Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults.

BACKGROUND: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission. METHODS: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point. RESULTS: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group. CONCLUSIONS: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.).

New strategies for relapsed acute myeloid leukemia: fertile ground for translational research.

PURPOSE OF REVIEW: Although frontline treatment of acute myeloid leukemia (AML) achieves high remission rates, approximately 75-80% of patients will either not respond to or relapse after initial therapy. Some patients, generally those who are younger, can be successfully salvaged with second-line chemotherapy followed by allogeneic stem cell transplantation. There is a great need for novel therapies in AML. RECENT FINDINGS: Advances in molecular technology recently identified recurrent mutations including mutations of DNMT3A, IDH1/2, and TET2. These mutations represent a major advance in the understanding of leukemogenesis and prognosis, and have enabled the development of targeted therapies. SUMMARY: Improved knowledge of the molecular pathogenesis of AML has allowed development of therapies targeting epigenetic modulation, intracellular signaling pathways, prosurvival proteins, and the tumor microenvironment.

Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial.

BACKGROUND: Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study were to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of olutasidenib, as monotherapy or in combination with azacitidine, in patients with acute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1. METHODS: In this phase 1/2, multicentre, open-label clinical trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia or intermediate, high, or very high risk myelodysplastic syndrome harbouring mutant IDH1 at 18 study sites in the USA, Australia, France, and Spain. Other key eligibility criteria included Eastern Cooperative Oncology Group performance status 0-2 with adequate liver and renal function. The primary outcomes were dose-limiting toxicities and the maximum tolerated dose, maximum evaluated dose, and the recommended phase 2 dose of olutasidenib. Olutasidenib was administered orally in doses of 150 mg once daily, 150 mg twice per day, and 300 mg once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously daily for 7 days on, 21 days off. The study was ongoing at the data cutoff (Oct 2, 2019) and is registered with ClinicalTrials.gov, NCT02719574. FINDINGS: Patients were enrolled between Aug 8, 2016, and Nov 14, 2018. 78 patients received olutasidenib as monotherapy (n=32) or in combination with azacitidine (n=46). The median follow-up was 8·3 months (IQR 3·1-13·3) for monotherapy and 10·1 months (4·2-15·3) for combination therapy. 16 (50%) of 32 patients in the monotherapy group and 24 (52%) of 46 patients in the combination therapy group were women. Most patients were White (26 [81%] for monotherapy and 31 [67%] for combination therapy). No dose-limiting toxicities were reported in the dose-escalation cohorts and 150 mg twice per day was declared the recommended phase 2 dose on the basis of safety, pharmacokinetics and pharmacodynamics, and clinical activity. The most common (≥20%) grade 3-4 treatment-emergent adverse events with monotherapy were thrombocytopenia (nine [28%] of 32 patients), febrile neutropenia (seven [22%] of 32), and anaemia (seven [22%] of 32); and with combination therapy were thrombocytopenia (19 [41%] of 46), febrile neutropenia (13 [28%] of 46), neutropenia (13 [28%] of 46), and anaemia (nine [20%] of 46). 11 (34%) of 32 patients in the monotherapy group and nine (20%) of 46 patients in the combination therapy group died (most commonly from disease progression [three (9%) of 32 and four (9%) of 46]). No deaths were considered study-drug related. For patients with relapsed or refractory acute myeloid leukaemia, 41% (95% CI 21-64; nine of 22) receiving monotherapy and 46% (27-67; 12 of 26) receiving combination therapy had an overall response. For treatment-naive patients with acute myeloid leukaemia, 25% (1-81; one of four) receiving monotherapy and 77% (46-95; ten of 13) receiving combination therapy had an overall response. INTERPRETATION: Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies. FUNDING: Forma Therapeutics.