 17.3; P less than .0001) and number of patients achieving at least a 50% reduction in lymph nodes from 6% to 92% (OR, 165.5; P less than .0001), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.
Median overall survival had yet to be reached at 18 months follow-up, but was significantly longer in the idelalisib arm (HR, 0.28; P = .003).
Adverse events were quite common in either arm, but "importantly, the combination demonstrated an acceptable and manageable safety profile," he said.
As previously seen, diarrhea, colitis, and grade 3/4 transaminase elevations were more common with idelalisib, but infusion site reactions were less frequent.
The 110 patients in the idelalisib arm, as compared with 108 controls, had more grade 3 or higher adverse events (AEs)(64% and 52%) and serious AEs (49% and 38%), but fewer AEs leading to treatment discontinuation (10% vs. 12%) or death (3% vs. 11%).
During a discussion of the results, the issue of the study’s comparator arm was raised once again. Dr. Coutre observed that while he is not a "big fan of single-agent rituximab" because "it is not particularly effective, certainly not in targeting the bone marrow, the reality in the United States is that it is probably the single most used regimen in this population ... so I think it is a very valid comparison."
Recruitment is currently underway for a phase II study, the first to evaluate idelalisib alone or combined with rituximab in untreated CLL and small lymphocytic lymphoma. Idelalisib has shown single-agent activity in relapsed or refractory CLL or small lymphocytic lymphoma, but Dr. Coutre said in an interview that "It is premature to consider idelalisib for front-line therapy. There are ongoing trials for this indication."
The study was supported by Gilead Sciences. Dr. Coutre reported personal fees from Gilead for a 1-day advisory board.
MILAN – The benefits of combining idelalisib with rituximab remained unchanged in heavily pretreated, relapsed chronic lymphocytic leukemia unsuitable for chemotherapy in the second interim analysis of a phase III trial and extension study.
With 63% of events reported in Study 116, the primary endpoint of progression-free survival was 5.5 months with rituximab (Rituxan) plus placebo and had not been reached with rituximab and idelalisib.
These data were identical to those observed in the first interim analysis, save for an almost imperceptible shift in the hazard ratio from 0.15 to 0.18, with the same P value of less than .0001.
In the poor-prognosis subsets of patients with the 17p deletion and/or TP53 mutations or unmutated immunoglobulin heavy chain variable disease, median progression-free survival had also yet to be reached with the combination, compared with medians of 4.0 months (HR, 0.16) and 5.5 months (HR, 0.14) with single-agent rituximab, Dr. Steven Coutre said at the annual congress of the European Hematology Association.
As previously reported by this publication, Study 116 was stopped early after the first interim analysis and 50% of events reported due to overwhelming efficacy. The results also prompted the Food & Drug Administration to grant idelalisib, an oral phosphoinositide 3–kinase-delta inhibitor, breakthrough therapy designation for relapsed chronic lymphocytic leukemia (CLL).
In the second interim analysis, the addition of idelalisib to rituximab significantly increased the overall response rate from 15% to 77% (Odds ratio 17.3; P less than .0001) and number of patients achieving at least a 50% reduction in lymph nodes from 6% to 92% (OR, 165.5; P less than .0001), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.
Median overall survival had yet to be reached at 18 months follow-up, but was significantly longer in the idelalisib arm (HR, 0.28; P = .003).
Adverse events were quite common in either arm, but "importantly, the combination demonstrated an acceptable and manageable safety profile," he said.
As previously seen, diarrhea, colitis, and grade 3/4 transaminase elevations were more common with idelalisib, but infusion site reactions were less frequent.
The 110 patients in the idelalisib arm, as compared with 108 controls, had more grade 3 or higher adverse events (AEs)(64% and 52%) and serious AEs (49% and 38%), but fewer AEs leading to treatment discontinuation (10% vs. 12%) or death (3% vs. 11%).
During a discussion of the results, the issue of the study’s comparator arm was raised once again. Dr. Coutre observed that while he is not a "big fan of single-agent rituximab" because "it is not particularly effective, certainly not in targeting the bone marrow, the reality in the United States is that it is probably the single most used regimen in this population ... so I think it is a very valid comparison."
Recruitment is currently underway for a phase II study, the first to evaluate idelalisib alone or combined with rituximab in untreated CLL and small lymphocytic lymphoma. Idelalisib has shown single-agent activity in relapsed or refractory CLL or small lymphocytic lymphoma, but Dr. Coutre said in an interview that "It is premature to consider idelalisib for front-line therapy. There are ongoing trials for this indication."
The study was supported by Gilead Sciences. Dr. Coutre reported personal fees from Gilead for a 1-day advisory board.
MILAN – The benefits of combining idelalisib with rituximab remained unchanged in heavily pretreated, relapsed chronic lymphocytic leukemia unsuitable for chemotherapy in the second interim analysis of a phase III trial and extension study.
With 63% of events reported in Study 116, the primary endpoint of progression-free survival was 5.5 months with rituximab (Rituxan) plus placebo and had not been reached with rituximab and idelalisib.
These data were identical to those observed in the first interim analysis, save for an almost imperceptible shift in the hazard ratio from 0.15 to 0.18, with the same P value of less than .0001.
In the poor-prognosis subsets of patients with the 17p deletion and/or TP53 mutations or unmutated immunoglobulin heavy chain variable disease, median progression-free survival had also yet to be reached with the combination, compared with medians of 4.0 months (HR, 0.16) and 5.5 months (HR, 0.14) with single-agent rituximab, Dr. Steven Coutre said at the annual congress of the European Hematology Association.
As previously reported by this publication, Study 116 was stopped early after the first interim analysis and 50% of events reported due to overwhelming efficacy. The results also prompted the Food & Drug Administration to grant idelalisib, an oral phosphoinositide 3–kinase-delta inhibitor, breakthrough therapy designation for relapsed chronic lymphocytic leukemia (CLL).
In the second interim analysis, the addition of idelalisib to rituximab significantly increased the overall response rate from 15% to 77% (Odds ratio 17.3; P less than .0001) and number of patients achieving at least a 50% reduction in lymph nodes from 6% to 92% (OR, 165.5; P less than .0001), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.
Median overall survival had yet to be reached at 18 months follow-up, but was significantly longer in the idelalisib arm (HR, 0.28; P = .003).
Adverse events were quite common in either arm, but "importantly, the combination demonstrated an acceptable and manageable safety profile," he said.
As previously seen, diarrhea, colitis, and grade 3/4 transaminase elevations were more common with idelalisib, but infusion site reactions were less frequent.
The 110 patients in the idelalisib arm, as compared with 108 controls, had more grade 3 or higher adverse events (AEs)(64% and 52%) and serious AEs (49% and 38%), but fewer AEs leading to treatment discontinuation (10% vs. 12%) or death (3% vs. 11%).
During a discussion of the results, the issue of the study’s comparator arm was raised once again. Dr. Coutre observed that while he is not a "big fan of single-agent rituximab" because "it is not particularly effective, certainly not in targeting the bone marrow, the reality in the United States is that it is probably the single most used regimen in this population ... so I think it is a very valid comparison."
Recruitment is currently underway for a phase II study, the first to evaluate idelalisib alone or combined with rituximab in untreated CLL and small lymphocytic lymphoma. Idelalisib has shown single-agent activity in relapsed or refractory CLL or small lymphocytic lymphoma, but Dr. Coutre said in an interview that "It is premature to consider idelalisib for front-line therapy. There are ongoing trials for this indication."
The study was supported by Gilead Sciences. Dr. Coutre reported personal fees from Gilead for a 1-day advisory board.
AT THE EHA CONGRESS
Major finding: Idelalisib and rituximab significantly increased progression-free survival (HR, 0.18; P less than .0001).
Data source: A prospective phase III study in 220 patients with relapsed CLL.
Key clinical point: Adding idelalisib to rituximab improves overall response rate, progression-free survival, and overall survival in heavily pretreated relapsed CLL.
Disclosures: The study was supported by Gilead Sciences. Dr. Coutre reported personal fees from Gilead for a 1-day advisory board.
Ibrutinib holds CLL at bay in majority of patients at 30 months
CHICAGO – Ibrutinib continues showing strength in a large majority of patients with chronic lymphocytic leukemia, including those with poor-prognosis chromosomal deletions, a study showed.
Three-year follow-up data of patients treated with ibrutinib (Imbruvica) monotherapy in a phase II trial and extension study showed 30-month overall survival (OS) rates of 96.6% for patients who received ibrutinib after an initial diagnosis, and 79.9% for patients with relapsed or refractory disease. Median overall survival has not been reached for either group, reported Dr. Susan M. O’Brien of the University of Texas M.D. Anderson Cancer Center, Houston.
Among patients with the poor-prognosis chromosome 17p deletion (del17p), 30-month OS was 65.9%, with the median OS not yet reached, Dr. O’Brien reported at the annual meeting of the American Society of Clinical Oncology.
"We achieved very rapid and quite durable responses with single-agent ibrutinib. We have not reached a median duration of response," she said.
The best investigator-assessed responses were 87% among 31 treatment-naive patients, and 90% among those with relapsed/refractory disease, some of whom had received four prior lines of therapy.
"I think one example of how this data will change clinical practice was the progression-free survival based on cytogenetics," commented invited discussant Dr. Nicole Lamanna of Columbia University Medical Center, New York.
The 30-month progression-free survival (PFS) by cytogenetics (as determined by fluorescence in situ hybridization) was 45.9% for patients with del17p, 74.2% for patients with the 11q deletion (del11q), and 89.0% for patients with neither deletion. The median PFS was 28.1 months among patients with del17p, but has not been reached in patients in the other two cytogenetic groups.
"With some of the other regimens that have been presented in patients with 17p, clearly a median PFS of this length has really not been achieved," she said.
In a separate study, also presented at ASCO 2014, investigators reported the results of the first interim analysis of a phase III randomized trial, which showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) assigned to receive ibrutinib was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).
Independent Review
Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase, an enzyme essential for B-cell receptor signaling and adhesion that is present in many types of B-cell malignancies. Based on the results of phase II studies, ibrutinib received Food and Drug Administration approval for relapsed mantle cell lymphoma in November 2013, and for CLL in February 2014.
Dr. O’Brien and colleagues reviewed data on 31 patients aged 65 and over with newly diagnosed, untreated CLL/SLL, and 101 patients with relapsed/refractory CLL/SLL. The relapsed/refractory group included patients with high-risk CLL/SLL, defined as disease progression within 24 months of starting a chemoimmunotherapy regimen, or as a failure to respond.
The investigators initially tested ibrutinib at 420 and 840 mg daily doses, but soon discovered that there were no differences in efficacy or toxicity between the two doses. Dr. O’Brien therefore reported combined data on patients treated at each dose level.
For patients with relapsed/refractory disease, the median number of prior therapies was 4 (range, 1-12). All patients in this group had received chemotherapy, and more than 90% had received a nucleoside analogue, an alkylating agent, and anti–CD20-based therapy.
In all, 6% of treatment-naive patients and 34% of relapsed/refractory patients had del17p. Del11q was seen in 3% and 35% of patients, respectively.
At the most recent analysis, 25 of 31 treatment-naive patients (81%) and 42% of relapsed/refractory patients had been on ibrutinib for 2-3 years. Only one patient in the treatment-naive group and 19 in the relapsed/refractory group discontinued therapy because of disease progression.
Of the treatment-naive patients with responses, 13% had a complete response (CR), 3% had a near CR, 65% had a partial response (PR), and 6% had a PR with lymphocytosis. Of the relapsed/refractory group, 6% had a CR, 80% had a PR, and 4% had a PR with lymphocytosis.
The responses tend to improve over time, with a median time to first response of 1.9 months, and a median time to best response of 7.3 months.
Adverse events of grade 3 or greater occurred in 19 treatment-naive patients and 83 relapsed/refractory patients. Of these events, 7 (23%) in treatment-naive patients and 32 (32%) in relapsed/refractory patients were deemed to be ibrutinib related. One patient in the treatment-naive group and 11 in the relapsed/refractory group died during the study.
"If we look now at the adverse events over time, we see that in fact they tend to go down, and so – this is important – we’re not seeing a late, surprising side effect with 2 or 3 years of follow-up in terms of things that we didn’t see when we first started the patient on study," Dr. O’Brien said.
The most common side effects were hypertension and pneumonia.
The PCYC-1002 and -1003 studies were supported by Pharmacyclics. Dr. O’Brien disclosed receiving research funding from the company. Dr. Lamanna disclosed consulting/advising for Celgene, and receiving research funding from several companies, but not Pharmacyclics.
CHICAGO – Ibrutinib continues showing strength in a large majority of patients with chronic lymphocytic leukemia, including those with poor-prognosis chromosomal deletions, a study showed.
Three-year follow-up data of patients treated with ibrutinib (Imbruvica) monotherapy in a phase II trial and extension study showed 30-month overall survival (OS) rates of 96.6% for patients who received ibrutinib after an initial diagnosis, and 79.9% for patients with relapsed or refractory disease. Median overall survival has not been reached for either group, reported Dr. Susan M. O’Brien of the University of Texas M.D. Anderson Cancer Center, Houston.
Among patients with the poor-prognosis chromosome 17p deletion (del17p), 30-month OS was 65.9%, with the median OS not yet reached, Dr. O’Brien reported at the annual meeting of the American Society of Clinical Oncology.
"We achieved very rapid and quite durable responses with single-agent ibrutinib. We have not reached a median duration of response," she said.
The best investigator-assessed responses were 87% among 31 treatment-naive patients, and 90% among those with relapsed/refractory disease, some of whom had received four prior lines of therapy.
"I think one example of how this data will change clinical practice was the progression-free survival based on cytogenetics," commented invited discussant Dr. Nicole Lamanna of Columbia University Medical Center, New York.
The 30-month progression-free survival (PFS) by cytogenetics (as determined by fluorescence in situ hybridization) was 45.9% for patients with del17p, 74.2% for patients with the 11q deletion (del11q), and 89.0% for patients with neither deletion. The median PFS was 28.1 months among patients with del17p, but has not been reached in patients in the other two cytogenetic groups.
"With some of the other regimens that have been presented in patients with 17p, clearly a median PFS of this length has really not been achieved," she said.
In a separate study, also presented at ASCO 2014, investigators reported the results of the first interim analysis of a phase III randomized trial, which showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) assigned to receive ibrutinib was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).
Independent Review
Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase, an enzyme essential for B-cell receptor signaling and adhesion that is present in many types of B-cell malignancies. Based on the results of phase II studies, ibrutinib received Food and Drug Administration approval for relapsed mantle cell lymphoma in November 2013, and for CLL in February 2014.
Dr. O’Brien and colleagues reviewed data on 31 patients aged 65 and over with newly diagnosed, untreated CLL/SLL, and 101 patients with relapsed/refractory CLL/SLL. The relapsed/refractory group included patients with high-risk CLL/SLL, defined as disease progression within 24 months of starting a chemoimmunotherapy regimen, or as a failure to respond.
The investigators initially tested ibrutinib at 420 and 840 mg daily doses, but soon discovered that there were no differences in efficacy or toxicity between the two doses. Dr. O’Brien therefore reported combined data on patients treated at each dose level.
For patients with relapsed/refractory disease, the median number of prior therapies was 4 (range, 1-12). All patients in this group had received chemotherapy, and more than 90% had received a nucleoside analogue, an alkylating agent, and anti–CD20-based therapy.
In all, 6% of treatment-naive patients and 34% of relapsed/refractory patients had del17p. Del11q was seen in 3% and 35% of patients, respectively.
At the most recent analysis, 25 of 31 treatment-naive patients (81%) and 42% of relapsed/refractory patients had been on ibrutinib for 2-3 years. Only one patient in the treatment-naive group and 19 in the relapsed/refractory group discontinued therapy because of disease progression.
Of the treatment-naive patients with responses, 13% had a complete response (CR), 3% had a near CR, 65% had a partial response (PR), and 6% had a PR with lymphocytosis. Of the relapsed/refractory group, 6% had a CR, 80% had a PR, and 4% had a PR with lymphocytosis.
The responses tend to improve over time, with a median time to first response of 1.9 months, and a median time to best response of 7.3 months.
Adverse events of grade 3 or greater occurred in 19 treatment-naive patients and 83 relapsed/refractory patients. Of these events, 7 (23%) in treatment-naive patients and 32 (32%) in relapsed/refractory patients were deemed to be ibrutinib related. One patient in the treatment-naive group and 11 in the relapsed/refractory group died during the study.
"If we look now at the adverse events over time, we see that in fact they tend to go down, and so – this is important – we’re not seeing a late, surprising side effect with 2 or 3 years of follow-up in terms of things that we didn’t see when we first started the patient on study," Dr. O’Brien said.
The most common side effects were hypertension and pneumonia.
The PCYC-1002 and -1003 studies were supported by Pharmacyclics. Dr. O’Brien disclosed receiving research funding from the company. Dr. Lamanna disclosed consulting/advising for Celgene, and receiving research funding from several companies, but not Pharmacyclics.
CHICAGO – Ibrutinib continues showing strength in a large majority of patients with chronic lymphocytic leukemia, including those with poor-prognosis chromosomal deletions, a study showed.
Three-year follow-up data of patients treated with ibrutinib (Imbruvica) monotherapy in a phase II trial and extension study showed 30-month overall survival (OS) rates of 96.6% for patients who received ibrutinib after an initial diagnosis, and 79.9% for patients with relapsed or refractory disease. Median overall survival has not been reached for either group, reported Dr. Susan M. O’Brien of the University of Texas M.D. Anderson Cancer Center, Houston.
Among patients with the poor-prognosis chromosome 17p deletion (del17p), 30-month OS was 65.9%, with the median OS not yet reached, Dr. O’Brien reported at the annual meeting of the American Society of Clinical Oncology.
"We achieved very rapid and quite durable responses with single-agent ibrutinib. We have not reached a median duration of response," she said.
The best investigator-assessed responses were 87% among 31 treatment-naive patients, and 90% among those with relapsed/refractory disease, some of whom had received four prior lines of therapy.
"I think one example of how this data will change clinical practice was the progression-free survival based on cytogenetics," commented invited discussant Dr. Nicole Lamanna of Columbia University Medical Center, New York.
The 30-month progression-free survival (PFS) by cytogenetics (as determined by fluorescence in situ hybridization) was 45.9% for patients with del17p, 74.2% for patients with the 11q deletion (del11q), and 89.0% for patients with neither deletion. The median PFS was 28.1 months among patients with del17p, but has not been reached in patients in the other two cytogenetic groups.
"With some of the other regimens that have been presented in patients with 17p, clearly a median PFS of this length has really not been achieved," she said.
In a separate study, also presented at ASCO 2014, investigators reported the results of the first interim analysis of a phase III randomized trial, which showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) assigned to receive ibrutinib was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).
Independent Review
Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase, an enzyme essential for B-cell receptor signaling and adhesion that is present in many types of B-cell malignancies. Based on the results of phase II studies, ibrutinib received Food and Drug Administration approval for relapsed mantle cell lymphoma in November 2013, and for CLL in February 2014.
Dr. O’Brien and colleagues reviewed data on 31 patients aged 65 and over with newly diagnosed, untreated CLL/SLL, and 101 patients with relapsed/refractory CLL/SLL. The relapsed/refractory group included patients with high-risk CLL/SLL, defined as disease progression within 24 months of starting a chemoimmunotherapy regimen, or as a failure to respond.
The investigators initially tested ibrutinib at 420 and 840 mg daily doses, but soon discovered that there were no differences in efficacy or toxicity between the two doses. Dr. O’Brien therefore reported combined data on patients treated at each dose level.
For patients with relapsed/refractory disease, the median number of prior therapies was 4 (range, 1-12). All patients in this group had received chemotherapy, and more than 90% had received a nucleoside analogue, an alkylating agent, and anti–CD20-based therapy.
In all, 6% of treatment-naive patients and 34% of relapsed/refractory patients had del17p. Del11q was seen in 3% and 35% of patients, respectively.
At the most recent analysis, 25 of 31 treatment-naive patients (81%) and 42% of relapsed/refractory patients had been on ibrutinib for 2-3 years. Only one patient in the treatment-naive group and 19 in the relapsed/refractory group discontinued therapy because of disease progression.
Of the treatment-naive patients with responses, 13% had a complete response (CR), 3% had a near CR, 65% had a partial response (PR), and 6% had a PR with lymphocytosis. Of the relapsed/refractory group, 6% had a CR, 80% had a PR, and 4% had a PR with lymphocytosis.
The responses tend to improve over time, with a median time to first response of 1.9 months, and a median time to best response of 7.3 months.
Adverse events of grade 3 or greater occurred in 19 treatment-naive patients and 83 relapsed/refractory patients. Of these events, 7 (23%) in treatment-naive patients and 32 (32%) in relapsed/refractory patients were deemed to be ibrutinib related. One patient in the treatment-naive group and 11 in the relapsed/refractory group died during the study.
"If we look now at the adverse events over time, we see that in fact they tend to go down, and so – this is important – we’re not seeing a late, surprising side effect with 2 or 3 years of follow-up in terms of things that we didn’t see when we first started the patient on study," Dr. O’Brien said.
The most common side effects were hypertension and pneumonia.
The PCYC-1002 and -1003 studies were supported by Pharmacyclics. Dr. O’Brien disclosed receiving research funding from the company. Dr. Lamanna disclosed consulting/advising for Celgene, and receiving research funding from several companies, but not Pharmacyclics.
AT THE ASCO ANNUAL MEETING 2014
Major finding: At 30 months of follow-up, overall survival with ibrutinib monotherapy was 96.6% among patients with newly diagnosed chronic lymphocytic leukemia, and 79.9% for patients with relapsed/refractory CLL.
Data source: Long-term follow-up of 132 patients in a phase II safety and efficacy trial and extension study.
Disclosures: The PCYC-1002 and -1003 studies were supported by Pharmacyclics. Dr. O’Brien disclosed receiving research funding from the company. Dr. Lamanna disclosed consulting/advising for Celgene, and receiving research funding from several companies, but not Pharmacyclics.
VIDEO: Ibrutinib boosts survival of relapsed/refractory CLL
CHICAGO – For the first time an oral drug, ibrutinib, has been shown to significantly improve both progression-free and overall survival of patients with relapsed or refractory chronic lymphocytic leukemia, compared with a systemic agent.
We interviewed lead author Dr. John Byrd about the first interim analysis from RESONATE, a phase III randomized trial, comparing ibrutinib with ofatumumab for the treatment of relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma at the annual meeting of the American Society of Clinical Oncology. The analysis showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma assigned to receive ibrutinib (Imbruvica) was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).
Dr. Byrd is professor of medicine at the Ohio State University Comprehensive Cancer Center, Columbus. The study was supported by Pharmacyclics. Dr. Byrd disclosed receiving research funding and serving as an unpaid advisor to the company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – For the first time an oral drug, ibrutinib, has been shown to significantly improve both progression-free and overall survival of patients with relapsed or refractory chronic lymphocytic leukemia, compared with a systemic agent.
We interviewed lead author Dr. John Byrd about the first interim analysis from RESONATE, a phase III randomized trial, comparing ibrutinib with ofatumumab for the treatment of relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma at the annual meeting of the American Society of Clinical Oncology. The analysis showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma assigned to receive ibrutinib (Imbruvica) was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).
Dr. Byrd is professor of medicine at the Ohio State University Comprehensive Cancer Center, Columbus. The study was supported by Pharmacyclics. Dr. Byrd disclosed receiving research funding and serving as an unpaid advisor to the company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – For the first time an oral drug, ibrutinib, has been shown to significantly improve both progression-free and overall survival of patients with relapsed or refractory chronic lymphocytic leukemia, compared with a systemic agent.
We interviewed lead author Dr. John Byrd about the first interim analysis from RESONATE, a phase III randomized trial, comparing ibrutinib with ofatumumab for the treatment of relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma at the annual meeting of the American Society of Clinical Oncology. The analysis showed that 1-year overall survival for patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma assigned to receive ibrutinib (Imbruvica) was 90%, compared with 81% for patients assigned to ofatumumab (Arzerra).
Dr. Byrd is professor of medicine at the Ohio State University Comprehensive Cancer Center, Columbus. The study was supported by Pharmacyclics. Dr. Byrd disclosed receiving research funding and serving as an unpaid advisor to the company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE ASCO ANNUAL MEETING 2014
Drugs approved in 2013
In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [223Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.
There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.
The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.
Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.
Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.
There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.
The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.
Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.
Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.
Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).
Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.
Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.
Technetium (99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (99mTc). Animal reproduction studies have not been conducted. 99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.
The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.
Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta2-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.
There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at [email protected].
In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [223Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.
There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.
The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.
Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.
Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.
There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.
The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.
Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.
Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.
Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).
Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.
Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.
Technetium (99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (99mTc). Animal reproduction studies have not been conducted. 99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.
The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.
Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta2-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.
There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at [email protected].
In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [223Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.
There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.
The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.
Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.
Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.
There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.
The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.
Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.
Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.
Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).
Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.
Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.
Technetium (99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (99mTc). Animal reproduction studies have not been conducted. 99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.
The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.
Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta2-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.
There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at [email protected].
FDA approves ofatumumab for chronic lymphocytic leukemia
The Food and Drug Administration has approved ofatumumab (Arzerra injection, for intravenous infusion) in combination with chlorambucil, for previously untreated patients with chronic lymphocytic leukemia for whom fludarabine-based therapy is considered inappropriate.
Ofatumumab, an anti-CD20-directed monoclonal antibody, manufactured by GlaxoSmithKline, was originally given an accelerated approval in 2009. As a condition of that approval, the company was required to conduct further studies. The trial used as the basis of the April 17 approval fulfilled that postmarketing requirement, and accelerated approval was converted to regular approval, said the FDA.
That multicenter, randomized, open-label trial compared ofatumumab in combination with chlorambucil to chlorambucil alone. Patients received an intravenous infusion of ofatumumab on the following schedule: 300 mg on cycle 1, day 1; 1,000 mg on cycle 1, day 8; and 1,000 mg on day 1 of all subsequent 28-day cycles. In both arms, chlorambucil was given at a dose of 10 mg/meter orally on days 1 to 7, every 28 days. Ofatumumab patients were premedicated with acetaminophen, an antihistamine, and a glucocorticoid.
Median progression-free survival was 22.4 months for patients receiving the combination, compared with 13.1 months for those who were given chlorambucil alone. Progression-free survival was assessed by a blinded independent review committee using the 2008 International Workshop on Chronic Lymphocytic Leukemia update of the National Cancer Institute Working Group guidelines.
The most common adverse reactions of the ofatumumab-chlorambucil combination were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain. Sixty-seven percent of patients who received ofatumumab experienced one or more symptoms of infusion reaction; 10% experienced a grade 3 or greater infusion reaction.
In September, the FDA added a black box warning to ofatumumab’s label on the risk of reactivation of hepatitis B virus infection in patients with prior infection.
For previously untreated chronic lymphocytic leukemia, the recommended dose and schedule is 300 mg on day 1; followed 1 week later by 1,000 mg on day 8; followed by 1,000 mg on day 1 of subsequent 28-day cycles for a minimum of 3 cycles until best response or a maximum of 12 cycles, according to the FDA.
On Twitter @aliciaault
The Food and Drug Administration has approved ofatumumab (Arzerra injection, for intravenous infusion) in combination with chlorambucil, for previously untreated patients with chronic lymphocytic leukemia for whom fludarabine-based therapy is considered inappropriate.
Ofatumumab, an anti-CD20-directed monoclonal antibody, manufactured by GlaxoSmithKline, was originally given an accelerated approval in 2009. As a condition of that approval, the company was required to conduct further studies. The trial used as the basis of the April 17 approval fulfilled that postmarketing requirement, and accelerated approval was converted to regular approval, said the FDA.
That multicenter, randomized, open-label trial compared ofatumumab in combination with chlorambucil to chlorambucil alone. Patients received an intravenous infusion of ofatumumab on the following schedule: 300 mg on cycle 1, day 1; 1,000 mg on cycle 1, day 8; and 1,000 mg on day 1 of all subsequent 28-day cycles. In both arms, chlorambucil was given at a dose of 10 mg/meter orally on days 1 to 7, every 28 days. Ofatumumab patients were premedicated with acetaminophen, an antihistamine, and a glucocorticoid.
Median progression-free survival was 22.4 months for patients receiving the combination, compared with 13.1 months for those who were given chlorambucil alone. Progression-free survival was assessed by a blinded independent review committee using the 2008 International Workshop on Chronic Lymphocytic Leukemia update of the National Cancer Institute Working Group guidelines.
The most common adverse reactions of the ofatumumab-chlorambucil combination were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain. Sixty-seven percent of patients who received ofatumumab experienced one or more symptoms of infusion reaction; 10% experienced a grade 3 or greater infusion reaction.
In September, the FDA added a black box warning to ofatumumab’s label on the risk of reactivation of hepatitis B virus infection in patients with prior infection.
For previously untreated chronic lymphocytic leukemia, the recommended dose and schedule is 300 mg on day 1; followed 1 week later by 1,000 mg on day 8; followed by 1,000 mg on day 1 of subsequent 28-day cycles for a minimum of 3 cycles until best response or a maximum of 12 cycles, according to the FDA.
On Twitter @aliciaault
The Food and Drug Administration has approved ofatumumab (Arzerra injection, for intravenous infusion) in combination with chlorambucil, for previously untreated patients with chronic lymphocytic leukemia for whom fludarabine-based therapy is considered inappropriate.
Ofatumumab, an anti-CD20-directed monoclonal antibody, manufactured by GlaxoSmithKline, was originally given an accelerated approval in 2009. As a condition of that approval, the company was required to conduct further studies. The trial used as the basis of the April 17 approval fulfilled that postmarketing requirement, and accelerated approval was converted to regular approval, said the FDA.
That multicenter, randomized, open-label trial compared ofatumumab in combination with chlorambucil to chlorambucil alone. Patients received an intravenous infusion of ofatumumab on the following schedule: 300 mg on cycle 1, day 1; 1,000 mg on cycle 1, day 8; and 1,000 mg on day 1 of all subsequent 28-day cycles. In both arms, chlorambucil was given at a dose of 10 mg/meter orally on days 1 to 7, every 28 days. Ofatumumab patients were premedicated with acetaminophen, an antihistamine, and a glucocorticoid.
Median progression-free survival was 22.4 months for patients receiving the combination, compared with 13.1 months for those who were given chlorambucil alone. Progression-free survival was assessed by a blinded independent review committee using the 2008 International Workshop on Chronic Lymphocytic Leukemia update of the National Cancer Institute Working Group guidelines.
The most common adverse reactions of the ofatumumab-chlorambucil combination were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain. Sixty-seven percent of patients who received ofatumumab experienced one or more symptoms of infusion reaction; 10% experienced a grade 3 or greater infusion reaction.
In September, the FDA added a black box warning to ofatumumab’s label on the risk of reactivation of hepatitis B virus infection in patients with prior infection.
For previously untreated chronic lymphocytic leukemia, the recommended dose and schedule is 300 mg on day 1; followed 1 week later by 1,000 mg on day 8; followed by 1,000 mg on day 1 of subsequent 28-day cycles for a minimum of 3 cycles until best response or a maximum of 12 cycles, according to the FDA.
On Twitter @aliciaault
