McCullough, Kristen B

ABSTRACT Patients with newly‐diagnosed acute myeloid leukemia (ND‐AML) derive variable survival benefit from venetoclax (Ven) plus hypomethylating agent (HMA) therapy, and the optimal Ven duration across genetic risk groups remains undefined. Among 540 ND‐AML patients receiving Ven‐HMA at Mayo Clinic, outcomes were compared across Ven 7‐ ( n = 33), 14‐ ( n = 117), 21‐ ( n = 96), and 28‐day ( n = 294) schedules during Cycle 1 and stratified by ELN 2024 and Mayo genetic risk groups. At a median follow‐up of 37.7 months, allogeneic stem cell transplant (ASCT) rates were similar across Ven duration groups (15%, 18%, 18%, and 20% for 7‐, 14‐, 21‐, and 28‐day; p = 0.86). Median transplant‐censored survival was comparable across Ven durations (13.3, 11.9, 16.8, and 13.2 months for 7, 14, 21, 28 days, respectively; p = 0.65), with outcomes driven by ELN risk (6.3, 11.5, 18.3 months for high, intermediate, low; p < 0.01) and Mayo genetic risk (6.9, 17.8 months, not reached; p < 0.01). Survival was comparable across Ven durations within ELN intermediate/low‐risk and all Mayo risk groups. Among ELN high‐risk patients, 14‐day Ven was associated with inferior transplant‐censored survival compared to 21‐ and 28‐day schedules ( p < 0.01). Notably, 30‐ and 60‐day mortality were higher with shorter Ven schedules (7‐day: 9%/18%; 14‐day: 7%/15%) versus 28‐day (2%/6%), which likely reflects treatment selection bias. In ND‐AML, no significant difference in transplant‐censored survival was observed across the 7‐, 14‐, 21‐, and 28‐day Ven schedules; prognosis was determined primarily by Mayo and ELN 2024 genetic risk rather than by Ven duration. Prospective trials are needed to establish risk‐adapted Ven dosing strategies.

ABSTRACT Venetoclax (Ven) plus hypomethylating agents (HMA) is standard frontline therapy for newly diagnosed AML (ND‐AML) patients unfit for intensive chemotherapy and is also considered in younger, fit patients. However, consolidation with allogeneic stem cell transplant (ASCT) is often required to secure durable remission. The current study examines posttransplant outcomes in patients with ND‐AML treated with frontline Ven‐HMA who subsequently underwent ASCT. A total of 111 ND‐AML patients (58% male, 60% secondary/therapy‐related, median age 70 years [range, 37–80]) received a median of 3 cycles of Ven‐HMA. Mutations at the time of diagnosis included RUNX1 (18%), SRSF2 (17%), TP53 (16%), ASXL1 , IDH2 , K/NRAS , TET2 (14% each), STAG2 (11%), DNMT3A (8%). All patients were in CR/CRi at the time of transplant including 88% after Ven‐HMA. Measurable residual disease (MRD) by flow cytometry was detectable in 18/76 (24%) patients. Donors were mostly HLA‐matched unrelated (75%); 51% receiving fludarabine/melphalan conditioning and 67% posttransplant cyclophosphamide. At a median follow‐up of 15 months, 42 (38%) of patients have died and 18 (16%) experienced posttransplant relapse. Median posttransplant survival was not reached (NR), with 1‐, 2‐, 3‐year survival rates of 69%/60%/57%, respectively. On multivariate analysis, age ≥ 65 years, STAG2 mutation ( STAG2 MUT ) , and DNMT3A MUT were associated with superior posttransplant survival. Patients were stratified into low‐ (0–1 point), intermediate‐ (2 points), and high‐risk (3 points); age < 65 years, STAG2 wild type, and DNMT3A wild type, with 3‐year survival rates of 89%, 59%, and 19%, respectively ( p < 0.01). Taken together, age, STAG2 MUT and DNMT3A MUT stratified posttransplant survival in Ven‐HMA treated patients with ND‐AML.

Abstract The comparative value of liposomal cytarabine/daunorubicin (CPX-351) versus venetoclax plus a hypomethylating agent (Ven-HMA) in the frontline treatment of older adults with primary ( de novo ) or secondary acute myeloid leukemia (AML) remains uncertain. In the current study, we retrospectively examined outcomes of 600 patients with newly diagnosed AML treated with CPX-351 (N = 112) or Ven-HMA (N = 488). AML subtypes included de novo (46%), post-myelodysplastic syndrome (MDS) (19%), post-myeloproliferative neoplasm (MPN) (12%), post-MDS/MPN (6%), therapy-related (17%) and AML with myelodysplasia-related genetic abnormalities (AML-MR; 46%). Patients receiving CPX-351 were younger (median 65 vs. 73 years; p < 0.01), predominantly female (50% vs. 38%; p = 0.02), more likely to have secondary AML (68% vs. 51%; p < 0.01), and less likely to harbor NPM1 MUT (5% vs. 12%; p = 0.02). Rates of complete response with or without count recovery (CR/CRi) were comparable between CPX-351 and Ven-HMA (55% vs. 60%; p = 0.30), including in AML-MR (60% vs. 63%; p = 0.70). Ven-HMA use was associated with fewer infectious complications (62% vs. 83%; p < 0.01) and yielded higher CR/CRi rates in males (60% vs. 45%; p = 0.04), de novo AML (68% vs. 50%; p = 0.03), and in the presence of STAG2 MUT (86% vs. 44%; p = 0.02), or CEBPA MUT (88% vs. 50%; p = 0.03). Overall survival censored for transplant, was similar (median 10 vs. 13 months; p = 0.90), with Ven-HMA being superior in post-MDS AML (median 12 vs. 7 months; p = 0.02) and CPX-351 in the presence of SF3B1 MUT (not reached vs. 14 months; p < 0.01). Our findings suggest that Ven-HMA is as effective and less toxic than CPX-351 in newly diagnosed AML, including AML-MR, despite selection of younger, fitter patients for CPX-351.

ABSTRACT Patients with newly diagnosed acute myeloid leukemia (ND‐AML) derive variable survival benefit from venetoclax + hypomethylating agent (Ven‐HMA) therapy. The primary objective in the current study was to develop genetic risk models that are predictive of survival and are applicable at the time of diagnosis and after establishing treatment response. Among 400 ND‐AML patients treated with Ven‐HMA at the Mayo Clinic, 247 (62%) achieved complete remission with (CR) or without (CRi) count recovery. Multivariable analysis–derived hazard ratios (HR), including 1.8 for European LeukemiaNet (ELN) adverse karyotype, 4.7 for KMT2Ar , 1.7 for TP53 MUT , 2.6 for KRAS MUT , and 2.1 for IDH2 WT were applied to develop an HR‐weighted risk model: low, intermediate, and high; respective median survival censored for allogeneic stem cell transplant (ASCT) (3‐year survival) were “not reached” (67%), 19.1 (33%), and 7.1 months (0%). In patients achieving CR/CRi, adverse karyotype, KMT2Ar , KRAS MUT , IDH2 WT predicted inferior survival, allowing for a complementary response‐stratified risk model. The model was externally validated and was shown to be superior to the ELN 2024 risk model (AIC 179 vs. 195 and AUC 0.77 vs. 0.69). Survival was inferior with failure to achieve CR/CRi or not receiving ASCT; 3‐year survival for high‐risk with or without ASCT was 42% versus 0% ( p < 0.01); intermediate 72% versus 43% ( p = 0.06); and low‐risk 88% versus 78% ( p = 0.53). The Mayo genetic risk models offer pre‐treatment and response‐based prognostic tools for ND‐AML treated with Ven‐HMA. The current study underscores the prognostically indispensable role of achieving CR/CRi and ASCT.

Abstract This phase 2 trial assessed high-dose IV ascorbic acid in TET2 mutant clonal cytopenia. Eight of 10 patients were eligible for response assessment, with no responses at week 20 by International Working Group Myelodysplasia Syndromes/Neoplasms criteria. This trial was registered at www.clinicaltrials.gov as #NCT03418038.

Abstract Clonal cytopenia of undetermined significance (CCUS) is defined by a myeloid driver mutation in the context of otherwise unexplained cytopenia. CCUS has an inherent risk of progressing to myeloid neoplasm. However, it is unknown how exposure to previous cytotoxic therapy may impact the risk of progression and survival. We stratified patients with CCUS by prior exposure to DNA-damaging therapy. Of 151 patients, 46 (30%) had received cytotoxic therapy and were classified as therapy-related CCUS (t-CCUS), whereas 105 (70%) had de novo CCUS. A lower proportion of t-CCUS had hypercellular marrows (17.8% vs 44.8%, P = .002) but had higher median bone marrow blast percentages. After a median follow-up of 2.2 years, t-CCUS had significantly shorter progression-free survival (PFS, 1.8 vs 6.3 years; hazard ratio [HR], 2.1; P = .007) and median overall survival (OS; 3.6 years vs not reached; HR, 2.3; P = .007) compared with CCUS. Univariable and multivariable time-to-event analyses showed that exposure to cytotoxic therapy independently accounted for inferior PFS and OS. Despite the similarities in clinical presentation between CCUS and t-CCUS, we show that exposure to prior cytotoxic therapies was an independent risk factor for inferior outcomes. This suggests that t-CCUS represents a unique clinical entity that needs more stringent monitoring or earlier intervention strategies.

Abstract Venetoclax + hypomethylating agent (Ven‐HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND‐AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND‐AML was to identify molecular predictors of treatment response to Ven‐HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, “favorable” predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and “unfavorable” TP53 (40% vs. 67%), FLT3‐ ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy‐related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow‐up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5–4.8), adverse karyotype (1.6, 1.1–2.6), TP53 mutation (1.6, 1.0–2.4), and absence of IDH2 mutation (2.2, 1.0–4.7); these risk factors were subsequently applied to construct an HR‐weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low ( n = 130; median survival 28.9 months), intermediate ( n = 105; median 9.6 months), and high ( n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3‐tiered, CR/CRi‐based, and genetics‐enhanced survival model for AML patients receiving upfront therapy with Ven‐HMA.

Processing grief from the outside. How a pharmacist experiences patient loss.