ABSTRACT:TP53 and PPM1D are key regulators of DNA damage response and repair, and somatic mutations in these genes often co-occur in hematopoietic cells, expanding under genotoxic stress. Unlike TP53 mutations, where mechanisms of progression are defined, pathways underlying clonal fitness and transformation in PPM1D mutant cells remain unclear. In collaboration with 5 academic institutions, we analyzed the clinical and molecular landscape of 337 patients with clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance (CCUS) across 4 genotypes: PPM1Dmt/TP53wt (n = 170 [50%]), PPM1Dmt/TP53mt (n = 25 [7%]), TP53mt/PPM1Dwt (n = 17 [5%]), and TP53wt/PPM1Dwt (n = 125 [38%]). All PPM1D variants were truncating, located in exon 6 of the gene, with a median variant allele frequency (VAF) of 6% (range, 0.3%-64%). The PPM1Dmt/TP53mt genotype was most frequently encountered in therapy-related CH/CCUS (t-CH/t-CCUS; 80%, 66.5%, 76.5%, and 19%; P ≤ .001) and had a shorter time interval to detection from last genotoxic exposure (6.2, 5.9, 11.25, and 24.5 months; P ≤ .001) compared with PPM1Dmt/TP53wt, TP53mt/PPM1Dwt, and TP53wt/PPM1Dwt genotypes, respectively. Acknowledging the short follow-up duration, rates of malignant transformation were lower in the PPM1Dmt/TP53wt (2%) and PPM1Dmt/TP53mt (4%) groups compared with PPM1Dwt/TP53wt (12%) and PPM1Dwt/TP53mt (17%) groups (P ≤ .001), respectively. In summary, PPM1D mutations are frequently observed in t-CH/t-CCUS, with low median VAFs, and are associated with low rates of progression, even when comutated with TP53.

Clofarabine is a second-generation purine nucleoside analog with encouraging reported 30-day induction mortality (IM) and complete remission (CR) or CRi (incomplete platelet recovery) rates, and represents a lower-intensity therapy for older adults with acute myeloid leukemia (AML). We evaluated long-term outcomes in a prospective phase 3 study using a noninferiority design. Patients aged ≥60 years with newly diagnosed AML and normal renal and cardiac function were randomized to standard intensive daunorubicin and cytarabine or single-agent clofarabine. The primary objective was overall survival (OS) using a weighted analysis. We incorporated prospective central testing for measurable residual disease (MRD; ≥0.1%) at remission using multiparameter flow cytometry. Among 727 patients (standard, n = 363; clofarabine, n = 364), there was no difference in CR/CRi (50%) or IM (8.5%) rates. The median follow-up was 58.6 months. In the primary analysis, OS was inferior with clofarabine (median, 10.4 vs 12.4 months [standard]; P = .04), although not in patients aged ≥70 years, with secondary AML, or unfavorable cytogenetics. Allogeneic transplantation was strongly associated with OS on multivariate analysis (HR, 0.53; P < .0001). MRD-negative remission was achieved in 41% of patients and strongly associated with 5-year OS irrespective of treatment (MRD-positive, 48.8% vs 12.2%; P = .003). In contrast, MRD-positive patients assigned to clofarabine (vs high-dose cytarabine) consolidation had significantly inferior OS. Clofarabine is inferior to standard intensive therapy despite similar remission rates. Achieving MRD-negative remission is associated with high, sustained rates of OS regardless of therapy. Increasing MRD negativity and improving outcomes among MRD-positive patients remain pressing, ongoing challenges. This trial was registered at www.clinicaltrials.gov as NCT02085408.

We examined the prognostic value of routine NGS data in newly diagnosed acute myeloid leukemia (AML) treated with intensive (7 + 3 backbone) induction, specified by AML subtype. A contemporary (2015-2025) series of 545 Mayo Clinic patients (median age 56 years, females 44%) was considered. Median follow-up was 49 months with 341 (63%) allogeneic hematopoietic stem cell transplantations (AHSCT) recorded. AML subtypes included core-binding factor (CBF; N = 72; 13%), primary non-CBF (N = 403; 74%), post-myelodysplastic syndromes (MDS) or post-myelodysplastic/myeloproliferative neoplasms (post-MDS-MDS/MPN; N = 28; 5%), post-MPN (N = 15; 3%), and therapy-related (t-AML; N = 27; 5%). Corresponding complete remission rates, with/without count recovery (CR/CRi), were 89%, 76%, 64%, 27%, and 78% (p < 0.01) and 5-year transplant-censored survival rates 68%, 57%, 21%, 0%, and 55% (p < 0.01). In multivariable analyses, the prognostic value of specific mutations was mostly limited to primary non-CBF AML where adverse karyotype (OR 1.9; p = 0.04) predicted inferior and FLT3-ITD (OR 0.4; p < 0.01) or NPM1 MUT/FLT3 WT (OR 0.1; p < 0.01) superior CR/CRi while KRAS MUT (HR 8.8; p < 0.01), TP53 MUT (HR 5.4; p < 0.01), and TET2 MUT (HR 2.3; p = 0.01) predicted inferior and NPM1 MUT/FLT3 WT (HR 0.3; p = 0.01) superior survival. Prognostication in intensively-treated AML should start with subtype specification and recognition of the limited value of NGS in non-primary AML. Post-MPN AML is particularly associated with dismal outcomes and should be prognostically distinguished from post-MDS-MDS/MPN AML. In primary non-CBF AML, in addition to previously established risk factors, the favorable impact of FLT3-ITD on achieving CR/CRi and the unfavorable impact of KRAS MUT and TET2 MUT on transplant-censored survival were noted and require confirmation from additional studies.

Cytokine receptor-like factor 2 rearrangement (CRLF2r), an aberration causing a Philadelphia chromosome-like (Ph-like) gene expression profile and a poor prognostic marker in B-cell acute lymphoblastic leukemia (B-ALL), endows relative chemotherapeutic-resistance. Extramedullary disease (EMD), including both central nervous system (CNS) and non-CNS involvement, can also be associated with worse outcomes. The relationship between CRLF2r and EMD is unknown. Based on an initial observation of patients with relapsed/refractory (r/r) CRLF2r B-ALL and EMD, a single-center retrospective review was conducted to evaluate the incidence of EMD in CRLF2-r B-ALL patients. Across 177 children, adolescents, and young adults with r/r B-ALL, 21 (11.9%) harbored CRLF2r of whom 19 (90.5%) had EMD at some point during their treatment course. In contrast, only 78 of 156 (50%) patients without CRLF2r ever had EMD (p=0.0003). In the CRLF2r cohort, 8 (38.1%) presented with EMD at diagnosis: 7 with CNS and 1 with non-CNS EMD. At relapse, 17 (80.9%) had EMD: 4 (19%) had CNS-EMD, 9 (42.9%) had non-CNS-EMD and 4 (19%) had both. Isolated EMD was observed in 2 (11.8%) patients at first relapse and in 3 (17.6%) patients with multiple relapses. Given these findings, further study to evaluate this potential association between EMD and CRLF2r in r/r B-ALL is indicated.

ABSTRACT:Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the proliferation of immature lymphoid cells. Despite advances in chemotherapy, a significant proportion of patients continue to have poor outcomes. Immunotherapy has emerged as a transformative approach in the treatment of ALL, offering new hope for these patients. This advances viewpoint article provides a comprehensive overview of the role of immunotherapy in ALL, focusing on the mechanisms of action, the timing of its use, the patient populations most likely to benefit, and drug resistance. We discussed the major immunotherapeutic modalities, including monoclonal antibodies, bispecific T-cell engagers, and chimeric antigen receptor T-cell therapy. We review key clinical trials that have shaped the current landscape of immunotherapy in B-cell precursor (BCP)-ALL, along with future directions in this rapidly evolving field and discussed our perspective on how best to exploit the use of immunotherapy for patients with newly diagnosed adult BCP-ALL.

BMT CTN 1506 ("MORPHO") was a phase 3 study of post-hematopoietic cell transplantation (HCT) maintenance with gilteritinib versus placebo for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) in first remission. Subgroup analysis indicated a significant benefit of post-HCT gilteritinib for participants in North America, but no benefit for those in Europe or Asia. We conducted a post-hoc analysis of the data focusing on days from AML diagnosis to HCT, pre-HCT FLT3 inhibitor use, and FLT3-ITD measurable residual disease (MRD). Participants transplanted < 120 days from AML diagnosis and/or those treated with FLT3 inhibition pre-HCT were more likely to have improved survival from post-HCT gilteritinib. Pre-HCT MRD levels were higher (P = 0.001) in participants transplanted within 120 days from diagnosis and in those treated with a FLT3 inhibitor pre-HCT and transplanted within 120 days (P = 0.008). Pre-HCT MRD was dependent on both FLT3 inhibitor use and time to HCT, as participants treated with successive courses of chemotherapy + FLT3 inhibition had successively lower MRD by the time of HCT. Time from AML diagnosis to HCT and pre-HCT FLT3 inhibitor use both appeared to impact MRD levels immediately prior to HCT, and geographic differences in these two practice patterns likely accounted for the observed regional differences in benefit from post-HCT gilteritinib. Increasing the number of courses of treatment pre-HCT may lower MRD sufficiently to eliminate the need for post-HCT inhibition, but with a presumed risk of some patients experiencing early progression. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

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.

Long-read whole-transcriptome sequencing (WTS) has the potential to precisely characterize fusion oncogenes that drive leukemia and other cancers. Although there is a variety of general-purpose fusion detection algorithms that use modern long-read sequencing data, they show poor sensitivity for precision diagnostics in B-cell acute lymphoblastic leukemia (B-ALL) and do not robustly assess technical and analytical parameters (eg, sequencing depth) to reliably detect fusion transcripts. FUSILLI (FUSions In Leukemia Long-read sequencing Investigator) is a novel long-read fusion detection algorithm, with a focus on targeted genomic subtyping in B-ALL. FUSILLI was evaluated against extant methods using nanopore WTS from 51 pediatric B-ALL samples sequenced at high depth and 68 at low depth (mean of 11.2 and 1.4 million reads, respectively). In the high-depth cohort, FUSILLI demonstrated increased sensitivity (0.81) compared with FusionSeeker, JAFFAL, and LongGF (0.63, 0.76, and 0.70, respectively), while maintaining high specificity (0.92). At lower sequencing depth, FUSILLI showed correspondingly lower sensitivity (0.27) but still outperformed the other fusion callers (sensitivities ranging from 0.09 to 0.16). Computational down sampling suggests that 10 million reads is sufficient to sensitively detect B-ALL-relevant fusions using this approach. FUSILLI detects B-ALL fusions with high sensitivity at modest sequencing depth, supporting implementation of nanopore WTS as a low-cost and globally accessible sequencing-based molecular diagnostic platform for pediatric B-ALL and other fusion-driven cancers.

CD25 is a subunit of the interleukin-2 (IL-2) receptor on T cells and natural killer (NK) cells. Acute leukemias with oncogenic tyrosine kinases often include CD25+ leukemia subpopulations, which portend poor clinical outcomes for patients; however, acute leukemia cells do not respond to IL-2. Here, we identified CD25 and its phosphorylation by protein kinase Cδ (PKCδ) as central elements of a feedback loop that stabilized fluctuations in oncogenic tyrosine kinase signaling in acute lymphoblastic and myeloid leukemia. Genetic ablation of CD25 in murine and patient-derived xenograft (PDX) models of acute leukemias reduced clonal fitness, colony formation, and leukemia-initiation capacity in serial transplant recipients. Oncogenic tyrosine kinase signaling in leukemia cells stimulated NF-κB-mediated CD25 expression, whereas PKCδ-mediated phosphorylation of CD25 suppressed oncogenic tyrosine kinase signaling through inhibitory phosphatases, such as PTPN6. Interactome analyses and mass spectrometry-based global phosphoproteomic analyses showed that CD25 deletion abolished the phosphatase activity of PTPN6, resulting in enhanced activation of tyrosine kinases and NF-κB. Four injections of a CD25 antibody-drug conjugate induced complete remission in mice transplanted with PDX refractory leukemia. These findings highlight the dependency of tyrosine kinase-driven leukemias on robust feedback control and the role of PKCδ and CD25 in assembling its components.

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 (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%), and t-AML (N = 103, 17%). 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 NPM1MUT (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 AML with myelodysplasia-related gene mutations or cytogenetic abnormalities (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 STAG2MUT (86% vs. 44%; p = 0.02), or CEBPAMUT (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 SF3B1MUT (median 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.

INTRODUCTION:The efficacy of donor lymphocyte infusions (DLIs) among various myeloid malignancies (particularly genetic subtypes) and the optimal timing of DLI initiation remains unclear. METHODS:This was a retrospective study of 62 patients with myeloid malignancies treated with alloHSCT and DLI from years 2001 to 2022. DLI indications were therapeutic 55 (89%), preemptive 6 (10%), and prophylactic in 1 (2%) patients with complete remission (CR/CRi) in 20 patients; diagnoses included 9 (45%) acute myeloid leukemia, 6 (30%) myelodysplastic syndromes, and 3 (15%) chronic myelomonocytic leukemia among others. RESULTS:Among patients who received therapeutic DLI (n = 55), the best response was CR/CRi in 16 (29%) patients. At a median follow-up from the date of DLI of 75 (95% CI 35-121) months, there were 49 (79%) deaths with a median OS of 6 (95% CI 4-14) months, higher in patients in CR/CRi versus no CR/CRi (median 51 versus 4 months, p = 0.008). Presence of cytogenetic abnormalities such as complex karyotype, deletions in chromosome 5, 7, and 17p, and mutations in TP53, KRAS, NRAS, RUNX1, or JAK2 were associated with adverse outcomes. CONCLUSION:DLI is an effective treatment strategy for post-transplant relapse across myeloid malignancies, with specific genetic subtypes showing poorer outcomes and survival.

ABSTRACT:The incidence of venous thromboembolism (VTE) in patients with acute lymphoblastic leukemia (ALL) receiving asparaginase-based induction is high despite primary thromboprophylaxis. Our aim was to derive and externally validate a VTE risk prediction model in patients with ALL receiving asparaginase-based induction. We conducted a multicenter retrospective cohort study of patients (aged ≥18 years) with newly diagnosed ALL receiving asparaginase-based induction. The derivation and external validation cohorts included 306 and 94 patients, respectively. Primary outcome was VTE at any site. A cause-specific Cox proportional hazards model stratified by thromboprophylaxis and center was performed to identify VTE risk factors in the derivation cohort. A risk prediction model for VTE at 30 days was derived using variables with P value < .05 in the multivariable model and was tested in the validation cohort. VTE risk factors on multivariable analysis in the derivation cohort included D-dimer ≥1 μg fibrinogen equivalent unit per mL (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.07-6.5) and hemoglobin (HR for each 1 g/dL increment, 1.19; 95% CI, 1.06-1.34) at ALL diagnosis. A VTE risk score based on these variables distinguished between a 4% (95% CI, 0.72-12) and 20% (95% CI, 14-27) 30-day cumulative incidence of VTE in the derivation cohort, with similar findings in the validation cohort (area under the curve, 0.56). The negative predictive value for VTE at 30 days was 96% and 93% in the derivation and validation cohorts, respectively, and the positive predictive value was 20% in both. We derived and validated a model using D-dimer and hemoglobin, which stratifies VTE risk in patients with ALL receiving asparaginase-based induction.

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 (STAG2MUT), and DNMT3AMUT 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, STAG2MUT and DNMT3AMUT stratified posttransplant survival in Ven-HMA treated patients with ND-AML.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal complication of acute myeloid leukemia (AML), and contemporary data on its clinical and genomic correlates remain sparse. We retrospectively identified 19 adults with AML who developed HLH across 3 Mayo Clinic sites (2020-2024) and compared them with 73 patients with AML without HLH. HLH occurred at a median of 34 days from AML diagnosis (range, 0-472) and was associated with fever, multiorgan dysfunction, and rapidly rising biomarkers. Morphologic hemophagocytosis was observed in only 18% of cases, underscoring its poor sensitivity. HLH was associated with markedly inferior overall survival (median, 5.7 vs 14.8 months, P = .005), including within adverse risk and TP53-mutated AML subsets. When modeled as a time-dependent covariate, HLH remained strongly associated with inferior survival (hazard ratio [HR], 3.9; P < .001). Genomic profiling demonstrated enrichment of TP53 (58%), NF1 (16%), and RAD21 (11%) mutations, with tumor suppressor and/or DNA damage repair pathway alterations in 68% vs 34% of controls (P = .009). On multivariable analysis, HLH (HR, 3.1; P = .003) and adverse-risk cytogenetics (HR, 2.2; P = .040) independently predicted worse survival. Age of ≥65 years was associated with accelerated HLH onset (14 vs 84 days, P = .032) and higher mortality (HR, 13.4; P = .005). All patients received high-dose corticosteroids; some received tocilizumab or ruxolitinib, and none received etoposide. Despite diverse leukemia-directed therapies, only 3 patients achieved long-term survival. Collectively, these findings indicate that AML-associated HLH arises predominantly in older patients with genomically unstable leukemias, portends poor prognosis, and warrants biomarker-guided surveillance and improved targeted immunomodulatory strategies with antileukemic therapy.

Introduction Post-transplant cyclophosphamide (PTCy) is widely being used for graft-versus-host disease prophylaxis (GvHD) following allogeneic hematopoietic stem cell transplantation (alloHCT). There is growing data pertaining to the risk of early cardiac events in patients and the use of reduced-dose PTCy (rPTCy) as a mitigating strategy. Objective Evaluate whether rPTCy reduces the incidence of early cardiac events after alloHCT and assess its long-term effects on non-relapse mortality (NRM) and survival. Methods All consecutive adult patients undergoing alloHCT from 2018-2024 and who received PTCy with mycophenolate mofetil (MMF) plus either tacrolimus or sirolimus as GVHD prophylaxis were included. rPTCy was defined as cyclophosphamide dosing <100 mg/kg given in two divided doses on days +3 and +4. Results A total of 248 patients were included (median age 61 years [range 18-76]) who mostly received a T-cell replete PBSC graft (89%, n=221), from matched-unrelated (52.8%, n=131) or haploidentical (30.7%, n=76) donor, after reduced-intesity conditioning (RIC; 65.3%, n=162).PTCy dose was reduced in 44 patients (17.7%; median 80mg/kg [range 50-80]); 9/44 (20.5%) received <80mg/kg.Relative to standard PTCy, the rPTCy group was older (median 63 v. 60 years, P=0.06), had more comorbidity: higher HCT-CI (median 4 v. 2, P=0.005), more hypertension (54.5% v. 37.9 %, P=0.04) and heart failure (25.6% v. 10.3%, P=0.007), and arrhythmia (15.9% v. 8.9%, P=0.056), with lower baseline iothalmate-measured GFR (median 67 ml/min v. 89 ml/min, P<0.001), and less haploidentical donor (11.4% v. 34.8%, P=0.002). Rates of RIC use (P=0.176) and high/very high DRI (P=0.56) did not differ.The 100-day cardiac events were comparable among rPTCy and standard dosing group (25% v. 25.5%, P= 0.946). In addition, rates of neutrophil engraftment (P=0.129), grade II-IV acute GvHD (P=0.762), or chronic GvHD requiring steroids (P=0.554) were similar, while there was a trend towards faster platelet engraftment (median 16 v. 18 days, P=0.056) in the rPTCy group.After a median follow up of 16 months (95% CI 15 – 18), rPTCy showed a trend toward higher NRM (1yr NRM 17.5% v. 8.2%, P=0.08), with no differences in cumulative incidence of relapse (1yr CIR 16.8% v. 26.2%, P=0.3), GvHD-free, relapse-free survival (median GRFS not reached v. 44 months; P=0.78), chronic GvHD-free, relapse-free survival (median CRFS 13 v. 44 months; P=0.58), or overall survival (median OS 22 months v. not reached, P=0.38). Conclusions Despite greater baseline cardiac/renal comorbidity and higher HCT-CI, patients receiving rPTCy had similar 100-day cardiac event rates. While rPTCy group had a non-significant trend toward higher 1-yr NRM, which may reflect the burden of comorbidity, there was no apparent compromise on the incidence of GVHD or survival.

With the advent of tyrosine kinase inhibitors (TKIs), the outcomes of patients with Philadelphia positive acute lymphoblastic leukemia (Ph + ALL) improved. We conducted a retrospective multicenter study of 467 adult patients with Ph + ALL (2003-2023) evaluating predictors of complete molecular response (CMR) at 3 months and its impact on outcomes. CMR was achieved in 297(63.7%) patients. In the multivariate analysis, WBC > 70,000/L at diagnosis (p = 0.01), p210 BCR::ABL1 fusion (p < 0.001) and monosomy 7 (p = 0.007) were independently associated with failure to achieve CMR, while use of ponatinib or dasatinib (p = 0.008) and intensive chemotherapy (IC) (p = 0.009) predicted higher CMR. Among patients who achieved CMR, the median relapse-free survival (RFS) was significantly better (123.1 vs. 30.3 months, p < 0.0001), however, overall survival (OS) was not significantly different (129.2. vs. 149.3 months, p = 0.07) with or without allogeneic hematopoietic cell transplantation (allo-HCT). These findings suggest that allo-HCT may be deferred in selected patients achieving early CMR, although prospective validation is needed.

Although azacitidine (AZA) and decitabine (DEC) demonstrate comparable efficacy in AML, prior data suggest that DEC may induce deeper TP53 mutation clearance and higher response rates; however, direct comparisons in TP53-mutant (TP53-MT) AML are lacking. We conducted a large multicenter retrospective analysis to compare outcomes between DEC- and AZA-based induction, including combinations with venetoclax (VEN). Of 652 patients with newly diagnosed TP53-MT AML, 321 received HMA-based induction (DEC, n = 183; AZA, n = 138). Baseline clinical and genomic characteristics were comparable between the DEC and AZA groups. TP53 mutation subtype were not associated with outcomes, whereas multi-hit TP53 status was independently associated with inferior EFS and OS. In the propensity score-matched cohort, no significant differences in event-free survival (EFS; P = 0.920) or overall survival (OS; P = 0.927) were observed. Median EFS was 5.1, 3.4, 5.9, and 5.6 months, with 12-month estimates of 24%, 17%, 18%, and 16%, while median OS was 5.7, 7.1, 9.2, and 7.1 months, with corresponding 12-month OS rates of 31%, 23%, 29%, and 32% for DEC + VEN, AZA + VEN, DEC, and AZA, respectively. No significant pairwise differences were observed between regimens. These findings from a large multicenter cohort suggest that AZA- and DEC-based induction yield comparable survival outcomes in TP53-MT AML.