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HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.
Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.
“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).
Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”
Studies are increasingly suggesting that posttransplant maintenance therapy may improve this outcome. For example, the small, randomized, phase 2 SORMAIN study presented at the 2018 annual meeting of the American Society of Hematology showed a signal for benefit with posttransplant maintenance with the TKI sorafenib. Data regarding midostaurin in this setting are limited, Dr. Maziarz noted.
The RADIUS trial was a small study designed to look for a similar signal with midostaurin and thus was not adequately powered to detect a statistical difference between the arms, he explained.
RADIUS included 60 AML patients aged 18-70 years who underwent myeloablative alloSCT and were in their first complete remission. The primary endpoint was relapse-free survival (RFS) at 18 months after transplant. Results were presented at ASH 2018.
RFS was 89% in 16 of 30 patients who were randomized to receive 50 mg of midostaurin twice daily along with standard-of-care (SOC) treatment and completed 12 4-week cycles. This compared with an RFS rate of 76% in 14 of 30 patients who received SOC only and completed 12 cycles (hazard ratio, 0.46).
The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54%, and at 24 months, both RFS and overall survival were 85% in the midostaurin group and 76% in the SOC-only group, Dr. Maziarz reported.
The median duration of exposure to midostaurin was 10.5 months and the median dose intensity was 93 mg/day, indicating that full-dose therapy was achievable in most patients who stayed on the study.
Treatment was generally well tolerated; there was a comparable number of early discontinuations in the midostaurin and SOC-only arms. The discontinuations were caused mainly by adverse events (typically gastrointestinal toxicities) in the midostaurin arm and by consent withdrawal in the SOC-only arm, he said, adding that there were no significant differences between the groups with respect to serious adverse events or acute or chronic graft-versus-host disease.
Following the presentation of the primary RADIUS results at ASH 2018, an exploratory analysis was conducted to assess midostaurin’s inhibitory effects on FLT3 in plasma.
FLT3 plasma inhibitor activity, assessed by coculturing plasma samples taken on the first day of the treatment cycles with the FLT3-positive AML to look for a reduction in pFLT3, was evaluable in 28 patients in each arm.
“What we see is when you start there are high levels of FLT3, but the pFLT3 drops significantly with exposure to the plasma,” he said, noting that the effect was most prominent during the first two cycles of therapy.
The patients with the highest levels of inhibition had the greatest likelihood of RFS, whereas RFS in those with suboptimal pFLT3 inhibition was similar to that seen in the SOC-only arm, Dr. Maziarz said. Two patients in the midostaurin group who relapsed did so after 12 months – when midostaurin had been discontinued, he noted.
“Our conclusion is that maintenance midostaurin may contribute to a reduction in relapse risk at 18 months post transplant ... and can be safely administered in the posttransplant setting,” Dr. Maziarz said. “pFLT3 inhibition to less than 70% of baseline, at least in this study, was associated with improved relapse-free survival and overall survival, and it was achieved in more than 50% of patients on the midostaurin.”
It is likely that a more definitive answer will be provided by the Blood and Marrow Transplant Clinical Trials Network Protocol 1506, a large, multinational, placebo-controlled trial now recruiting to look at this question of whether maintenance therapy in the posttransplant setting will improve outcomes.
However, it is important to note that no patient in the RADIUS trial received pretransplant midostaurin, as RADIUS was conducted at the same time as the RATIFY trial.
“Patients today who will go to transplant with FLT3-ITD, the vast majority will have been treated during induction ... and we may have a totally different biology going forward,” he said.
Dr. Maziarz reported financial relationships with Incyte, Novartis, Celgene/Juno, Kite/Gilead, Juno Therapeutics, Kite Therapeutics, and Athersys.
HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.
Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.
“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).
Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”
Studies are increasingly suggesting that posttransplant maintenance therapy may improve this outcome. For example, the small, randomized, phase 2 SORMAIN study presented at the 2018 annual meeting of the American Society of Hematology showed a signal for benefit with posttransplant maintenance with the TKI sorafenib. Data regarding midostaurin in this setting are limited, Dr. Maziarz noted.
The RADIUS trial was a small study designed to look for a similar signal with midostaurin and thus was not adequately powered to detect a statistical difference between the arms, he explained.
RADIUS included 60 AML patients aged 18-70 years who underwent myeloablative alloSCT and were in their first complete remission. The primary endpoint was relapse-free survival (RFS) at 18 months after transplant. Results were presented at ASH 2018.
RFS was 89% in 16 of 30 patients who were randomized to receive 50 mg of midostaurin twice daily along with standard-of-care (SOC) treatment and completed 12 4-week cycles. This compared with an RFS rate of 76% in 14 of 30 patients who received SOC only and completed 12 cycles (hazard ratio, 0.46).
The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54%, and at 24 months, both RFS and overall survival were 85% in the midostaurin group and 76% in the SOC-only group, Dr. Maziarz reported.
The median duration of exposure to midostaurin was 10.5 months and the median dose intensity was 93 mg/day, indicating that full-dose therapy was achievable in most patients who stayed on the study.
Treatment was generally well tolerated; there was a comparable number of early discontinuations in the midostaurin and SOC-only arms. The discontinuations were caused mainly by adverse events (typically gastrointestinal toxicities) in the midostaurin arm and by consent withdrawal in the SOC-only arm, he said, adding that there were no significant differences between the groups with respect to serious adverse events or acute or chronic graft-versus-host disease.
Following the presentation of the primary RADIUS results at ASH 2018, an exploratory analysis was conducted to assess midostaurin’s inhibitory effects on FLT3 in plasma.
FLT3 plasma inhibitor activity, assessed by coculturing plasma samples taken on the first day of the treatment cycles with the FLT3-positive AML to look for a reduction in pFLT3, was evaluable in 28 patients in each arm.
“What we see is when you start there are high levels of FLT3, but the pFLT3 drops significantly with exposure to the plasma,” he said, noting that the effect was most prominent during the first two cycles of therapy.
The patients with the highest levels of inhibition had the greatest likelihood of RFS, whereas RFS in those with suboptimal pFLT3 inhibition was similar to that seen in the SOC-only arm, Dr. Maziarz said. Two patients in the midostaurin group who relapsed did so after 12 months – when midostaurin had been discontinued, he noted.
“Our conclusion is that maintenance midostaurin may contribute to a reduction in relapse risk at 18 months post transplant ... and can be safely administered in the posttransplant setting,” Dr. Maziarz said. “pFLT3 inhibition to less than 70% of baseline, at least in this study, was associated with improved relapse-free survival and overall survival, and it was achieved in more than 50% of patients on the midostaurin.”
It is likely that a more definitive answer will be provided by the Blood and Marrow Transplant Clinical Trials Network Protocol 1506, a large, multinational, placebo-controlled trial now recruiting to look at this question of whether maintenance therapy in the posttransplant setting will improve outcomes.
However, it is important to note that no patient in the RADIUS trial received pretransplant midostaurin, as RADIUS was conducted at the same time as the RATIFY trial.
“Patients today who will go to transplant with FLT3-ITD, the vast majority will have been treated during induction ... and we may have a totally different biology going forward,” he said.
Dr. Maziarz reported financial relationships with Incyte, Novartis, Celgene/Juno, Kite/Gilead, Juno Therapeutics, Kite Therapeutics, and Athersys.
HOUSTON – Midostaurin maintenance therapy along with standard-of-care treatment after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) appears to reduce the risk of relapse, according to findings from the randomized, phase 2 RADIUS trial.
Notably, the effect of midostaurin in this open-label, exploratory trial was most pronounced in patients with high levels of phosphorylated FLT3 (pFLT3) inhibition as assessed by plasma inhibitor activity assay, Richard T. Maziarz, MD, reported at the Transplantation & Cellular Therapy Meetings.
“The median [pFLT3 reduction] was less than 70% ... those patients who had the deepest level inhibition maintained the highest likelihood of staying free of disease,” Dr. Maziarz, a professor of medicine at Oregon Health & Science University, Portland, said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that was shown in the pivotal RATIFY trial to significantly improve event-free and overall survival versus placebo when interspersed with induction and consolidation chemotherapy and also when used for maintenance in adults with newly diagnosed FLT3-mutated AML, Dr. Maziarz explained. He noted that patients in the RATIFY study who underwent alloSCT did not receive midostaurin maintenance (N Engl J Med. 2017; 377:454-64).
Although alloSCT provides the greatest likelihood of sustained remission in AML, relapse rates remain high at 30%-59%, he said, adding that, “in the setting of transplantation, FLT3 expression, or FLT3-ITD [internal tandem duplication] ... is a poor risk feature.”
Studies are increasingly suggesting that posttransplant maintenance therapy may improve this outcome. For example, the small, randomized, phase 2 SORMAIN study presented at the 2018 annual meeting of the American Society of Hematology showed a signal for benefit with posttransplant maintenance with the TKI sorafenib. Data regarding midostaurin in this setting are limited, Dr. Maziarz noted.
The RADIUS trial was a small study designed to look for a similar signal with midostaurin and thus was not adequately powered to detect a statistical difference between the arms, he explained.
RADIUS included 60 AML patients aged 18-70 years who underwent myeloablative alloSCT and were in their first complete remission. The primary endpoint was relapse-free survival (RFS) at 18 months after transplant. Results were presented at ASH 2018.
RFS was 89% in 16 of 30 patients who were randomized to receive 50 mg of midostaurin twice daily along with standard-of-care (SOC) treatment and completed 12 4-week cycles. This compared with an RFS rate of 76% in 14 of 30 patients who received SOC only and completed 12 cycles (hazard ratio, 0.46).
The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54%, and at 24 months, both RFS and overall survival were 85% in the midostaurin group and 76% in the SOC-only group, Dr. Maziarz reported.
The median duration of exposure to midostaurin was 10.5 months and the median dose intensity was 93 mg/day, indicating that full-dose therapy was achievable in most patients who stayed on the study.
Treatment was generally well tolerated; there was a comparable number of early discontinuations in the midostaurin and SOC-only arms. The discontinuations were caused mainly by adverse events (typically gastrointestinal toxicities) in the midostaurin arm and by consent withdrawal in the SOC-only arm, he said, adding that there were no significant differences between the groups with respect to serious adverse events or acute or chronic graft-versus-host disease.
Following the presentation of the primary RADIUS results at ASH 2018, an exploratory analysis was conducted to assess midostaurin’s inhibitory effects on FLT3 in plasma.
FLT3 plasma inhibitor activity, assessed by coculturing plasma samples taken on the first day of the treatment cycles with the FLT3-positive AML to look for a reduction in pFLT3, was evaluable in 28 patients in each arm.
“What we see is when you start there are high levels of FLT3, but the pFLT3 drops significantly with exposure to the plasma,” he said, noting that the effect was most prominent during the first two cycles of therapy.
The patients with the highest levels of inhibition had the greatest likelihood of RFS, whereas RFS in those with suboptimal pFLT3 inhibition was similar to that seen in the SOC-only arm, Dr. Maziarz said. Two patients in the midostaurin group who relapsed did so after 12 months – when midostaurin had been discontinued, he noted.
“Our conclusion is that maintenance midostaurin may contribute to a reduction in relapse risk at 18 months post transplant ... and can be safely administered in the posttransplant setting,” Dr. Maziarz said. “pFLT3 inhibition to less than 70% of baseline, at least in this study, was associated with improved relapse-free survival and overall survival, and it was achieved in more than 50% of patients on the midostaurin.”
It is likely that a more definitive answer will be provided by the Blood and Marrow Transplant Clinical Trials Network Protocol 1506, a large, multinational, placebo-controlled trial now recruiting to look at this question of whether maintenance therapy in the posttransplant setting will improve outcomes.
However, it is important to note that no patient in the RADIUS trial received pretransplant midostaurin, as RADIUS was conducted at the same time as the RATIFY trial.
“Patients today who will go to transplant with FLT3-ITD, the vast majority will have been treated during induction ... and we may have a totally different biology going forward,” he said.
Dr. Maziarz reported financial relationships with Incyte, Novartis, Celgene/Juno, Kite/Gilead, Juno Therapeutics, Kite Therapeutics, and Athersys.
REPORTING FROM TCT 2019