Matin, Aasiya

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.

ABO incompatibility is frequent in haematopoietic stem cell transplantation (HSCT), yet the clinical impact of non-ABO red blood cell (RBC) alloimmunisation remains less defined. We describe the clinical course of a man in his 50s with chronic eosinophilic leukaemia who underwent a mismatched unrelated donor (MMUD) HSCT. Despite a major ABO mismatch and high-titre pre-existing anti-E antibodies against an E-antigen positive donor, the patient achieved successful trilineage engraftment without haemolysis. Six months after the transplant, he developed severe pancytopenia and a positive direct antiglobulin test (DAT) with anti-E elution. These serologic findings coincided with disease relapse rather than isolated immune-mediated haemolysis. This case illustrates that successful engraftment is possible across RhE-incompatibility and underscores the need to interpret late serologic abnormalities within the broader context of graft function and disease status.

ABSTRACT The recently published BLAST clinical risk model for chronic myelomonocytic leukemia (CMML) and its molecular version (BLAST‐Mol) differentiate low, intermediate, and high‐risk groups. The objective of the current retrospective study was to examine the survival impact of allogeneic stem cell transplant (ASCT) in a consecutive series of Mayo Clinic patients ( n = 775; 68% males, median age 71 years) with CMML, overall and adjusted for baseline BLAST/BLAST‐Mol risk categories. At a median follow‐up of 77 months, 151 (20%) patients underwent ASCT. Overall survival (OS) was longer in the ASCT compared to the non‐ASCT cohorts (median 77 vs. 28 months; p < 0.01). The significant difference in OS between the ASCT and non‐ASCT cohorts was retained after adjusting for BLAST clinical risk groups: high‐risk (median 50 vs. 14 months; p < 0.01), intermediate‐risk (81 vs. 28 months; p < 0.01), and low‐risk (111 vs. 65 months; p = 0.04), respectively. The same was mostly the case when OS comparison was adjusted for BLAST‐Mol with respective p values of < 0.01, < 0.01, and 0.08, respectively. Time‐dependent cox models confirmed the favorable survival impact of ASCT in the BLAST/BLAST‐Mol high‐ and intermediate‐risk groups. The current study highlights the benefit of ASCT for BLAST/BLAST‐Mol high‐ and intermediate‐risk groups in CMML and its potential to overcome the adverse impact of some high risk cytogenetic or molecular abnormalities. These observations support the early use of ASCT in CMML, ideally before BT and regardless of genetic characteristics.

ABSTRACT Hypomethylating agents (HMA) and allogeneic hematopoietic stem cell transplantation (alloHSCT) have both demonstrated remissions in VEXAS; however, comparative data is lacking. We conducted a multicenter, retrospective analysis of 66 patients diagnosed with VEXAS syndrome treated with HMA ( n = 35) or alloHSCT ( n = 31). Baseline characteristics such as genetics, co‐morbidities, and performance status were balanced between the groups, except older age in the HMA group. Median follow‐up from therapy initiation was 18 months (95% CI: 11–26), and 14 (21%) deaths were reported (alloHSCT n = 3; HMA n = 11). Among all evaluable patients within the alloHSCT cohort, all patients achieved molecular remission, and a substantial proportion of patients discontinued glucocorticoids (58%). In contrast, HMA therapy was associated with lower but meaningful rates of molecular remission (22%) and glucocorticoid discontinuation (6%). In a real‐world setting, HMA therapy was associated with a high discontinuation rate related to toxicity or lack of response. On multivariable analysis adjusted for age and Charlson Comorbidity Index, alloHSCT was associated with improved overall survival (HR = 0.20, 95% CI: 0.05–0.81; p = 0.024). This association remained consistent across multiple ancillary sensitivity analyses, including restriction to transplant‐eligible patients, patients aged ≤ 75 years, 1:1 matching, and propensity score‐based weighted analyses. Although limited by retrospective design, these findings suggest that alloHSCT remains an attractive and potentially curative strategy in selected patients with VEXAS. Prospective validation of these findings is warranted.

6530 Background: Venetoclax (Ven) plus hypomethylating agents (HMA) is standard frontline therapy for newly diagnosed AML (ND-AML) patients unfit for intensive chemotherapy and is also being considered in younger and fit patients (Fathi, Blood 2025). However, consolidation with allogeneic stem cell transplant (ASCT) is often required to secure durable remission. The current study examines predictors of post-transplant survival (PTS) in the particular scenario. Methods: ND-AML patients who received upfront Ven+HMA and underwent ASCT were retrospectively studied. PTS, relapse rate, and non-relapse mortality (NRM) were evaluated. Results: 111 ND-AML patients (58% male, 60% secondary/therapy-related, median age 70 [37-80 years]) received median 3 cycles of Ven-HMA. 22% had complex karyotype. Mutations at diagnosis included RUNX1 (18%), SRSF2 (17%), TP53 (16%), ASXL1 , IDH2 , K/NRAS and TET2 (14% each), STAG2 (11%), DNMT3A (8%) and at time of ASCT (N=78 evaluable); RUNX1 (8%), NPM1 (6%), TP53 and ASXL1 (5% each), and SRSF2 and TET2 (4% each). At ASCT, all patients were in CR/CRi; 88% after Ven-HMA and 12% after additional bridging therapy. MRD by flow cytometry was detected in 18 (24%) of 76 evaluable patients and complex karyotype in 8 (9%) of 94. Donors were mostly HLA-matched unrelated (75%), with 51% receiving fludarabine/melphalan conditioning and 67% post-transplant cyclophosphamide (PTCy). At a median follow-up of 30 months, 42 patients (38%) have died including 18 (40%) from relapse. Median PTS was not reached (NR) with 1-2-3-year survival of 69%/60%57%. On multivariate analysis, age ≥65 years (median NR vs 10 months p<0.01), STAG2 (NR vs 44 months; p=0.04), and DNMT3A mutations (NR vs.NR p=0.05) were associated with superior PTS. In analysis limited to variables at time of ASCT, age ≥65 years remained significant (p<0.01) while TP53 mutations, donor type, and MRD status were not (p>0.1). Patients <65 years more often received bridging therapy compared to ≥65 years (23% vs 7%; p<0.05); excluding salvage-treated patients did not change survival results. 18 patients (16%) experienced post-ASCT relapse with median RFS of 7 months. Relapse rates at 1/2/3 years were 22%, 30% and 31% and NRM 13%, 24%, 46%, respectively. Patients <65 years had a higher 1 yr relapse incidence than those ≥65 years (36% vs 18%; p=0.01), with similar NRM (p=0.58). PTCy was not associated with relapse (p=0.66) but showed a borderline association with higher NRM (1-/2-/3-year 17%/31%/58% vs 4%/7%/16% in non-PTCy recipients; p=0.06). GVHD rate was 44% (50% ≥grade 2) with no association with relapse (p=0.43) or NRM (p=0.99). Conclusions: In the current study, older age (>65 years), including >75 years, was independently associated with superior PTS in ND-AML patients receiving Ven-HMA. By contrast, PTS was not affected by genetic profile at the time of ASCT, donor type, conditioning regimen, or GVHD prophylaxis.

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 Background IDH mutations are found in 15%–20% of acute myeloid leukemia (AML). Recent evidence suggests that IDH mutation subtypes may respond differently to intensive chemotherapy. We evaluated blast clearance patterns, remission outcomes, and overall survival (OS) in AML patients with IDH2 R140, IDH2 R172, and IDH1 R132 mutations to assess differences in treatment response. Methods We retrospectively reviewed AML patients diagnosed at Mayo Clinic, Rochester (2016–2023) with NGS data and treated with intensive chemotherapy (7+3 or CPX‐351). Bone marrow blasts were assessed at diagnosis, mid‐induction, and end‐of‐cycle; blast clearance was defined as < 5%. Composite remission (CRc) included CR/CRi per ELN 2022. IDH2 responders were classified as early (after Cycle 1) or late (≥ 2 cycles). Blast reduction was calculated as log 10 (diagnosis blasts/end‐induction blasts) and normalized per day. OS was measured from diagnosis. Results Among 381 patients, 31 had IDH2 mutations (23 R140, 8 R172) and eight had IDH1 R132. Baseline blasts were similar. Mid‐cycle blasts were lower in R140 versus R172 (4% vs. 10%), with higher clearance (68% vs. 38%). End‐induction blasts were lower in R140 versus R172 (2% vs. 4%) with higher clearance (100% vs. 75%). IDH1 and IDH2 showed similar clearance patterns. Log 10 analyses showed deeper and faster blast reduction in R140 versus R172, with comparable kinetics between IDH1 and IDH2 . OS did not differ across subtypes. Early CRc in IDH2 ‐mutated patients was associated with numerically longer OS. Conclusion IDH2 R140 demonstrated faster blast clearance than R172, while remission and survival were similar across IDH subtypes. Trial Registration : The authors have confirmed clinical trial registration is not needed for this submission.

Abstract Venetoclax (Ven) in combination with hypomethylating agents (HMA) is widely used as frontline treatment in older or unfit patients with acute myeloid leukemia (AML). Liposomal cytarabine and daunorubicin (CPX-351) is FDA-approved for the treatment of secondary AML, including therapy-related (t-AML) and AML with myelodysplasia-related changes (AML-MR). The current study aimed to provide a comprehensive comparison between the two treatment strategies to better inform clinical decisions. Methods The current retrospective analysis was performed under an institutional review board approved minimal risk protocol at Mayo Clinic (MN, AZ, FL). AML-MR gene mutations or cytogenetic abnormalities were categorized according to the International Consensus Classification (Arber et al. Blood 2022;140:1200). Treatment response was assessed according to the 2022 European LeukemiaNet (ELN) criteria (Dohner et al. Blood 2022;140:1345). Overall survival (OS) analysis was censored for allogeneic stem cell transplant (ASCT). Statistical analyses were performed using JMP Pro (Version 18.0.0). Results A total of 600 patients with newly diagnosed AML (ND-AML) treated with CPX-351 (N-112, 19%), or Ven-HMA (N=488, 81%) were included. AML subtypes included de novo (N=277, 46%), post-myelodysplastic syndrome (post-MDS, N=114,19%), post-myeloproliferative neoplasm (post-MPN, N=70, 12%), post-MDS/MPN (N=36, 6%), t-AML (N=103, 17%) and AML-MR (N=274, 46%). Compared with those treated with Ven-HMA, patients receiving CPX-351 were younger (median age 65 vs 73 years; p&lt;0.01), more likely to be female (50% vs 38%; p=0.02), more frequently diagnosed withsecondaryAML (68% vs 51%; p&lt;0.01), and less likely to have NPM1MUT (5% vs 12%; p=0.02) whereas ELN 2022 cytogenetic risk distribution was similar between the two (adverse risk; 43% vs 40%; p=0.5). Comparison of treatment response and survival Complete response rates with (CR) or without (CRi) count recovery were similar between CPX-351 and Ven-HMA overall (55% vs 60%) as well as specifically in patients with AML-MR (60% vs 63%), adverse karyotype (44% vs 44%), NPM1MUT (100% vs 89%), TP53MUT(32% vs 45%), IDH1MUT (60% vs 76%), IDH2MUT (63% vs 77%), SF3B1MUT(71% vs 45%), and CBLMUT (33% vs 69%) [p&gt;0.05 in all instances]. Compared to those with CPX-351, CR/CRi rates with Ven-HMA were superior in males (60% vs. 45%; p=0.04) and in patients with de novo AML (68% vs. 50%; p=0.03), STAG2MUT (86% vs. 44%; p=0.02), or CEBPAMUT (88% vs. 50%; p=0.03); infectious complications were significantly more frequent with CPX-351 (83% vs 62%, p&lt;0.01). At a median follow-up of 12 months (range; 1-88), 416 (69%) deaths, 179 relapses (44% in CPX-351 and 52% in Ven-HMA responders) and 149 ASCTs (53% in CPX-351 and 18% in Ven-HMA) were documented. OS rates were similar between CPX-351 and Ven-HMA, in general (median 10 vs 13 months), as well as in patients with adverse karyotype, TP53MUT, IDH1MUT, and IDH2MUT (p&gt;0.05 in all instances). By contrast, OS was superior in Ven-HMA-treated patients with post-MDS AML (median 12 vs. 7 months; age-adjusted p=0.02) and in CPX-351-treated patients harboring SF3B1MUT(median not reached vs 14 months; age-adjusted p&lt;0.01). In addition, a borderline-significant OS advantage for CPX-351 was apparent in patients with PTPN11MUT (13.5 vs 8 months; p=0.08). Comparison in ICC defined AML-myelodysplasia-related CR/CRi and OS rates were comparable between patients treated with CPX-351 (N=57) or Ven-HMA (N=217), with response rates of 60% vs 63% (p=0.68) and median OS of 10 vs 14 months (p=0.61), respectively. However, OS was superior with Ven-HMA in patients with post-MDS AML (15 vs 8 months; age-adjusted p=0.02) and with CPX-351 in those with SF3B1MUT (NR vs 14 months; age-adjusted p=0.02). Conclusions: The current study suggests that Ven-HMA was as effective and possibly less toxic than CPX-351 for the treatment of ND-AML, including AML-MR, despite the bias for younger and fitter patients treated with the latter regimen. Observed differences involving patients with SF3B1MUT or post-MDS AML require validation in prospective studies and provide parameters for developing treatment-specific predictive models that will be presented at the meeting.