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• Cytotoxic therapy increases the risk for therapy-related myeloid neoplasms (t-MN). • While HSC-intrinsic effects are crucial, t-MN is also dependent on extrinsic factors. • Cytotoxic therapy drives senescence in the bone marrow microenvironment (BMME). • Current studies support a role for BMME senescence in the development of t-MN. • Targeting of senescent BMSCs may alleviate BM dysfunction and mitigate t-MN. Therapy-related myeloid neoplasms (t-MN) are a growing concern due to the continued use of cytotoxic therapies to treat malignancies. Cytotoxic therapies have been shown to drive therapy-induced senescence in normal tissues, including in the bone marrow microenvironment (BMME), which plays a crucial role in supporting normal hematopoiesis. This review examines recent work that focuses on the contribution of BMME senescence to t-MN pathogenesis, as well as offers a perspective on potential opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

We studied if the inclusion of early post–stem cell transplantation (SCT) minimal residual disease (MRD) assessments improved prognostication in patients with acute myeloid leukemia (AML). Two hundred sixty-nine AML patients in morphological complete remission (CR) who underwent a first SCT were included if they had evaluable pre-SCT MRD assessment by multiparametric flow cytometry. Post-SCT MRD assessments were performed at days +30, +100, and +180. The primary outcome was 1-year relapse incidence (RI). Of 269 patients in CR, 83 (30.8%) had detectable MRD pre-SCT. Post-SCT, during routine disease assessment time points, 9 of 241 evaluable patients (3.7%) at day +30, 6 of 191 evaluable patients (3.1%) at day +100, and 4 of 133 evaluable patients (3%) at day +180 were MRD positive while in CR. MRD positivity at day +30 predicted the highest risk of relapse at 1 year (group 1, 1-year RI 78%). Among MRD-negative patients at day +30, either adverse risk category by European Leukemia Net (ELN) or intermediate risk who were aged ≥60 years and/or pre-SCT MRD-positive represented the intermediate-risk group (group 2, 1-year RI 29%). The remaining patients represented the low-risk group (group 3, 1-year RI 5%). For patients in CR beyond day +30 post-SCT, detectable MRD at any time point predicted impending relapse within 2 months. Early post-SCT MRD assessment—combined with pre-SCT MRD assessment, ELN risk category, and age—improves risk stratification for relapse in AML patients post-transplant. Studies aimed at preventing impending relapse in this high-risk population are urgently needed. [ABSTRACT FROM AUTHOR]

Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50–1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov , NCT04067336 , and the EU Clinical Trials register, EudraCT 2019-001545-41. From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50–1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4–30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. Kura Oncology. [ABSTRACT FROM AUTHOR]