Idasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial

The phase III MIRROS trial (NCT02545283) evaluated the efficacy and safety of the small-molecule MDM2 antagonist idasanutlin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Adults (N=447) with R/R AML whose disease relapsed or was refractory after ≤2 prior induction regimens as initial treatment or following salvage chemotherapy regimen, with Eastern Cooperative Oncology Group performance status ≤2 were enrolled regardless of TP53 mutation status and randomly assigned 2:1 to idasanutlin 300 mg or placebo orally twice daily plus cytarabine 1 g/m2 intravenously on days 1 to 5 of 28-day cycles. At primary analysis (cutoff, November 2019), 436 patients were enrolled, including 355 in the TP53 wild-type intention-to-treat (TP53WT-ITT) population. The primary endpoint, overall survival in the TP53WT-ITT population, was not met (median, 8.3 vs 9.1 months with idasanutlin-cytarabine vs placebo-cytarabine; stratified hazard ratio, 1.08; 95% CI, 0.81-1.45; p = .58). The complete remission (CR) rate, a key secondary endpoint, was 20.3% vs 17.1% (odds ratio [OR], 1.23; 95% CI, 0.70-2.18). The overall response rate (ORR) was 38.8% vs 22.0% (OR, 2.25; 95% CI, 1.36-3.72). Common any-grade adverse events (≥10% incidence in any arm) were diarrhea (87.0% vs 32.9%), febrile neutropenia (52.8% vs 49.3%), and nausea (52.5% vs 31.5%). In summary, despite improved ORR, adding idasanutlin to cytarabine did not improve overall survival or CR rates in patients with R/R AML

Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial

BACKGROUND: Intravenous rituximab is the standard of care in B-cell non-Hodgkin lymphoma, and is administered over 1·5-6 h. A subcutaneous formulation could reduce patients' treatment burden and improve resource utilisation in health care. We aimed to show the pharmacokinetic non-inferiority of subcutaneous rituximab to intravenous rituximab in follicular lymphoma and to provide efficacy and safety data.METHODS: SABRINA is a two-stage, randomised, open-label phase 3 study at 113 centres in 30 countries. Eligible patients were aged 18 years or older and had histologically confirmed, previously untreated, CD20-positive grade 1, 2, or 3a follicular lymphoma; Eastern Co-operative Oncology Group performance statuses of 0-2; bidimensionally measurable disease (by CT or MRI); life expectancy of 6 months or more; adequate haematological function for 28 days or more; and one or more symptoms requiring treatment according to the Groupe d'Etudes des Lymphomes Folliculaires criteria. Patients were randomly assigned (1:1) by investigators or members of the research team via a dynamic randomisation algorithm to 375 mg/m2 intravenous rituximab or 1400 mg subcutaneous rituximab, plus chemotherapy (six-to-eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or eight cycles of cyclophosphamide, vincristine, and prednisone [CVP]), every 3 weeks during induction, then rituximab maintenance every 8 weeks. Randomisation was stratified by selected chemotherapy, Follicular Lymphoma International Prognostic Index, and region. The primary endpoint for stage 2 was overall response (ie, confirmed complete response, unconfirmed complete response, and partial response) at the end of induction. Efficacy analyses were done in the intention-to-treat population. Pooled data from stages 1 and 2 are reported on the basis of the clinical cutoff date of the last patient completing the maintenance phase of the study. This trial is registered with ClinicalTrials.gov, number NCT01200758; new patients are no longer being recruited, but some patients are still being followed up.FINDINGS: Between Feb 15, 2011, and May 15, 2013, 410 patients were randomly assigned, 205 to intravenous rituximab and 205 to subcutaneous rituximab. Investigator-assessed overall response at the end of induction was 84·9% (95% CI 79·2-89·5) in the intravenous group and 84·4% (78·7-89·1) in the subcutaneous group. The frequency of adverse events was similar in both groups (199 [95%] of 210 in the intravenous group vs 189 [96%] of 197 in the subcutaneous group); the frequency of adverse events of grade 3 or higher was also similar (116 [55%] vs 111 [56%]). The most common grade 3 or higher adverse event was neutropenia, which occurred in 44 patients (21%) in the intravenous group and 52 (26%) in the subcutaneous group. Serious adverse events occurred in 72 patients (34%) in the intravenous group and 73 (37%) in the subcutaneous group. Administration-related reactions occurred in 73 patients (35%) in the intravenous group and 95 (48%) patients in the subcutaneous group (mainly grade 1 or 2 local injection-site reactions).INTERPRETATION: Intravenous and subcutaneous rituximab had similar efficacy and safety profiles, and no new safety concerns were noted. Subcutaneous administration does not compromise the anti-lymphoma activity of rituximab when given with chemotherapy.FUNDING: F Hoffmann-La Roche.</p