Category: Hematologic malignancies

  • Oral Menin-Based Triplet Shows Strong Early Activity in ND AML

    The phase II SAVE trial presented at the 2025 American Society of Hematology (ASH) Annual Meeting (Abstract 47) delivered early but compelling results from an all-oral regimen pairing the menin inhibitor revumenib with decitabine/cedazuridine and venetoclax for newly diagnosed acute myeloid leukemia (AML) with mutations in nucleophosmin 1 (NPM1) or rearrangements involving lysine methyltransferase 2A (KMT2A). Among an older, molecularly defined cohort, the combination produced rapid measurable residual disease (MRD)–negative remissions and encouraging early survival signals, raising the possibility that menin inhibition may meaningfully strengthen current low-intensity frontline approaches.

    The newly diagnosed cohort included 21 patients with a median age of 70 years. The NPM1-mutated cohort was older, with a median age of 73 years and 71% aged 70 years or older. Co-mutations were common and included NRAS, KRAS, fms-related tyrosine kinase 3 (FLT3), and isocitrate dehydrogenase 1/2 (IDH1/2). Myelodysplasia-related mutations were present in 43%. Treatment incorporated revumenib through Day 21 of induction to allow confirmation of Day 14 marrow findings before adjustment, and both venetoclax and decitabine/cedazuridine durations were reduced in later cycles as cytopenias emerged. The median cycle length extended to approximately six weeks because of delayed count recovery.

    The overall response rate (ORR) was 86%, and 81% of patients achieved complete remission (CR) or CR with partial hematologic recovery (CRh). All composite remissions were MRD negative by multiparameter flow cytometry with a sensitivity of 10^-4 NPM1-based MRD measured by next-generation sequencing (NGS; sensitivity 5 × 10^-5) showed similar kinetics, and the 2 patients who failed to clear ultimately relapsed. With nine months of median follow-up, the median duration of response (DOR), overall survival (OS), and event-free survival (EFS) had not been reached. Estimated one-year remission rates were 71% in NPM1-mutated AML and 80% in KMT2A-rearranged AML. Most responses occurred within the first cycle, and 33% of patients proceeded to allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, and none of those patients have relapsed.

    Differentiation syndrome (DS) occurred in 19% of patients, including 2 grade 3 events that resolved with corticosteroids. QT interval prolongation occurred in 43% of patients but was limited to grade 2 and did not prompt treatment discontinuation. Infections reflected substantial myelosuppression, with gram-negative rod bacteremia representing the dominant pathogen group. Four deaths occurred including one patient who died post HCT of respiratory failure while receiving revumenib maintenance.

    Taken together, the SAVE trial offers early evidence that integrating a menin inhibitor into an oral hypomethylating agent–venetoclax backbone may produce deep and rapid remissions in newly diagnosed AML with NPM1 mutations or KMT2A rearrangements. Longer follow-up and larger cohorts will be required to define durability, safety in older adults, and the prevalence of resistance mechanisms such as MEN1 mutation.

    References:

    Jen WY, Short NJ, Farhat A, et al. Phase II study of the all-oral combination of revumenib with decitabine/cedazuridine and venetoclax (SAVE) in newly diagnosed AML. Presented at: American Society of Hematology Annual Meeting; 2025; Orlando, FL. Abstract 47.

  • FDA Approves Liso-Cel for R/R MZL

    On December 4, 2025, the US Food and Drug Administration (FDA) approved the CD19/CD3-directed CAR T-cell therapy lisocabtagene maraleucel (Breyanzi) for adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received 2 or more prior lines of systemic therapy.

    The approval was supported by the MZL cohort of the open-label, multicenter, single-arm phase 2 TRANSCEND FL trial (NCT04245839). A total of 77 patients underwent leukapheresis, and 66 treated patients comprised the primary efficacy analysis set. Patients received a single lisocabtagene maraleucel infusion 2 to 7 days after lymphodepleting chemotherapy.

    The primary endpoint was overall response rate (ORR), assessed per Lugano criteria by an independent review committee. In the intention-to-treat population, the ORR was 84.4% (95% CI, 74.4%–91.7%), including a 55.8% complete response rate (95% CI, 44.1%–67.2%). Median duration of response had not been reached at the time of analysis.

    The safety profile reflected the known adverse-event spectrum of lisocabtagene maraleucel. The prescribing information contains boxed warnings for cytokine release syndrome (CRS) and neurologic toxicities. Additional risks include hypogammaglobulinemia, serious infections, prolonged cytopenias, secondary malignancies, and immune-effector-cell–associated hemophagocytic lymphohistiocytosis–like syndrome.

    References:

    US Food and Drug Administration. FDA approves lisocabtagene maraleucel for relapsed or refractory marginal zone lymphoma. Published December 4, 2025. Accessed December 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lisocabtagene-maraleucel-relapsed-or-refractory-marginal-zone-lymphoma

  • FDA Approves Epcoritamab with Rituximab and Lenalidomide for R/R FL

    On November 18, 2025, the US Food and Drug Administration approved epcoritamab-bysp in combination with rituximab and lenalidomide for adult patients with relapsed or refractory follicular lymphoma (FL). On the same day, the FDA also converted the prior accelerated approval of epcoritamab-bysp monotherapy in patients with FL who have received at least two prior lines of systemic therapy to full approval.

    The combination approval was supported by data from EPCORE FL-1 (Study M20-638; NCT05409066), a phase 3, open-label, randomized trial enrolling 488 patients with relapsed or refractory FL. Patients were randomized 1:1 to receive epcoritamab-bysp with rituximab and lenalidomide (R²) or R² alone. The coprimary endpoints were progression-free survival (PFS) and overall response rate (ORR) assessed by independent review per Lugano 2014 criteria. ORR was 89% (95% CI, 84–93) in the epcoritamab arm compared to 74% (95% CI, 68–79) in the control arm. Median PFS was not reached in the epcoritamab arm (95% CI, 21.9 months–not reached) and was 11.2 months (95% CI, 10.5–not reached) in the R² arm, corresponding to a hazard ratio of 0.21 (95% CI, 0.13–0.33; P < .0001).

    Treatment-related adverse events included cytokine release syndrome (CRS) in 24% of patients (12% serious) and immune effector cell-associated neurotoxicity syndrome (ICANS) in 0.8%. Serious adverse reactions occurred in 51% of patients, including serious infections in 28%. Common adverse events (≥20%) included injection-site reactions, CRS, fatigue, upper respiratory tract infections, rash, diarrhea, pyrexia, cough, and headache. Grade 3–4 cytopenias included neutropenia (~30%), anemia (~10%), and thrombocytopenia (~8%). Epcoritamab-bysp is administered subcutaneously with a cycle 1 step-up dosing regimen followed by weekly and then every 4-week maintenance dosing.

    This approval offers a fixed-duration, outpatient, chemotherapy-free treatment option for relapsed or refractory FL, a disease marked by inevitable relapse and treatment resistance. The addition of epcoritamab-bysp to R² provides a novel immunotherapeutic strategy with clinically meaningful improvements in PFS and response rates.

    References:

    US Food and Drug Administration. FDA approves epcoritamab-bysp for follicular lymphoma indications. FDA. Published November 18, 2025. Accessed November 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-epcoritamab-bysp-follicular-lymphoma-indications

  • Ziftomenib Approved for NPM1-Mutant R/R AML

    On November 13, 2025, the US Food and Drug Administration approved the menin inhibitor ziftomenib (Komzifti) for adult patients with relapsed or refractory acute myeloid leukemia (AML) harboring a susceptible NPM1 mutation and for whom no satisfactory alternative treatments are available.

    The approval was based on the phase 1/2 KOMET-001 trial (NCT04067336), an open-label, multicenter study enrolling 112 adults with relapsed or refractory AML and confirmed NPM1 mutation. In the phase 2 cohort (n = 92), the primary endpoint was the combined complete remission (CR) and CR with partial hematologic recovery (CRh) rate. Ziftomenib achieved a CR + CRh rate of 21.4% (95% CI, 14.2–30.2), including CR in 17.0% and CRh in 4.5% of patients. Median duration of CR/CRh was 5.0 months (95% CI, 1.9–8.1). Among 66 patients who were transfusion dependent at baseline, 21.2% achieved transfusion independence for at least 56 days; 26.1% of 46 patients who were transfusion independent at baseline maintained that status.

    Adverse reactions included differentiation syndrome (25% overall; 15% grade ≥3), febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). QTc prolongation was not clinically significant. Three percent of patients discontinued ziftomenib due to treatment-related adverse events. The prescribing information includes warnings for differentiation syndrome, QTc prolongation, and embryo-fetal toxicity.

    Ziftomenib is the first targeted therapy approved specifically for NPM1-mutant AML, a subset representing approximately 25%–30% of adult AML cases. Responses were observed across subgroups regardless of prior venetoclax exposure or hematopoietic stem cell transplant. “In these heavily pretreated, relapsed/refractory patients, similar response rates were seen … regardless of multiple lines of therapy,” said Dr. Eunice Wang, KOMET-001 investigator (OncLive, November 2023).

    References:

    FDA announcement: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ziftomenib-relapsed-or-refractory-acute-myeloid-leukemia-npm1-mutation