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FDA approves ravulizumab for PNH
The U.S. Food and Drug Administration (FDA) has approved ravulizumab-cwvz (Ultomiris) to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).
Ravulizumab is a long-acting C5 complement inhibitor, administered every 8 weeks, that has been shown to prevent hemolysis.
The prescribing information for ravulizumab includes a boxed warning stating that meningococcal infections/sepsis have occurred in patients treated with the drug, and these adverse effects can become life-threatening or fatal if not recognized and treated early.
Ravulizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.
The FDA previously granted the application for ravulizumab priority review, and the product received orphan drug designation from the FDA.
The FDA granted the approval of ravulizumab to Alexion Pharmaceuticals.
The FDA’s approval of ravulizumab is based on results from two phase 3 studies, one in patients who had previously received treatment with a complement inhibitor and one in patients who were complement-inhibitor-naïve. Both studies were recently published in Blood.
Efficacy in inhibitor-experienced patients
In one study (NCT03056040), researchers compared ravulizumab administered every 8 weeks to eculizumab administered every 2 weeks in complement-inhibitor-experienced patients.
The trial included 195 PNH patients who were taking eculizumab for more than 6 months. They were randomized to switch to ravulizumab (n=97) or continue on eculizumab (n=98).
Ravulizumab proved noninferior to eculizumab for all endpoints studied (P<0.0006), including:
- Percentage change in lactate dehydrogenase (LDH): difference, 9.21% (95% CI: -0.42 to 18.84; P=0.058 for superiority)
- Breakthrough hemolysis: difference, 5.1 (95% CI: -8.89 to 18.99)
- Change in FACIT-Fatigue score: difference, 1.47 (95% CI: -0.21 to 3.15)
- Transfusion avoidance: difference, 5.5 (95% CI: -4.27 to 15.68)
- Stabilized hemoglobin: difference, 1.4 (95% CI: -10.41 to 13.31).
Efficacy in inhibitor-naïve patients
In another study (NCT02946463), researchers compared ravulizumab and eculizumab in 246 PNH patients who had not previously received a complement inhibitor.
Ravulizumab was noninferior to eculizumab for all endpoints (P<0.0001), including:
- Transfusion avoidance: 73.6% vs 66.1%; difference of 6.8% (95% CI: -4.66 to 18.14)
- LDH normalization: 53.6% vs 49.4%; odds ratio=1.19 (95% CI: 0.80 to 1.77)
- Percent reduction in LDH: -76.8% vs -76.0%; difference of -0.83% (95% CI: -5.21 to 3.56)
- Change in FACIT-Fatigue score: 7.07 vs 6.40; difference of 0.67 (95% CI: -1.21 to 2.55)
- Breakthrough hemolysis: 4.0% vs 10.7%; difference of -6.7% (95% CI: -14.21 to 0.18)
- Stabilized hemoglobin: 68.0% vs 64.5%; difference of 2.9 (95% CI: -8.80 to 14.64).
Safety in both trials
The safety data from both trials included 441 adults who received ravulizumab (n=222) or eculizumab (n=219) for a median of 6 months.
The most frequent adverse events in both arms (ravulizumab and eculizumab, respectively) were upper respiratory tract infection (39% and 39%) and headache (32% and 26%).
Serious adverse events occurred in 15 (6.8%) patients treated with ravulizumab. These events included hyperthermia and pyrexia.
There was one fatal case of sepsis in a patient treated with ravulizumab.
The U.S. Food and Drug Administration (FDA) has approved ravulizumab-cwvz (Ultomiris) to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).
Ravulizumab is a long-acting C5 complement inhibitor, administered every 8 weeks, that has been shown to prevent hemolysis.
The prescribing information for ravulizumab includes a boxed warning stating that meningococcal infections/sepsis have occurred in patients treated with the drug, and these adverse effects can become life-threatening or fatal if not recognized and treated early.
Ravulizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.
The FDA previously granted the application for ravulizumab priority review, and the product received orphan drug designation from the FDA.
The FDA granted the approval of ravulizumab to Alexion Pharmaceuticals.
The FDA’s approval of ravulizumab is based on results from two phase 3 studies, one in patients who had previously received treatment with a complement inhibitor and one in patients who were complement-inhibitor-naïve. Both studies were recently published in Blood.
Efficacy in inhibitor-experienced patients
In one study (NCT03056040), researchers compared ravulizumab administered every 8 weeks to eculizumab administered every 2 weeks in complement-inhibitor-experienced patients.
The trial included 195 PNH patients who were taking eculizumab for more than 6 months. They were randomized to switch to ravulizumab (n=97) or continue on eculizumab (n=98).
Ravulizumab proved noninferior to eculizumab for all endpoints studied (P<0.0006), including:
- Percentage change in lactate dehydrogenase (LDH): difference, 9.21% (95% CI: -0.42 to 18.84; P=0.058 for superiority)
- Breakthrough hemolysis: difference, 5.1 (95% CI: -8.89 to 18.99)
- Change in FACIT-Fatigue score: difference, 1.47 (95% CI: -0.21 to 3.15)
- Transfusion avoidance: difference, 5.5 (95% CI: -4.27 to 15.68)
- Stabilized hemoglobin: difference, 1.4 (95% CI: -10.41 to 13.31).
Efficacy in inhibitor-naïve patients
In another study (NCT02946463), researchers compared ravulizumab and eculizumab in 246 PNH patients who had not previously received a complement inhibitor.
Ravulizumab was noninferior to eculizumab for all endpoints (P<0.0001), including:
- Transfusion avoidance: 73.6% vs 66.1%; difference of 6.8% (95% CI: -4.66 to 18.14)
- LDH normalization: 53.6% vs 49.4%; odds ratio=1.19 (95% CI: 0.80 to 1.77)
- Percent reduction in LDH: -76.8% vs -76.0%; difference of -0.83% (95% CI: -5.21 to 3.56)
- Change in FACIT-Fatigue score: 7.07 vs 6.40; difference of 0.67 (95% CI: -1.21 to 2.55)
- Breakthrough hemolysis: 4.0% vs 10.7%; difference of -6.7% (95% CI: -14.21 to 0.18)
- Stabilized hemoglobin: 68.0% vs 64.5%; difference of 2.9 (95% CI: -8.80 to 14.64).
Safety in both trials
The safety data from both trials included 441 adults who received ravulizumab (n=222) or eculizumab (n=219) for a median of 6 months.
The most frequent adverse events in both arms (ravulizumab and eculizumab, respectively) were upper respiratory tract infection (39% and 39%) and headache (32% and 26%).
Serious adverse events occurred in 15 (6.8%) patients treated with ravulizumab. These events included hyperthermia and pyrexia.
There was one fatal case of sepsis in a patient treated with ravulizumab.
The U.S. Food and Drug Administration (FDA) has approved ravulizumab-cwvz (Ultomiris) to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).
Ravulizumab is a long-acting C5 complement inhibitor, administered every 8 weeks, that has been shown to prevent hemolysis.
The prescribing information for ravulizumab includes a boxed warning stating that meningococcal infections/sepsis have occurred in patients treated with the drug, and these adverse effects can become life-threatening or fatal if not recognized and treated early.
Ravulizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.
The FDA previously granted the application for ravulizumab priority review, and the product received orphan drug designation from the FDA.
The FDA granted the approval of ravulizumab to Alexion Pharmaceuticals.
The FDA’s approval of ravulizumab is based on results from two phase 3 studies, one in patients who had previously received treatment with a complement inhibitor and one in patients who were complement-inhibitor-naïve. Both studies were recently published in Blood.
Efficacy in inhibitor-experienced patients
In one study (NCT03056040), researchers compared ravulizumab administered every 8 weeks to eculizumab administered every 2 weeks in complement-inhibitor-experienced patients.
The trial included 195 PNH patients who were taking eculizumab for more than 6 months. They were randomized to switch to ravulizumab (n=97) or continue on eculizumab (n=98).
Ravulizumab proved noninferior to eculizumab for all endpoints studied (P<0.0006), including:
- Percentage change in lactate dehydrogenase (LDH): difference, 9.21% (95% CI: -0.42 to 18.84; P=0.058 for superiority)
- Breakthrough hemolysis: difference, 5.1 (95% CI: -8.89 to 18.99)
- Change in FACIT-Fatigue score: difference, 1.47 (95% CI: -0.21 to 3.15)
- Transfusion avoidance: difference, 5.5 (95% CI: -4.27 to 15.68)
- Stabilized hemoglobin: difference, 1.4 (95% CI: -10.41 to 13.31).
Efficacy in inhibitor-naïve patients
In another study (NCT02946463), researchers compared ravulizumab and eculizumab in 246 PNH patients who had not previously received a complement inhibitor.
Ravulizumab was noninferior to eculizumab for all endpoints (P<0.0001), including:
- Transfusion avoidance: 73.6% vs 66.1%; difference of 6.8% (95% CI: -4.66 to 18.14)
- LDH normalization: 53.6% vs 49.4%; odds ratio=1.19 (95% CI: 0.80 to 1.77)
- Percent reduction in LDH: -76.8% vs -76.0%; difference of -0.83% (95% CI: -5.21 to 3.56)
- Change in FACIT-Fatigue score: 7.07 vs 6.40; difference of 0.67 (95% CI: -1.21 to 2.55)
- Breakthrough hemolysis: 4.0% vs 10.7%; difference of -6.7% (95% CI: -14.21 to 0.18)
- Stabilized hemoglobin: 68.0% vs 64.5%; difference of 2.9 (95% CI: -8.80 to 14.64).
Safety in both trials
The safety data from both trials included 441 adults who received ravulizumab (n=222) or eculizumab (n=219) for a median of 6 months.
The most frequent adverse events in both arms (ravulizumab and eculizumab, respectively) were upper respiratory tract infection (39% and 39%) and headache (32% and 26%).
Serious adverse events occurred in 15 (6.8%) patients treated with ravulizumab. These events included hyperthermia and pyrexia.
There was one fatal case of sepsis in a patient treated with ravulizumab.
FDA approves calaspargase pegol-mknl for ALL
The U.S. Food and Drug Administration (FDA) has approved calaspargase pegol-mknl (Asparlas) as a component of a multi-agent chemotherapeutic regimen to treat acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years.
Calaspargase pegol-mknl is an asparagine-specific enzyme intended to provide a longer interval between doses compared to other available pegaspargase products.
The recommended dosage of calaspargase pegol-mknl is 2,500 U/m2 given no more frequently than every 21 days.
The FDA said it approved calaspargase pegol-mknl because the drug maintained nadir serum asparaginase activity above the level of 0.1 U/mL when given at 2,500 U/m2 every 3 weeks.
Calaspargase pegol-mknl was evaluated in Study DFCI 11-001, a trial of 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma. The patients’ median age was 5 years (range, 1 to 20 years).
They received calaspargase pegol-mknl at 2,500 U/m2 (n=118) or pegaspargase at 2,500 U/m2 (n=119) as part of a Dana-Farber Cancer Institute (DFCI) ALL Consortium backbone therapy.
The median duration of exposure was 8 months for both calaspargase pegol-mknl and pegaspargase.
Among the patients with B-cell lineage ALL, the complete remission rate was 98% in the calaspargase pegol-mknl arm and 99% in the pegaspargase arm. Estimated overall survival rates were comparable between the arms.
Common grade 3 or higher adverse events (in the calaspargase pegol-mknl and pegaspargase arms, respectively) included elevated transaminase (52% and 66%), bilirubin increase (20% and 25%), pancreatitis (18% and 24%), and abnormal clotting studies (14% and 21%).
There was one fatal adverse event among patients on calaspargase pegol-mknl—multi-organ failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst.
The safety of calaspargase pegol-mknl was also evaluated in Study AALL07P4, a trial of patients with newly diagnosed, high-risk B-precursor ALL.
The patients received calaspargase pegol-mknl at 2,500 U/m2 (n=43) or 2,100 U/m2 (n=68) or pegaspargase at 2,500 U/m2 (n=52) as a component of an augmented Berlin-Frankfurt-Münster regimen.
The patients’ median age was 11 years (range, 1 to 26 years). The median duration of exposure was 7 months for both calaspargase pegol-mknl and pegaspargase.
There were three induction deaths among the 111 patients who received calaspargase pegol-mknl (2.8%) but no induction deaths among the 52 patients treated with pegaspargase.
Additional details on these studies and calaspargase pegol-mknl can be found in the drug’s prescribing information.
Calaspargase pegol-mknl is a product of Servier Pharmaceuticals LLC.
The U.S. Food and Drug Administration (FDA) has approved calaspargase pegol-mknl (Asparlas) as a component of a multi-agent chemotherapeutic regimen to treat acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years.
Calaspargase pegol-mknl is an asparagine-specific enzyme intended to provide a longer interval between doses compared to other available pegaspargase products.
The recommended dosage of calaspargase pegol-mknl is 2,500 U/m2 given no more frequently than every 21 days.
The FDA said it approved calaspargase pegol-mknl because the drug maintained nadir serum asparaginase activity above the level of 0.1 U/mL when given at 2,500 U/m2 every 3 weeks.
Calaspargase pegol-mknl was evaluated in Study DFCI 11-001, a trial of 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma. The patients’ median age was 5 years (range, 1 to 20 years).
They received calaspargase pegol-mknl at 2,500 U/m2 (n=118) or pegaspargase at 2,500 U/m2 (n=119) as part of a Dana-Farber Cancer Institute (DFCI) ALL Consortium backbone therapy.
The median duration of exposure was 8 months for both calaspargase pegol-mknl and pegaspargase.
Among the patients with B-cell lineage ALL, the complete remission rate was 98% in the calaspargase pegol-mknl arm and 99% in the pegaspargase arm. Estimated overall survival rates were comparable between the arms.
Common grade 3 or higher adverse events (in the calaspargase pegol-mknl and pegaspargase arms, respectively) included elevated transaminase (52% and 66%), bilirubin increase (20% and 25%), pancreatitis (18% and 24%), and abnormal clotting studies (14% and 21%).
There was one fatal adverse event among patients on calaspargase pegol-mknl—multi-organ failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst.
The safety of calaspargase pegol-mknl was also evaluated in Study AALL07P4, a trial of patients with newly diagnosed, high-risk B-precursor ALL.
The patients received calaspargase pegol-mknl at 2,500 U/m2 (n=43) or 2,100 U/m2 (n=68) or pegaspargase at 2,500 U/m2 (n=52) as a component of an augmented Berlin-Frankfurt-Münster regimen.
The patients’ median age was 11 years (range, 1 to 26 years). The median duration of exposure was 7 months for both calaspargase pegol-mknl and pegaspargase.
There were three induction deaths among the 111 patients who received calaspargase pegol-mknl (2.8%) but no induction deaths among the 52 patients treated with pegaspargase.
Additional details on these studies and calaspargase pegol-mknl can be found in the drug’s prescribing information.
Calaspargase pegol-mknl is a product of Servier Pharmaceuticals LLC.
The U.S. Food and Drug Administration (FDA) has approved calaspargase pegol-mknl (Asparlas) as a component of a multi-agent chemotherapeutic regimen to treat acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years.
Calaspargase pegol-mknl is an asparagine-specific enzyme intended to provide a longer interval between doses compared to other available pegaspargase products.
The recommended dosage of calaspargase pegol-mknl is 2,500 U/m2 given no more frequently than every 21 days.
The FDA said it approved calaspargase pegol-mknl because the drug maintained nadir serum asparaginase activity above the level of 0.1 U/mL when given at 2,500 U/m2 every 3 weeks.
Calaspargase pegol-mknl was evaluated in Study DFCI 11-001, a trial of 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma. The patients’ median age was 5 years (range, 1 to 20 years).
They received calaspargase pegol-mknl at 2,500 U/m2 (n=118) or pegaspargase at 2,500 U/m2 (n=119) as part of a Dana-Farber Cancer Institute (DFCI) ALL Consortium backbone therapy.
The median duration of exposure was 8 months for both calaspargase pegol-mknl and pegaspargase.
Among the patients with B-cell lineage ALL, the complete remission rate was 98% in the calaspargase pegol-mknl arm and 99% in the pegaspargase arm. Estimated overall survival rates were comparable between the arms.
Common grade 3 or higher adverse events (in the calaspargase pegol-mknl and pegaspargase arms, respectively) included elevated transaminase (52% and 66%), bilirubin increase (20% and 25%), pancreatitis (18% and 24%), and abnormal clotting studies (14% and 21%).
There was one fatal adverse event among patients on calaspargase pegol-mknl—multi-organ failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst.
The safety of calaspargase pegol-mknl was also evaluated in Study AALL07P4, a trial of patients with newly diagnosed, high-risk B-precursor ALL.
The patients received calaspargase pegol-mknl at 2,500 U/m2 (n=43) or 2,100 U/m2 (n=68) or pegaspargase at 2,500 U/m2 (n=52) as a component of an augmented Berlin-Frankfurt-Münster regimen.
The patients’ median age was 11 years (range, 1 to 26 years). The median duration of exposure was 7 months for both calaspargase pegol-mknl and pegaspargase.
There were three induction deaths among the 111 patients who received calaspargase pegol-mknl (2.8%) but no induction deaths among the 52 patients treated with pegaspargase.
Additional details on these studies and calaspargase pegol-mknl can be found in the drug’s prescribing information.
Calaspargase pegol-mknl is a product of Servier Pharmaceuticals LLC.
CHMP recommends treosulfan for allo-HSCT conditioning
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for treosulfan (Trecondi) as part of conditioning prior to allogeneic hematopoietic stem cell transplant (allo-HSCT).
The full indication is for treosulfan to be used in combination with fludarabine for conditioning prior to allo-HSCT in adults with malignant and non-malignant diseases and in pediatric patients older than 1 month who have malignant diseases.
The CHMP’s recommendation for treosulfan will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of a CHMP recommendation.
The CHMP’s opinion of treosulfan is supported by results from a phase 3 trial (NCT00822393), which were presented at the 2017 ASH Annual Meeting.
In this trial, investigators compared two conditioning regimens, treosulfan-fludarabine and busulfan-fludarabine, in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes who were undergoing allo-HSCT.
The ASH data included 476 patients from the final analysis.
Investigators said safety results between day -6 and day +28 were similar with the two regimens.
The same was true for trilineage engraftment and the cumulative incidence of relapse/progression at 24 months after allo-HSCT.
However, survival rates were higher in the treosulfan arm.
The event-free survival at 24 months was 64.0% in the treosulfan arm and 50.4% in the busulfan arm (P=0.0000164). The overall survival at 24 months was 72.5% and 56.4%, respectively (P=0.0082).
Transplant-related mortality at 24 months was 11.3% in the treosulfan arm and 28.2% in the busulfan arm (P=0.0201).
This trial was sponsored by medac GmbH.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for treosulfan (Trecondi) as part of conditioning prior to allogeneic hematopoietic stem cell transplant (allo-HSCT).
The full indication is for treosulfan to be used in combination with fludarabine for conditioning prior to allo-HSCT in adults with malignant and non-malignant diseases and in pediatric patients older than 1 month who have malignant diseases.
The CHMP’s recommendation for treosulfan will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of a CHMP recommendation.
The CHMP’s opinion of treosulfan is supported by results from a phase 3 trial (NCT00822393), which were presented at the 2017 ASH Annual Meeting.
In this trial, investigators compared two conditioning regimens, treosulfan-fludarabine and busulfan-fludarabine, in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes who were undergoing allo-HSCT.
The ASH data included 476 patients from the final analysis.
Investigators said safety results between day -6 and day +28 were similar with the two regimens.
The same was true for trilineage engraftment and the cumulative incidence of relapse/progression at 24 months after allo-HSCT.
However, survival rates were higher in the treosulfan arm.
The event-free survival at 24 months was 64.0% in the treosulfan arm and 50.4% in the busulfan arm (P=0.0000164). The overall survival at 24 months was 72.5% and 56.4%, respectively (P=0.0082).
Transplant-related mortality at 24 months was 11.3% in the treosulfan arm and 28.2% in the busulfan arm (P=0.0201).
This trial was sponsored by medac GmbH.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for treosulfan (Trecondi) as part of conditioning prior to allogeneic hematopoietic stem cell transplant (allo-HSCT).
The full indication is for treosulfan to be used in combination with fludarabine for conditioning prior to allo-HSCT in adults with malignant and non-malignant diseases and in pediatric patients older than 1 month who have malignant diseases.
The CHMP’s recommendation for treosulfan will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of a CHMP recommendation.
The CHMP’s opinion of treosulfan is supported by results from a phase 3 trial (NCT00822393), which were presented at the 2017 ASH Annual Meeting.
In this trial, investigators compared two conditioning regimens, treosulfan-fludarabine and busulfan-fludarabine, in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndromes who were undergoing allo-HSCT.
The ASH data included 476 patients from the final analysis.
Investigators said safety results between day -6 and day +28 were similar with the two regimens.
The same was true for trilineage engraftment and the cumulative incidence of relapse/progression at 24 months after allo-HSCT.
However, survival rates were higher in the treosulfan arm.
The event-free survival at 24 months was 64.0% in the treosulfan arm and 50.4% in the busulfan arm (P=0.0000164). The overall survival at 24 months was 72.5% and 56.4%, respectively (P=0.0082).
Transplant-related mortality at 24 months was 11.3% in the treosulfan arm and 28.2% in the busulfan arm (P=0.0201).
This trial was sponsored by medac GmbH.
CHMP backs lusutrombopag for severe thrombocytopenia
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for lusutrombopag to treat severe thrombocytopenia in adults with chronic liver disease who are undergoing invasive procedures.
Lusutrombopag is a thrombopoietin (TPO) receptor agonist that acts on the transmembrane domain of TPO receptors to induce proliferation and differentiation of megakaryocyte progenitor cells, thus leading to thrombocytopoiesis.
Lusutrombopag is intended to reduce the need for platelet transfusions before an invasive procedure and for rescue therapy for bleeding in the 7 days after the procedure.
The CHMP’s recommendation for lusutrombopag will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of a CHMP recommendation.
Lusutrombopag trials
The efficacy of lusutrombopag was evaluated in two phase 3 trials—L-PLUS1 (1304M0631) and L-PLUS2 (1423M0634, NCT02389621).
The trials included 312 patients with chronic liver disease, severe thrombocytopenia (platelet counts below 50,000/μL), and a scheduled invasive procedure. The patients received lusutrombopag or placebo once daily for up to 7 days.
In L-PLUS1, 78% (38/49) of patients receiving lusutrombopag did not require platelet transfusions prior to the primary invasive procedure. The same was true for 13% (6/48) of patients who received placebo (P<0.0001).
In L-PLUS2 , 65% (70/108) of patients who received lusutrombopag did not require platelet transfusions prior to the primary invasive procedure or rescue therapy for bleeding in the 7 days after the procedure. The same was true for 29% (31/107) of patients receiving placebo (P<0.0001).
The safety of lusutrombopag was evaluated in three trials—L‐PLUS 1, L‐PLUS 2, and M0626 (1208M062).
The most common adverse event (AE) in these trials (n=341) was headache, which occurred in 5% of patients on lusutrombopag and 4% of patients on placebo.
Serious AEs occurred in 5% of patients on lusutrombopag and 7% of patients on placebo. The most common serious AE was portal vein thrombosis, which occurred in 1% of patients in both treatment groups.
None of the patients discontinued lusutrombopag due to AEs.
The trials were sponsored by Shionogi & Co., Ltd.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for lusutrombopag to treat severe thrombocytopenia in adults with chronic liver disease who are undergoing invasive procedures.
Lusutrombopag is a thrombopoietin (TPO) receptor agonist that acts on the transmembrane domain of TPO receptors to induce proliferation and differentiation of megakaryocyte progenitor cells, thus leading to thrombocytopoiesis.
Lusutrombopag is intended to reduce the need for platelet transfusions before an invasive procedure and for rescue therapy for bleeding in the 7 days after the procedure.
The CHMP’s recommendation for lusutrombopag will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of a CHMP recommendation.
Lusutrombopag trials
The efficacy of lusutrombopag was evaluated in two phase 3 trials—L-PLUS1 (1304M0631) and L-PLUS2 (1423M0634, NCT02389621).
The trials included 312 patients with chronic liver disease, severe thrombocytopenia (platelet counts below 50,000/μL), and a scheduled invasive procedure. The patients received lusutrombopag or placebo once daily for up to 7 days.
In L-PLUS1, 78% (38/49) of patients receiving lusutrombopag did not require platelet transfusions prior to the primary invasive procedure. The same was true for 13% (6/48) of patients who received placebo (P<0.0001).
In L-PLUS2 , 65% (70/108) of patients who received lusutrombopag did not require platelet transfusions prior to the primary invasive procedure or rescue therapy for bleeding in the 7 days after the procedure. The same was true for 29% (31/107) of patients receiving placebo (P<0.0001).
The safety of lusutrombopag was evaluated in three trials—L‐PLUS 1, L‐PLUS 2, and M0626 (1208M062).
The most common adverse event (AE) in these trials (n=341) was headache, which occurred in 5% of patients on lusutrombopag and 4% of patients on placebo.
Serious AEs occurred in 5% of patients on lusutrombopag and 7% of patients on placebo. The most common serious AE was portal vein thrombosis, which occurred in 1% of patients in both treatment groups.
None of the patients discontinued lusutrombopag due to AEs.
The trials were sponsored by Shionogi & Co., Ltd.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for lusutrombopag to treat severe thrombocytopenia in adults with chronic liver disease who are undergoing invasive procedures.
Lusutrombopag is a thrombopoietin (TPO) receptor agonist that acts on the transmembrane domain of TPO receptors to induce proliferation and differentiation of megakaryocyte progenitor cells, thus leading to thrombocytopoiesis.
Lusutrombopag is intended to reduce the need for platelet transfusions before an invasive procedure and for rescue therapy for bleeding in the 7 days after the procedure.
The CHMP’s recommendation for lusutrombopag will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of a CHMP recommendation.
Lusutrombopag trials
The efficacy of lusutrombopag was evaluated in two phase 3 trials—L-PLUS1 (1304M0631) and L-PLUS2 (1423M0634, NCT02389621).
The trials included 312 patients with chronic liver disease, severe thrombocytopenia (platelet counts below 50,000/μL), and a scheduled invasive procedure. The patients received lusutrombopag or placebo once daily for up to 7 days.
In L-PLUS1, 78% (38/49) of patients receiving lusutrombopag did not require platelet transfusions prior to the primary invasive procedure. The same was true for 13% (6/48) of patients who received placebo (P<0.0001).
In L-PLUS2 , 65% (70/108) of patients who received lusutrombopag did not require platelet transfusions prior to the primary invasive procedure or rescue therapy for bleeding in the 7 days after the procedure. The same was true for 29% (31/107) of patients receiving placebo (P<0.0001).
The safety of lusutrombopag was evaluated in three trials—L‐PLUS 1, L‐PLUS 2, and M0626 (1208M062).
The most common adverse event (AE) in these trials (n=341) was headache, which occurred in 5% of patients on lusutrombopag and 4% of patients on placebo.
Serious AEs occurred in 5% of patients on lusutrombopag and 7% of patients on placebo. The most common serious AE was portal vein thrombosis, which occurred in 1% of patients in both treatment groups.
None of the patients discontinued lusutrombopag due to AEs.
The trials were sponsored by Shionogi & Co., Ltd.
Long-acting interferon recommended for PV
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for ropeginterferon alfa-2b (BESREMi®) to treat adults who have polycythemia vera (PV) without symptomatic splenomegaly.
Ropeginterferon alfa-2b is a long-acting interferon, which is administered once every 2 weeks or monthly after stabilization of hematological parameters.
The CHMP’s recommendation for ropeginterferon alfa-2b will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of a CHMP recommendation.
The CHMP’s positive opinion of ropeginterferon alfa-2b is supported by data from CONTINUATION-PV (NCT02218047), a phase 3b extension trial of PROUD-PV (NCT01949805).
Results from the PROUD-PV study were presented at the 2016 ASH Annual Meeting. The latest data from CONTINUATION-PV were presented at the 2018 ASH Annual Meeting.
PROUD-PV enrolled 254 PV patients who were treatment-naive or pretreated with hydroxyurea (HU). They were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127).
The latest analysis of CONTINUATION-PV included 83 of the patients on ropeginterferon alfa-2b and 70 of the patients who either remained on HU or switched to best available therapy (BAT) as selected by investigators.
At 24 months, the complete hematologic response (CHR) rate was 70.5% with ropeginterferon alfa-2b and 49.3% with HU/BAT (P=0.0101).
At 36 months, the CHR rate was 70.5% with ropeginterferon alfa-2b and 51.4% with HU/BAT (P=0.0122).
A composite endpoint of CHR plus symptom improvement occurred in 52.6% of patients treated with ropeginterferon alfa-2b and 37.8% of patients on HU/BAT (P=0.0437).
Disease- or treatment-related secondary malignancies in patients receiving HU/BAT included two cases of acute myeloid leukemia, one melanoma, and two basaliomas.
There were three malignancies—glioblastoma, seminoma, and adrenal neoplasm—reported in patients treated with ropeginterferon alfa-2b. Investigators said these malignancies were most likely unrelated to treatment.
The rate of adverse events was 89.8% in the ropeginterferon alfa-2b arm and 90.6% in the HU/BAT arm. Treatment-related adverse events occurred in 74.8% and 78.7% of patients, respectively.
Anemia, thrombocytopenia, and leukopenia occurred more frequently with HU/BAT, whereas liver enzyme increase was mainly observed with ropeginterferon alfa-2b.
CONTINUATION-PV was sponsored by AOP Orphan Pharmaceuticals AG in collaboration with PharmaEssentia.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for ropeginterferon alfa-2b (BESREMi®) to treat adults who have polycythemia vera (PV) without symptomatic splenomegaly.
Ropeginterferon alfa-2b is a long-acting interferon, which is administered once every 2 weeks or monthly after stabilization of hematological parameters.
The CHMP’s recommendation for ropeginterferon alfa-2b will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of a CHMP recommendation.
The CHMP’s positive opinion of ropeginterferon alfa-2b is supported by data from CONTINUATION-PV (NCT02218047), a phase 3b extension trial of PROUD-PV (NCT01949805).
Results from the PROUD-PV study were presented at the 2016 ASH Annual Meeting. The latest data from CONTINUATION-PV were presented at the 2018 ASH Annual Meeting.
PROUD-PV enrolled 254 PV patients who were treatment-naive or pretreated with hydroxyurea (HU). They were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127).
The latest analysis of CONTINUATION-PV included 83 of the patients on ropeginterferon alfa-2b and 70 of the patients who either remained on HU or switched to best available therapy (BAT) as selected by investigators.
At 24 months, the complete hematologic response (CHR) rate was 70.5% with ropeginterferon alfa-2b and 49.3% with HU/BAT (P=0.0101).
At 36 months, the CHR rate was 70.5% with ropeginterferon alfa-2b and 51.4% with HU/BAT (P=0.0122).
A composite endpoint of CHR plus symptom improvement occurred in 52.6% of patients treated with ropeginterferon alfa-2b and 37.8% of patients on HU/BAT (P=0.0437).
Disease- or treatment-related secondary malignancies in patients receiving HU/BAT included two cases of acute myeloid leukemia, one melanoma, and two basaliomas.
There were three malignancies—glioblastoma, seminoma, and adrenal neoplasm—reported in patients treated with ropeginterferon alfa-2b. Investigators said these malignancies were most likely unrelated to treatment.
The rate of adverse events was 89.8% in the ropeginterferon alfa-2b arm and 90.6% in the HU/BAT arm. Treatment-related adverse events occurred in 74.8% and 78.7% of patients, respectively.
Anemia, thrombocytopenia, and leukopenia occurred more frequently with HU/BAT, whereas liver enzyme increase was mainly observed with ropeginterferon alfa-2b.
CONTINUATION-PV was sponsored by AOP Orphan Pharmaceuticals AG in collaboration with PharmaEssentia.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for ropeginterferon alfa-2b (BESREMi®) to treat adults who have polycythemia vera (PV) without symptomatic splenomegaly.
Ropeginterferon alfa-2b is a long-acting interferon, which is administered once every 2 weeks or monthly after stabilization of hematological parameters.
The CHMP’s recommendation for ropeginterferon alfa-2b will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of a CHMP recommendation.
The CHMP’s positive opinion of ropeginterferon alfa-2b is supported by data from CONTINUATION-PV (NCT02218047), a phase 3b extension trial of PROUD-PV (NCT01949805).
Results from the PROUD-PV study were presented at the 2016 ASH Annual Meeting. The latest data from CONTINUATION-PV were presented at the 2018 ASH Annual Meeting.
PROUD-PV enrolled 254 PV patients who were treatment-naive or pretreated with hydroxyurea (HU). They were randomized to receive ropeginterferon alfa-2b (n=127) or HU (n=127).
The latest analysis of CONTINUATION-PV included 83 of the patients on ropeginterferon alfa-2b and 70 of the patients who either remained on HU or switched to best available therapy (BAT) as selected by investigators.
At 24 months, the complete hematologic response (CHR) rate was 70.5% with ropeginterferon alfa-2b and 49.3% with HU/BAT (P=0.0101).
At 36 months, the CHR rate was 70.5% with ropeginterferon alfa-2b and 51.4% with HU/BAT (P=0.0122).
A composite endpoint of CHR plus symptom improvement occurred in 52.6% of patients treated with ropeginterferon alfa-2b and 37.8% of patients on HU/BAT (P=0.0437).
Disease- or treatment-related secondary malignancies in patients receiving HU/BAT included two cases of acute myeloid leukemia, one melanoma, and two basaliomas.
There were three malignancies—glioblastoma, seminoma, and adrenal neoplasm—reported in patients treated with ropeginterferon alfa-2b. Investigators said these malignancies were most likely unrelated to treatment.
The rate of adverse events was 89.8% in the ropeginterferon alfa-2b arm and 90.6% in the HU/BAT arm. Treatment-related adverse events occurred in 74.8% and 78.7% of patients, respectively.
Anemia, thrombocytopenia, and leukopenia occurred more frequently with HU/BAT, whereas liver enzyme increase was mainly observed with ropeginterferon alfa-2b.
CONTINUATION-PV was sponsored by AOP Orphan Pharmaceuticals AG in collaboration with PharmaEssentia.
CHMP backs dasatinib for kids with newly diagnosed ALL
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for dasatinib (Sprycel).
The CHMP’s recommendation is to approve dasatinib in combination with chemotherapy to treat pediatric patients with newly diagnosed, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of a CHMP recommendation.
Dasatinib is already EC-approved to treat:
- Adults with newly diagnosed, Ph+ chronic myelogenous leukemia (CML) in the chronic phase
- Adults with chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy including imatinib
- Adults with Ph+ ALL and lymphoid blast CML with resistance or intolerance to prior therapy
- Pediatric patients with newly diagnosed, Ph+ CML in chronic phase
- Pediatric patients with Ph+ CML in chronic phase that is resistant or intolerant to prior therapy including imatinib.
Phase 2 trial
The CHMP’s recommendation to approve dasatinib in pediatric patients with newly diagnosed, Ph+ ALL is based on data from a phase 2 trial (NCT01460160). In this trial, researchers are evaluating dasatinib in combination with a chemotherapy regimen modeled on a Berlin-Frankfurt-Munster high-risk backbone.
Results from the trial were presented at the 2017 ASH Annual Meeting.
At that time, 106 patients had been treated. They received continuous daily dasatinib (60 mg/m2) beginning at day 15 of induction chemotherapy. All treated patients achieved complete remission.
Patients who had evidence of minimal residual disease (MRD) ≥ 0.05% at the end of the first block of treatment (day 78) and those with MRD 0.005% to 0.05% who remained MRD-positive at any detectable level after three additional high-risk chemotherapy blocks were eligible for hematopoietic stem cell transplant (HSCT) in first remission.
Nineteen patients met these criteria, and 15 (14.2%) received HSCT. The remaining 85.8% of patients received dasatinib plus chemotherapy for two years.
The 3-year event-free survival rate was 65.5%, and the 3-year overall survival rate was 91.5%.
Two patients discontinued dasatinib due to toxicity—one due to allergy and one due to prolonged thrombocytopenia.
Grade 3/4 adverse events attributed to dasatinib included elevated alanine aminotransferase (21.7%), elevated aspartate transaminase (10.4%), pleural effusion (3.8%), edema (2.8%), hemorrhage (5.7%), and cardiac failure (0.8%).
Five patients died while receiving chemotherapy (three from sepsis, one due to pneumonia, and one of an unknown cause). Two deaths were HSCT-related.
This trial was sponsored by Bristol-Myers Squibb.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for dasatinib (Sprycel).
The CHMP’s recommendation is to approve dasatinib in combination with chemotherapy to treat pediatric patients with newly diagnosed, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of a CHMP recommendation.
Dasatinib is already EC-approved to treat:
- Adults with newly diagnosed, Ph+ chronic myelogenous leukemia (CML) in the chronic phase
- Adults with chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy including imatinib
- Adults with Ph+ ALL and lymphoid blast CML with resistance or intolerance to prior therapy
- Pediatric patients with newly diagnosed, Ph+ CML in chronic phase
- Pediatric patients with Ph+ CML in chronic phase that is resistant or intolerant to prior therapy including imatinib.
Phase 2 trial
The CHMP’s recommendation to approve dasatinib in pediatric patients with newly diagnosed, Ph+ ALL is based on data from a phase 2 trial (NCT01460160). In this trial, researchers are evaluating dasatinib in combination with a chemotherapy regimen modeled on a Berlin-Frankfurt-Munster high-risk backbone.
Results from the trial were presented at the 2017 ASH Annual Meeting.
At that time, 106 patients had been treated. They received continuous daily dasatinib (60 mg/m2) beginning at day 15 of induction chemotherapy. All treated patients achieved complete remission.
Patients who had evidence of minimal residual disease (MRD) ≥ 0.05% at the end of the first block of treatment (day 78) and those with MRD 0.005% to 0.05% who remained MRD-positive at any detectable level after three additional high-risk chemotherapy blocks were eligible for hematopoietic stem cell transplant (HSCT) in first remission.
Nineteen patients met these criteria, and 15 (14.2%) received HSCT. The remaining 85.8% of patients received dasatinib plus chemotherapy for two years.
The 3-year event-free survival rate was 65.5%, and the 3-year overall survival rate was 91.5%.
Two patients discontinued dasatinib due to toxicity—one due to allergy and one due to prolonged thrombocytopenia.
Grade 3/4 adverse events attributed to dasatinib included elevated alanine aminotransferase (21.7%), elevated aspartate transaminase (10.4%), pleural effusion (3.8%), edema (2.8%), hemorrhage (5.7%), and cardiac failure (0.8%).
Five patients died while receiving chemotherapy (three from sepsis, one due to pneumonia, and one of an unknown cause). Two deaths were HSCT-related.
This trial was sponsored by Bristol-Myers Squibb.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for dasatinib (Sprycel).
The CHMP’s recommendation is to approve dasatinib in combination with chemotherapy to treat pediatric patients with newly diagnosed, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of a CHMP recommendation.
Dasatinib is already EC-approved to treat:
- Adults with newly diagnosed, Ph+ chronic myelogenous leukemia (CML) in the chronic phase
- Adults with chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy including imatinib
- Adults with Ph+ ALL and lymphoid blast CML with resistance or intolerance to prior therapy
- Pediatric patients with newly diagnosed, Ph+ CML in chronic phase
- Pediatric patients with Ph+ CML in chronic phase that is resistant or intolerant to prior therapy including imatinib.
Phase 2 trial
The CHMP’s recommendation to approve dasatinib in pediatric patients with newly diagnosed, Ph+ ALL is based on data from a phase 2 trial (NCT01460160). In this trial, researchers are evaluating dasatinib in combination with a chemotherapy regimen modeled on a Berlin-Frankfurt-Munster high-risk backbone.
Results from the trial were presented at the 2017 ASH Annual Meeting.
At that time, 106 patients had been treated. They received continuous daily dasatinib (60 mg/m2) beginning at day 15 of induction chemotherapy. All treated patients achieved complete remission.
Patients who had evidence of minimal residual disease (MRD) ≥ 0.05% at the end of the first block of treatment (day 78) and those with MRD 0.005% to 0.05% who remained MRD-positive at any detectable level after three additional high-risk chemotherapy blocks were eligible for hematopoietic stem cell transplant (HSCT) in first remission.
Nineteen patients met these criteria, and 15 (14.2%) received HSCT. The remaining 85.8% of patients received dasatinib plus chemotherapy for two years.
The 3-year event-free survival rate was 65.5%, and the 3-year overall survival rate was 91.5%.
Two patients discontinued dasatinib due to toxicity—one due to allergy and one due to prolonged thrombocytopenia.
Grade 3/4 adverse events attributed to dasatinib included elevated alanine aminotransferase (21.7%), elevated aspartate transaminase (10.4%), pleural effusion (3.8%), edema (2.8%), hemorrhage (5.7%), and cardiac failure (0.8%).
Five patients died while receiving chemotherapy (three from sepsis, one due to pneumonia, and one of an unknown cause). Two deaths were HSCT-related.
This trial was sponsored by Bristol-Myers Squibb.
Health Canada approves new indication for daratumumab
Health Canada has approved a third indication for daratumumab (Darzalex®) in multiple myeloma (MM).
The drug is now approved for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat patients with newly diagnosed MM who are ineligible for autologous stem cell transplant.
Health Canada previously approved daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone to treat MM patients who have received at least one prior therapy.
Health Canada also approved daratumumab as monotherapy for MM patients who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are refractory to both a proteasome inhibitor and an immunomodulatory agent.
For the product monograph and more information about daratumumab, visit https://www.janssen.com/canada/products.
Trial results
Health Canada’s latest approval of daratumumab is supported by data from the phase 3 ALCYONE study (NCT02195479), which were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).
The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.
The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.
The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.
The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.
The ALCYONE trial was sponsored by Janssen Research & Development, LLC.
Health Canada has approved a third indication for daratumumab (Darzalex®) in multiple myeloma (MM).
The drug is now approved for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat patients with newly diagnosed MM who are ineligible for autologous stem cell transplant.
Health Canada previously approved daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone to treat MM patients who have received at least one prior therapy.
Health Canada also approved daratumumab as monotherapy for MM patients who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are refractory to both a proteasome inhibitor and an immunomodulatory agent.
For the product monograph and more information about daratumumab, visit https://www.janssen.com/canada/products.
Trial results
Health Canada’s latest approval of daratumumab is supported by data from the phase 3 ALCYONE study (NCT02195479), which were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).
The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.
The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.
The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.
The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.
The ALCYONE trial was sponsored by Janssen Research & Development, LLC.
Health Canada has approved a third indication for daratumumab (Darzalex®) in multiple myeloma (MM).
The drug is now approved for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat patients with newly diagnosed MM who are ineligible for autologous stem cell transplant.
Health Canada previously approved daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone to treat MM patients who have received at least one prior therapy.
Health Canada also approved daratumumab as monotherapy for MM patients who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are refractory to both a proteasome inhibitor and an immunomodulatory agent.
For the product monograph and more information about daratumumab, visit https://www.janssen.com/canada/products.
Trial results
Health Canada’s latest approval of daratumumab is supported by data from the phase 3 ALCYONE study (NCT02195479), which were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.
ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).
The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.
The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.
The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).
Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.
The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.
The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).
The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.
The ALCYONE trial was sponsored by Janssen Research & Development, LLC.
CHMP recommends BV+AVD for Hodgkin lymphoma
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for brentuximab vedotin (BV).
The CHMP has recommended approval for BV (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of a CHMP recommendation.
BV is already EC-approved to treat adults with:
- CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT)
- Relapsed or refractory, CD30+ HL following ASCT or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
- Relapsed or refractory systemic anaplastic large-cell lymphoma
- CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.
Phase 3 trial
The CHMP’s recommendation to approve BV in combination with AVD is supported by the phase 3 ECHELON-1 trial (NCT01712490).
Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.
In this trial, researchers compared BV plus AVD (BV+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.
The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review committee, BV+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
The 2-year modified PFS rate was 82.1% in the BV+AVD arm and 77.2% in the ABVD arm.
There was no significant difference between the treatment arms when it came to response rates or overall survival.
The objective response rate was 86% in the BV+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The interim 2-year overall survival rate was 97% in the BV+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
The overall incidence of adverse events (AEs) was 99% in the BV+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV+AVD, while pulmonary toxicity was more common with ABVD.
The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals, Inc. (a Takeda company) in collaboration with Seattle Genetics, Inc.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for brentuximab vedotin (BV).
The CHMP has recommended approval for BV (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of a CHMP recommendation.
BV is already EC-approved to treat adults with:
- CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT)
- Relapsed or refractory, CD30+ HL following ASCT or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
- Relapsed or refractory systemic anaplastic large-cell lymphoma
- CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.
Phase 3 trial
The CHMP’s recommendation to approve BV in combination with AVD is supported by the phase 3 ECHELON-1 trial (NCT01712490).
Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.
In this trial, researchers compared BV plus AVD (BV+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.
The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review committee, BV+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
The 2-year modified PFS rate was 82.1% in the BV+AVD arm and 77.2% in the ABVD arm.
There was no significant difference between the treatment arms when it came to response rates or overall survival.
The objective response rate was 86% in the BV+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The interim 2-year overall survival rate was 97% in the BV+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
The overall incidence of adverse events (AEs) was 99% in the BV+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV+AVD, while pulmonary toxicity was more common with ABVD.
The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals, Inc. (a Takeda company) in collaboration with Seattle Genetics, Inc.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for brentuximab vedotin (BV).
The CHMP has recommended approval for BV (Adcetris) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of a CHMP recommendation.
BV is already EC-approved to treat adults with:
- CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT)
- Relapsed or refractory, CD30+ HL following ASCT or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
- Relapsed or refractory systemic anaplastic large-cell lymphoma
- CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.
Phase 3 trial
The CHMP’s recommendation to approve BV in combination with AVD is supported by the phase 3 ECHELON-1 trial (NCT01712490).
Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.
In this trial, researchers compared BV plus AVD (BV+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.
The primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.
According to an independent review committee, BV+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.
The 2-year modified PFS rate was 82.1% in the BV+AVD arm and 77.2% in the ABVD arm.
There was no significant difference between the treatment arms when it came to response rates or overall survival.
The objective response rate was 86% in the BV+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).
The interim 2-year overall survival rate was 97% in the BV+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).
The overall incidence of adverse events (AEs) was 99% in the BV+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.
Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV+AVD, while pulmonary toxicity was more common with ABVD.
The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals, Inc. (a Takeda company) in collaboration with Seattle Genetics, Inc.
Romiplostim now approved for children with ITP
The thrombopoietin receptor agonist romiplostim (NPlate®) is now approved by the U.S. Food and Drug Administration (FDA) to treat pediatric patients 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have not responded sufficiently to corticosteroids, immunoglobulins, or splenectomy.
Romiplostim was originally FDA-approved in 2008 to treat adult patients with chronic ITP who had an insufficient response to the same treatments.
Romiplostim is manufactured by Amgen, Inc.
The FDA based its approval on two double-blind, placebo-controlled clinical trials.
NCT01444417
The phase 3 study (NCT01444417) enrolled 62 pediatric patients 1 year and older who had ITP for at least 6 months. They were refractory to or relapsed after at least one prior therapy.
Investigators randomized them 2:1 to receive romiplostim (n=42) or placebo (n=20).
The starting dose was 1 μg/kg weekly for all ages. The dose was titrated up over a 24-week period to a maximum of 10 μg/kg weekly.
Patients were a median age of 9.5 years (range, 3–17), and 57% were female. A little over half (58%) had baseline platelet counts of 20 x 109/L or less, which was similar in both treatment arms.
Eighty-one percent of romiplostim-treated patients had at least two prior ITP therapies, compared with 70% in the placebo group. One patient in each group had undergone splenectomy.
Twenty-two (52%) of the romiplostim-treated patients had durable platelet responses of 50 x 109/L or greater for at least six weekly assessments during weeks 18 through 25 of treatment. Two (10%) patients in the placebo arm achieved durable platelet responses.
Thirty (71%) romiplostim-treated patients achieved an overall platelet response, defined as a durable or transient platelet response. This compared with four (20%) patients in the placebo group.
Romiplostim-treated patients had platelet counts of at least 50 x 109/L for a median of 12 weeks, compared to 1 week for patients in the placebo arm.
All response endpoints were significant at P<0.05.
NCT00515203
The phase 1/2 study (NCT00515203) enrolled 22 patients who had ITP for at least 6 months prior to study enrollment and were relapsed from or refractory to prior treatment.
Investigators randomized the patients 3:1 to romiplostim (n=17) or placebo (n=5).
Patients were a median age of 10 years (range, 1–17), and 27.3% were female.
Approximately 82% of patients had baseline platelet counts of 20 x 109/L or less, which was similar between the treatment arms.
Eighty-eight percent of patients in the romiplostim arm had at least two prior ITP therapies, as did 100% in the placebo group.
Six patients in the romiplostim group and two in the placebo group had undergone splenectomy.
Of the 17 patients treated with romiplostim, 15 (88.2%) achieved a platelet count of 50 x 109/L or great for 2 consecutive weeks.
The same 15 patients also achieved an increase in platelet count of 20 x 109/L or greater above baseline for 2 consecutive weeks during the treatment period.
None of the placebo-treated patients achieved either endpoint.
The adverse events profile in pediatric patients was compiled from the two trials and reflects a median drug exposure of 168 days for 59 patients.
The most common adverse events, occurring in 25% or more of romiplostim-treated patients, were contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%). These occurred with an incidence at least 5% higher than in the placebo group.
Dosing
The recommended starting dose for pediatric patients is 1 µg/kg based on actual body weight and administered as a weekly subcutaneous injection.
The dose should be adjusted in increments of 1 µg/kg until the patient achieves a platelet count of 50 x 109/L or greater.
The prescribing information recommends reassessing patients’ body weight every 12 weeks.
The thrombopoietin receptor agonist romiplostim (NPlate®) is now approved by the U.S. Food and Drug Administration (FDA) to treat pediatric patients 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have not responded sufficiently to corticosteroids, immunoglobulins, or splenectomy.
Romiplostim was originally FDA-approved in 2008 to treat adult patients with chronic ITP who had an insufficient response to the same treatments.
Romiplostim is manufactured by Amgen, Inc.
The FDA based its approval on two double-blind, placebo-controlled clinical trials.
NCT01444417
The phase 3 study (NCT01444417) enrolled 62 pediatric patients 1 year and older who had ITP for at least 6 months. They were refractory to or relapsed after at least one prior therapy.
Investigators randomized them 2:1 to receive romiplostim (n=42) or placebo (n=20).
The starting dose was 1 μg/kg weekly for all ages. The dose was titrated up over a 24-week period to a maximum of 10 μg/kg weekly.
Patients were a median age of 9.5 years (range, 3–17), and 57% were female. A little over half (58%) had baseline platelet counts of 20 x 109/L or less, which was similar in both treatment arms.
Eighty-one percent of romiplostim-treated patients had at least two prior ITP therapies, compared with 70% in the placebo group. One patient in each group had undergone splenectomy.
Twenty-two (52%) of the romiplostim-treated patients had durable platelet responses of 50 x 109/L or greater for at least six weekly assessments during weeks 18 through 25 of treatment. Two (10%) patients in the placebo arm achieved durable platelet responses.
Thirty (71%) romiplostim-treated patients achieved an overall platelet response, defined as a durable or transient platelet response. This compared with four (20%) patients in the placebo group.
Romiplostim-treated patients had platelet counts of at least 50 x 109/L for a median of 12 weeks, compared to 1 week for patients in the placebo arm.
All response endpoints were significant at P<0.05.
NCT00515203
The phase 1/2 study (NCT00515203) enrolled 22 patients who had ITP for at least 6 months prior to study enrollment and were relapsed from or refractory to prior treatment.
Investigators randomized the patients 3:1 to romiplostim (n=17) or placebo (n=5).
Patients were a median age of 10 years (range, 1–17), and 27.3% were female.
Approximately 82% of patients had baseline platelet counts of 20 x 109/L or less, which was similar between the treatment arms.
Eighty-eight percent of patients in the romiplostim arm had at least two prior ITP therapies, as did 100% in the placebo group.
Six patients in the romiplostim group and two in the placebo group had undergone splenectomy.
Of the 17 patients treated with romiplostim, 15 (88.2%) achieved a platelet count of 50 x 109/L or great for 2 consecutive weeks.
The same 15 patients also achieved an increase in platelet count of 20 x 109/L or greater above baseline for 2 consecutive weeks during the treatment period.
None of the placebo-treated patients achieved either endpoint.
The adverse events profile in pediatric patients was compiled from the two trials and reflects a median drug exposure of 168 days for 59 patients.
The most common adverse events, occurring in 25% or more of romiplostim-treated patients, were contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%). These occurred with an incidence at least 5% higher than in the placebo group.
Dosing
The recommended starting dose for pediatric patients is 1 µg/kg based on actual body weight and administered as a weekly subcutaneous injection.
The dose should be adjusted in increments of 1 µg/kg until the patient achieves a platelet count of 50 x 109/L or greater.
The prescribing information recommends reassessing patients’ body weight every 12 weeks.
The thrombopoietin receptor agonist romiplostim (NPlate®) is now approved by the U.S. Food and Drug Administration (FDA) to treat pediatric patients 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have not responded sufficiently to corticosteroids, immunoglobulins, or splenectomy.
Romiplostim was originally FDA-approved in 2008 to treat adult patients with chronic ITP who had an insufficient response to the same treatments.
Romiplostim is manufactured by Amgen, Inc.
The FDA based its approval on two double-blind, placebo-controlled clinical trials.
NCT01444417
The phase 3 study (NCT01444417) enrolled 62 pediatric patients 1 year and older who had ITP for at least 6 months. They were refractory to or relapsed after at least one prior therapy.
Investigators randomized them 2:1 to receive romiplostim (n=42) or placebo (n=20).
The starting dose was 1 μg/kg weekly for all ages. The dose was titrated up over a 24-week period to a maximum of 10 μg/kg weekly.
Patients were a median age of 9.5 years (range, 3–17), and 57% were female. A little over half (58%) had baseline platelet counts of 20 x 109/L or less, which was similar in both treatment arms.
Eighty-one percent of romiplostim-treated patients had at least two prior ITP therapies, compared with 70% in the placebo group. One patient in each group had undergone splenectomy.
Twenty-two (52%) of the romiplostim-treated patients had durable platelet responses of 50 x 109/L or greater for at least six weekly assessments during weeks 18 through 25 of treatment. Two (10%) patients in the placebo arm achieved durable platelet responses.
Thirty (71%) romiplostim-treated patients achieved an overall platelet response, defined as a durable or transient platelet response. This compared with four (20%) patients in the placebo group.
Romiplostim-treated patients had platelet counts of at least 50 x 109/L for a median of 12 weeks, compared to 1 week for patients in the placebo arm.
All response endpoints were significant at P<0.05.
NCT00515203
The phase 1/2 study (NCT00515203) enrolled 22 patients who had ITP for at least 6 months prior to study enrollment and were relapsed from or refractory to prior treatment.
Investigators randomized the patients 3:1 to romiplostim (n=17) or placebo (n=5).
Patients were a median age of 10 years (range, 1–17), and 27.3% were female.
Approximately 82% of patients had baseline platelet counts of 20 x 109/L or less, which was similar between the treatment arms.
Eighty-eight percent of patients in the romiplostim arm had at least two prior ITP therapies, as did 100% in the placebo group.
Six patients in the romiplostim group and two in the placebo group had undergone splenectomy.
Of the 17 patients treated with romiplostim, 15 (88.2%) achieved a platelet count of 50 x 109/L or great for 2 consecutive weeks.
The same 15 patients also achieved an increase in platelet count of 20 x 109/L or greater above baseline for 2 consecutive weeks during the treatment period.
None of the placebo-treated patients achieved either endpoint.
The adverse events profile in pediatric patients was compiled from the two trials and reflects a median drug exposure of 168 days for 59 patients.
The most common adverse events, occurring in 25% or more of romiplostim-treated patients, were contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%). These occurred with an incidence at least 5% higher than in the placebo group.
Dosing
The recommended starting dose for pediatric patients is 1 µg/kg based on actual body weight and administered as a weekly subcutaneous injection.
The dose should be adjusted in increments of 1 µg/kg until the patient achieves a platelet count of 50 x 109/L or greater.
The prescribing information recommends reassessing patients’ body weight every 12 weeks.
Serious side effect of AML treatment going unnoticed, FDA warns
The U.S. Food and Drug Administration (FDA) has released a safety communication warning that cases of differentiation syndrome are going unnoticed in patients treated with the IDH2 inhibitor enasidenib (Idhifa).
Enasidenib is FDA-approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation.
The drug is known to be associated with differentiation syndrome, and the prescribing information contains a boxed warning about this life-threatening condition.
However, the FDA has found that patients and healthcare providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.
The FDA is also warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).
However, the agency has not provided many details on cases related to this drug, which is FDA-approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.
Recognizing differentiation syndrome
The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.
The agency is advising healthcare providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.
Symptoms of differentiation syndrome include:
- Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen
- Pulmonary infiltrates and pleural effusion
- Fever
- Lymphadenopathy
- Bone pain
- Peripheral edema with rapid weight gain
- Pericardial effusion
- Hepatic, renal, and multiorgan dysfunction.
The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.
Treatment
If healthcare providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA.
Providers should also monitor hemodynamics until improvement and provide supportive care as necessary.
If patients continue to experience renal dysfunction or severe pulmonary symptoms requiring intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.
Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon.
Cases of differentiation syndrome
The FDA notes that, in the phase 1/2 trial that supported the U.S. approval of enasidenib, at least 14% of patients experienced differentiation syndrome.
The manufacturer’s latest safety report includes 5 deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.
Differentiation syndrome was listed as the only cause of death in two cases. In the remaining three cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.
One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly. Treatment details are not available for the remaining three patients, according to the FDA.
The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n=214) or ivosidenib (n=179).
With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in 6% (n=2) of ivosidenib-treated patients and 5% (n=2) of enasidenib-treated patients.
Additional results from this analysis are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 288).
The U.S. Food and Drug Administration (FDA) has released a safety communication warning that cases of differentiation syndrome are going unnoticed in patients treated with the IDH2 inhibitor enasidenib (Idhifa).
Enasidenib is FDA-approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation.
The drug is known to be associated with differentiation syndrome, and the prescribing information contains a boxed warning about this life-threatening condition.
However, the FDA has found that patients and healthcare providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.
The FDA is also warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).
However, the agency has not provided many details on cases related to this drug, which is FDA-approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.
Recognizing differentiation syndrome
The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.
The agency is advising healthcare providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.
Symptoms of differentiation syndrome include:
- Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen
- Pulmonary infiltrates and pleural effusion
- Fever
- Lymphadenopathy
- Bone pain
- Peripheral edema with rapid weight gain
- Pericardial effusion
- Hepatic, renal, and multiorgan dysfunction.
The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.
Treatment
If healthcare providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA.
Providers should also monitor hemodynamics until improvement and provide supportive care as necessary.
If patients continue to experience renal dysfunction or severe pulmonary symptoms requiring intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.
Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon.
Cases of differentiation syndrome
The FDA notes that, in the phase 1/2 trial that supported the U.S. approval of enasidenib, at least 14% of patients experienced differentiation syndrome.
The manufacturer’s latest safety report includes 5 deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.
Differentiation syndrome was listed as the only cause of death in two cases. In the remaining three cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.
One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly. Treatment details are not available for the remaining three patients, according to the FDA.
The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n=214) or ivosidenib (n=179).
With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in 6% (n=2) of ivosidenib-treated patients and 5% (n=2) of enasidenib-treated patients.
Additional results from this analysis are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 288).
The U.S. Food and Drug Administration (FDA) has released a safety communication warning that cases of differentiation syndrome are going unnoticed in patients treated with the IDH2 inhibitor enasidenib (Idhifa).
Enasidenib is FDA-approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) and an IDH2 mutation.
The drug is known to be associated with differentiation syndrome, and the prescribing information contains a boxed warning about this life-threatening condition.
However, the FDA has found that patients and healthcare providers are missing the signs and symptoms of differentiation syndrome, and some patients are not receiving the necessary treatment in time.
The FDA is also warning that differentiation syndrome has been observed in AML patients taking the IDH1 inhibitor ivosidenib (Tibsovo).
However, the agency has not provided many details on cases related to this drug, which is FDA-approved to treat adults with relapsed or refractory AML who have an IDH1 mutation.
Recognizing differentiation syndrome
The FDA says differentiation syndrome may occur anywhere from 10 days to 5 months after starting enasidenib.
The agency is advising healthcare providers to describe the symptoms of differentiation syndrome to patients, both when starting them on enasidenib and at follow-up visits.
Symptoms of differentiation syndrome include:
- Acute respiratory distress represented by dyspnea and/or hypoxia and a need for supplemental oxygen
- Pulmonary infiltrates and pleural effusion
- Fever
- Lymphadenopathy
- Bone pain
- Peripheral edema with rapid weight gain
- Pericardial effusion
- Hepatic, renal, and multiorgan dysfunction.
The FDA notes that differentiation syndrome may be mistaken for cardiogenic pulmonary edema, pneumonia, or sepsis.
Treatment
If healthcare providers suspect differentiation syndrome, they should promptly administer oral or intravenous corticosteroids, such as dexamethasone at 10 mg every 12 hours, according to the FDA.
Providers should also monitor hemodynamics until improvement and provide supportive care as necessary.
If patients continue to experience renal dysfunction or severe pulmonary symptoms requiring intubation or ventilator support for more than 48 hours after starting corticosteroids, enasidenib should be stopped until signs and symptoms of differentiation syndrome are no longer severe.
Corticosteroids should be tapered only after the symptoms resolve completely, as differentiation syndrome may recur if treatment is stopped too soon.
Cases of differentiation syndrome
The FDA notes that, in the phase 1/2 trial that supported the U.S. approval of enasidenib, at least 14% of patients experienced differentiation syndrome.
The manufacturer’s latest safety report includes 5 deaths (from May 1, 2018, to July 31, 2018) associated with differentiation syndrome in patients taking enasidenib.
Differentiation syndrome was listed as the only cause of death in two cases. In the remaining three cases, patients also had hemorrhagic stroke, pneumonia and sepsis, and sepsis alone.
One patient received systemic corticosteroids promptly but may have died of sepsis during hospitalization. In another patient, differentiation syndrome was not diagnosed or treated promptly. Treatment details are not available for the remaining three patients, according to the FDA.
The FDA has also performed a systematic analysis of differentiation syndrome in 293 patients treated with enasidenib (n=214) or ivosidenib (n=179).
With both drugs, the incidence of differentiation syndrome was 19%. The condition was fatal in 6% (n=2) of ivosidenib-treated patients and 5% (n=2) of enasidenib-treated patients.
Additional results from this analysis are scheduled to be presented at the 2018 ASH Annual Meeting (abstract 288).