Mutant isocitrate dehydrogenase (IDH) 1 and 2 play a pathogenic role in cancers, including acute myeloid leukemia (AML), by producing oncometabolite 2-hydroxyglutarate (2-HG). We recently reported that tyrosine phosphorylation activates IDH1 R132H mutant in AML cells. Here, we show that mutant IDH2 (mIDH2) R140Q commonly has K413 acetylation, which negatively regulates mIDH2 activity in human AML cells by attenuating dimerization and blocking binding of substrate (α-ketoglutarate) and cofactor (NADPH). Mechanistically, K413 acetylation of mitochondrial mIDH2 is achieved through a series of hierarchical phosphorylation events mediated by tyrosine kinase FLT3, which phosphorylates mIDH2 to recruit upstream mitochondrial acetyltransferase ACAT1 and simultaneously activates ACAT1 and inhibits upstream mitochondrial deacetylase SIRT3 through tyrosine phosphorylation. Moreover, we found that the intrinsic enzyme activity of mIDH2 is much higher than mIDH1, thus the inhibitory K413 acetylation optimizes leukemogenic ability of mIDH2 in AML cells by both producing sufficient 2-HG for transformation and avoiding cytotoxic accumulation of intracellular 2-HG.

Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH1 inhibitor–naive patients with mIDH1R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) received olutasidenib monotherapy 150 mg twice daily in the pivotal cohort of this study. The median age of participants was 71 years (range, 32-87 years) and the median number of prior regimens received by patients was 2 (1-7). The rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 35%, and the overall response rate was 48%. Response rates were similar in patients who had, and who had not, received prior venetoclax. With 55% of patients censored at the time of data cut-off, the median duration of CR/CRh was 25.9 months. The median duration of overall response was 11.7 months, and the median overall survival was 11.6 months. Of 86 patients who were transfusion dependent at baseline, a 56-day transfusion independence was achieved in 29 (34%), which included patients in all response groups. Grade 3 or 4 treatment-emergent adverse events (≥10%) were febrile neutropenia and anemia (n = 31; 20% each), thrombocytopenia (n = 25; 16%), and neutropenia (n = 20; 13%). Differentiation syndrome adverse events of special interest occurred in 22 (14%) patients, with 14 (9%) grade ≥3 and 1 fatal case reported. Overall, olutasidenib induced durable remissions and transfusion independence with a well-characterized and manageable side effect profile. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognostic population of patients with mIDH1 R/R AML.

None

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome1,2. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient’s leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60–92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.

None

In recent years, several research programs in acute myeloid leukemia (AML) have investigated the use of therapeutic monoclonal antibodies, which primarily elicit their effects through direct cell killing (apoptosis), via antibody-dependent cellular cytotoxicity (ADCC) or antibody- dependent cellular phagocytosis (ADCP).1,2 Attention has been particularly focused on the myeloid differentiation antigen CD33,2 which is expressed on the surface of leukemic blast cells of almost all AML patients.1 While the activity of unconjugated anti-CD33 antibodies such as lintuzumab has been generally disappointing to date,3-6 clinical experience with gemtuzumab ozogamicin, a humanized anti-CD33 antibody-drug conjugate, provides proof-of-principle for targeting CD33 in patients with AML.7,8

Hematopoietic cell transplantation (HCT) is an intensive treatment resulting in disease control however subsequent psychosocial distress is common. Screening for psychosocial risk factors that contribute to morbidity is underutilized; moreover, the value in screening is uncertain. We performed a retrospective study of 395 HCT patients who were screened for psychosocial risk using the Transplant Evaluation Rating Scale (TERS). Patients were classified by psychosocial risk as no-risk (TERS = 26.5, 52%) vs. at-risk (TERS > 26.5, 48%), with at-risk patients stratified by cumulative deficits into mild risk (TERS = 27–35.5, 39%) and moderate risk (TERS > 35.5, 9%). At-risk patients were more likely to be readmitted within 90 days (mild risk HR = 1.62, p = 0.02; moderate risk HR = 2.50, p = 0.002). Prior psychiatric history (HR = 1.81, p = 0.002) and poor coping skills (HR = 1.64, p = 0.04) also influenced readmission. At-risk patients were more likely to be readmitted for infection (no-risk = 12% vs. at-risk = 25%, p = 0.002). Pre-HCT screening with the TERS did not predict survival or length of stay although at-risk patients are at a heighted risk of readmission. Implementing strategies to reduce readmission in higher risk patients is warranted.

This phase I trial sought to determine a biologically safe and effective dose of AR-42, a novel histone deacetylase inhibitor, which would lead to a doubling of miR-29b prior to decitabine administration. Thirteen patients with previously untreated or relapsed/refractory AML were treated at 3 dose levels (DL): AR-42 20 mg qd on d1,3,5 in DL1, 40 mg qd on d1,3,5 in DL2 and 40 mg qd on d1,3,4,5 in DL3. Patients received decitabine 20 mg/m2 on d6–15 of each induction cycle and 20 mg/m2 on d6–10 of each maintenance cycle. One DLT of polymicrobial sepsis and multi-organ failure occurred at DL3. Two patients achieved a CRi and one patient achieved a CR for an ORR of 23.1%. The higher risk features of this patient population and the dosing schedule of AR-42 may have led to the observed clinical response and failure to meet the biologic endpoint.

Survival of patients with acute myeloid leukemia (AML) is inversely associated with age, but the impact of race on outcomes of adolescent and young adult (AYA; range, 18-39 years) patients is unknown. We compared survival of 89 non-Hispanic Black and 566 non-Hispanic White AYA patients with AML treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols. Samples of 327 patients (50 Black and 277 White) were analyzed via targeted sequencing. Integrated genomic profiling was performed on select longitudinal samples. Black patients had worse outcomes, especially those aged 18 to 29 years, who had a higher early death rate (16% vs 3%; P=.002), lower complete remission rate (66% vs 83%; P=.01), and decreased overall survival (OS; 5-year rates: 22% vs 51%; P<.001) compared with White patients. Survival disparities persisted across cytogenetic groups: Black patients aged 18 to 29 years with non–core-binding factor (CBF)-AML had worse OS than White patients (5-year rates: 12% vs 44%; P<.001), including patients with cytogenetically normal AML (13% vs 50%; P<.003). Genetic features differed, including lower frequencies of normal karyotypes and NPM1 and biallelic CEBPA mutations, and higher frequencies of CBF rearrangements and ASXL1, BCOR, and KRAS mutations in Black patients. Integrated genomic analysis identified both known and novel somatic variants, and relative clonal stability at relapse. Reduced response rates to induction chemotherapy and leukemic clone persistence suggest a need for different treatment intensities and/or modalities in Black AYA patients with AML. Higher early death rates suggest a delay in diagnosis and treatment, calling for systematic changes to patient care.

Acutemyeloid leukemia (AML)witheither t(8;21)(q22;q22)or inv(16)(p13q22)/t(16;16)(p13;q22) is referred to as core binding factor (CBF) AML. Although categorized as favorable risk, long-term survival for these patients is only ∼50% to 60%. Mutated (mut) or overexpressed KIT, a gene encoding a receptor tyrosine kinase, has been found almost exclusively in CBF AML and may increase the risk of disease relapse. We tested the safety and clinical activity of dasatinib, a multi-kinase inhibitor, in combination with chemotherapy. Sixty-one adult patients with AML and CBF fusion transcripts (RUNX1/RUNX1T1 or CBFB/MYH11) were enrolled on Cancer and Leukemia Group B (CALGB) 10801. Patients received cytarabine/daunorubicin induction on days 1 to 7 and oral dasatinib 100 mg/d on days 8 to 21. Upon achieving complete remission, patients received consolidation with high-dose cytarabine followed by dasatinib 100 mg/d on days 6 to 26 for 4 courses, followed by dasatinib 100 mg/d for 12 months. Fifteen (25%) patients were older (aged ≥60 years); 67% were CBFB/MYH11-positive, and 19% harbored KITmut. There were no unexpected or dose-limiting toxicities. Fifty-five (90%) patients achieved complete remission. With a median follow-up of 45 months, only 16% have relapsed. The 3-year disease-free survival and overall survival rates were 75% and 77% (79% and 85% for younger patients [aged <60 years], and 60% and 51% for older patients). Patients with KITmut had comparable outcome to those with wild-type KIT (3-year rates: Disease-free survival, 67% vs 75%; overall survival, 73% vs 76%), thereby raising the question of whether dasatinib may overcome the negative impact of these genetic lesions.