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IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3 × 3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100mg daily. Attributable grade ≥3 toxicities were rare, with the most common being cytopenias. Eight patients stopped maintenance before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft-vs-host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID infection (n=1). No cases of grade ≥3 acute GVHD were seen, and 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); 1 subject relapsed while receiving maintenance. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (95% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at www.clinicaltrials.gov (#NCT03515512).

Key Points A novel PCM1-FGFR1 gene rearrangement was identified in a patient with a myeloid neoplasm with eosinophilia. Futibatinib, an oral selective small molecule inhibitor of FGFR1-4, resulted in a durable complete hematologic and cytogenetic remission.

Patients diagnosed with acute myeloid leukemia (AML) face sudden-onset life-threatening disease that requires intensive treatments. Although their early disease trajectory is characterized by significant, toxic side effects, limited data are available describing coping strategies among patients with AML and how these inform patient-reported outcomes. We used cross-sectional secondary data analyses to describe coping in 160 patients with newly diagnosed high-risk AML. The Brief COPE, Hospital Anxiety and Depression Scale, Post-Traumatic Stress Disorder Checklist–Civilian Version, and Functional Assessment of Cancer Therapy–Leukemia were used at time of AML diagnosis to measure coping strategies, psychological distress, and quality of life (QOL), respectively. The median split method for distribution of coping domains and multivariate regression models were used to assess the relationship between coping and patient-reported outcomes. Participants (median age, 64.4 years) were mostly non-Hispanic White (86.3%), male (60.0%), and married (73.8%). Most (51.9%) had high utilization of approach-oriented coping strategies, whereas 38.8% had high utilization of avoidant coping strategies. At time of diagnosis, use of approach-oriented coping was associated with less psychological distress (anxiety, β = –0.262, P = .002; depression symptoms, β = –0.311, P < .001; and posttraumatic distress disorder symptoms, β = –0.596, P = .006) and better QOL (β = 1.491, P = .003). Use of avoidant coping was associated with more psychological distress (anxiety, β = 0.884, P < .001; depression symptoms, β = 0.697, P < .001; and posttraumatic distress disorder symptoms, β = 3.048, P < .001) and worse QOL (β = –5.696, P < .001). Patients with high-risk AML use various approach-oriented and avoidant coping strategies at time of diagnosis. Use of approach-oriented coping strategies was associated with less psychological distress and better QOL, suggesting a possible target for supportive oncology interventions.

Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (2-HG) and impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme inhibitor, can restore normal differentiation and results in clinical responses in a subset of patients with mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms of ivosidenib resistance in 174 patients with confirmed mIDH1 R/R AML from a phase 1 trial. Receptor tyrosine kinase (RTK) pathway mutations were associated with primary resistance to ivosidenib. Multiple mechanisms contributed to acquired resistance, particularly outgrowth of RTK pathway mutations and 2-HG–restoring mutations (second-site IDH1 mutations, IDH2 mutations). Observation of multiple concurrent mechanisms in individual patients underscores the complex biology of resistance and has important implications for rational combination therapy design. This trial was registered at www.clinicaltrials.gov as #NCT02074839

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders associated with progression to leukemia and poor survival. Clonal hematopoiesis in people without an MDS diagnosis carries an increased risk of cardiovascular death. Many clonally restricted mutations are shared between patients with MDS and those with non-MDS clonal hematopoiesis; therefore, we evaluated the risk of cardiovascular death among patients with MDS. We evaluated adults with MDS in the Surveillance, Epidemiology, and End Results database of the National Cancer Institute and compared them with the general population living in the same states. We grouped histological subtypes of MDS into lower-, intermediate-, and higher-risk disease. The primary outcomes were overall survival and primary cause of death (COD) as reported to state registries. A total of 21 372 patients with MDS between 2001 and 2011 died during follow-up with a known COD. The rate of death due to cardiovascular disease (CVD) was 4613 per 100 000 person-years, compared with 2091 in the age- and-sex-adjusted US population (standardized mortality ratio, 2.21). At 24 months, the cumulative incidence of death attributed to MDS or leukemia was 23% vs 8% for CVD. Among those alive at 60 months, 27% eventually died of CVD compared with 29% from MDS or leukemia; those with lower-risk disease who survived >60 months had more deaths attributed to cardiovascular causes (30%; 95% confidence interval [CI], 26.7-33.2%) than MDS itself (24%; 95% CI, 21.4-27.5%). Patients with MDS are more likely to die of cardiovascular causes than the general population. Modifying cardiovascular risk factors, especially among those with lower-risk disease, may be warranted for MDS-related clinical care.