In patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) and proceeding to allogeneic stem-cell transplantation (alloHSCT), pretransplant risk assessment remains dominated by morphologic remission–based frameworks despite uncertain prognostic value in the transplant setting. We retrospectively analyzed 280 HMA-treated MDS patients undergoing alloHSCT at DFCI and Moffitt between 2013-2021 to evaluate the predictive performance of IWG 2023 response criteria and to develop an alternative framework integrating functional marrow reserve (FMR) with baseline molecular risk. Progression-free survival (PFS) was the primary outcome. Median overall survival (OS) was 52 months, with 5-year PFS and OS of 43% and 48%, respectively. IWG 2023 response categories showed substantial overlap in outcomes, and assessment by composite complete remission status did not discriminate PFS (5-year PFS 46% vs 40%; p=0.16). In contrast, preconditioning hemoglobin and platelet counts were strongly associated with outcomes, whereas marrow blasts and absolute neutrophil count were not. Recursive partitioning identified clinically relevant platelet and hemoglobin thresholds, enabling construction of FMR strata with markedly distinct 5-year PFS (70%, 40%, and 24% for favorable, intermediate and poor risk, respectively; p<0.0001). Baseline IPSS-M independently predicted outcomes (5-year PFS 58%, 45%, and 29%; p=0.003) and further refined prognostication when integrated with FMR. In multivariable analysis, the integrated IPSS-M/FMR model remained independently associated with PFS (HR 3.00–8.31 across risk tiers; p<0.004) and showed superior discrimination compared with IWG 2023 and classical transplant variables (PFS c-index 0.676). These findings support an integrated framework that outperforms remission-based criteria for post-alloHSCT risk prediction in HMA-treated MDS.

ABSTRACT:Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic stem cell transplant (HSCT) portends a dismal prognosis. One approach for reinvigorating a graft-versus-leukemia response is consolidation with donor lymphocyte infusions (DLI) or second HSCT (HSCT2). However, the role of DLI/HSCT2 in patients who achieve complete remission (CR) after salvage therapy is unclear. In this retrospective study, we evaluated the outcomes of 464 patients with post-HSCT AML relapse, focusing on those who achieved CR before consolidation with cellular therapy. In multivariable analysis (MVA), achieving CR after post-HSCT1 relapse was associated with improved overall survival (OS; hazard ratio [HR], 0.42; P< .0001). Of 133 patients (29%) who achieved CR after posttransplant AML relapse and before cellular therapy, 64 received DLI, 28 underwent HSCT2, and 41 received neither. Four-year outcomes from CR for the entire cohort (n = 133) were: OS 29%, relapse-free survival (RFS) 22%, cumulative incidence of relapse 58%, and nonrelapse mortality (NRM) 20%. In MVA, there was no association between receipt of DLI (HR, 0.87; P = .59) or HSCT2 (HR, 1.08; P = .83) and OS. Furthermore, we did not identify a benefit with DLI or HSCT2 with respect to RFS, relapse, or NRM. Patients with donor chimerism <90% at the time of CR had reduced 4-year OS (20% vs 32%; P = .03), as did measurable residual disease-positive patients (17% vs 62%; P = .024). Our results question the benefit of consolidation with DLI or HSCT2 in patients with AML who achieve CR, and we identify high-risk subgroups that should be the focus of future studies with larger cohorts.

Table S4: Cycle duration and reason for cycle delays.

ABSTRACT:Clinical trial eligibility criteria select a target population and reduce anticipated risks for participants but may unnecessarily limit participation both overall and differently across demographic groups. We previously abstracted eligibility criteria for 190 phase 2/3 acute myeloid leukemia (AML) trials and used US Food and Drug Administration and professional society guidance on modernizing criteria to develop alternative, safety-based eligibility criteria for each trial. In this analysis, these trial- and safety-based eligibility criteria sets were applied to a retrospective cohort of 2226 newly diagnosed patients across 8 hospitals to assess the impact on eligibility. Eligibility proportions increased from a median of 47.9% with trial-based criteria to 84.2% with safety-based criteria (median difference, 30.0%; P< .001); excluding age criteria, the increase was 11.5% (P< .001). Non-Hispanic (NH) Asian, NH Black, NH White, and Hispanic patients were eligible for median proportions of 41.1%, 44.0%, 47.9%, and 50.0%, respectively, with trial-based criteria, increasing by 27.9% to 31.6% when using safety-based criteria (within-group changes, all P< .001; between-group changes, all P> .05). Excluding age criteria, increases were between 10.0% and 11.9%. Moving from trial- to safety-based criteria decreased the proportion of trials with significant eligibility differences between NH White and NH Asian (-11.1%), NH Black (-4.2%), and Hispanic (-12.1%) patients. Criteria significantly associated with increased eligibility and decreased between-group differences in eligibility were coronary artery disease, congestive heart failure, aspartate transaminase level, upper age limits, and previous malignancy. These data suggest that modernization of eligibility for AML trials to focus on safety-based criteria can improve both overall enrollment and population representation.

Rapid progress in leukemia management has increased treatment complexity, resulting in clinical scenarios not fully addressed by standard guidelines. To provide expert guidance, the Bridging the Gaps in Hematology Consensus Conference reunited U.S.-based experts in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and acute lymphoblastic leukemia (ALL) on February 25-26, 2025. Key consensus recommendations were established across AML, MDS, and ALL. For AML, consensus favored CPX-351 for fit patients with secondary or therapy-related AML, without access to clinical trials, and prioritized clinical trial enrollment for other specific molecular subtypes, including those eligible for menin inhibitors. In MDS, consensus supported moving to a harmonized World Health Organization/International Consensus Classification, diagnosing AML based on genetic markers in conjunction with blast counts, and prioritizing stem cell transplant (HSCT) for high-risk patients regardless of response to hypomethylating therapy, particularly for multi-hit TP53-mutated MDS. For ALL, recommendations highlighted avoiding transplant in most Philadelphia chromosome-positive patients achieving minimal residual disease (MRD)-negativity by noting the high relapse risk with certain IKZF1, CDKN2A/B, and PAX5 aberrations, and administering blinatumomab regardless of MRD status in Philadelphia chromosome-positive and -negative ALL. Areas lacking consensus were also identified, highlighting the need for further research. Future directions include refining treatment sequencing, improving outcomes for high-risk subtypes, evaluating the role of HSCT in the era of novel therapies, and standardizing MRD assessment. This consensus report provides valuable expert insights to inform clinical practice and guide future research in leukemia.

Table S5: Subsequent cycle duration following best overall response.

6503 Background: Outcomes for patients with IDH1 mut AML have improved with the advent of targeted therapies. Two doublet regimens are approved for IDH1 mut AML: venetoclax (VEN) with a hypomethylating agent (HMA), and azacitidine (AZA) plus ivosidenib (IVO). Both regimens are effective, yet a substantial proportion of patients fail to respond or eventually relapse. Combining all three agents into a “triplet” regimen may improve outcomes. Herein, we report results from the fully enrolled newly diagnosed (ND) cohort of the multicenter phase Ib/II study of AZA+VEN+IVO for IDH1 mut AML (NCT03471260). Methods: Adults ≥18 years with ND IDH1 mut AML not eligible for standard induction chemotherapy and treated at the RP2D in the phase Ib or II cohorts were included. Patients received AZA 75 mg/m 2 days 1-7, VEN 400mg days 1-14, and IVO 500mg continuously starting C1D14. Dose attenuations in remission were permitted to minimize myelosuppression. The primary objectives were to determine the safety and overall response rate (ORR: CR + CRh + CRi + MLFS). Results: From November 2019 to October 2025, 40 patients with ND AML at four U.S. academic centers initiated treatment (Phase Ib: 9, Phase II: 31). The median age was 72 years (range, 51-80), and 26 patients (65%) were male. AML was classified as de novo in 21 (53%), therapy-related in 4 (10%), and secondary to antecedent myeloid neoplasm in 15 (38%). Six (15%) had received a prior HMA. The ORR was 95% (38/40) with 93% (37/40) achieving a composite CR (CRc; CR+CRh+CRi). The median number of cycles to best response was two (range, 1-7). Measurable residual disease (MRD) negativity by flow cytometry (sensitivity <0.1%) was achieved in 92% (34/37) of CRc responders. With a median follow up of 35 months, median overall survival (OS) and duration of remission (DOR) were not reached. The 3-year OS was 79% (95% CI 64-96%). Three patients relapsed during follow-up with IDH1 -negative clones, and 18 patients (45%) transitioned to SCT. The 3-year DOR censored and not-censored at SCT was 82% (95% CI 68-98%) and 83% (95% CI 64-100%), respectively. Among the 22 patients who did not undergo SCT, the median number of cycles received is 14, with 10 patients (45%) remaining on study. Reasons for discontinuation included lack of response/relapse (n=5), development of another malignancy (n=2), adverse events (AEs; n=2), and patient preference (n=1). Non-hematologic AEs occurred in 32 patients (80%), with 12 (30%) experiencing grade ≥3 AEs. Most grade ≥3 AEs were infectious (n=7, 23%), although two patients each experienced grade ≥3 QTc prolongation, tumor lysis syndrome, and differentiation syndrome, all successfully managed with supportive care and/or with dose modifications. Conclusions: Triplet therapy with AZA+VEN+IVO demonstrates high MRD negative response rates, durable remissions, and comparable safety to doublet regimens in this multicenter study for patients with ND IDH1 mut AML. Clinical trial information: NCT03471260 .

6526 Background: ATP-competitive tyrosine kinase inhibitors (TKIs) in combination with chemoimmunotherapy have improved outcomes in Ph+ ALL; still, some pts relapse despite appropriate frontline therapy and have limited options. ASC is approved for Ph+ chronic myeloid leukemia in chronic phase. The ASC managed access program (MAP) allowed adults with Ph+ ALL refractory/resistant or intolerant to available treatment (Tx) to receive ASC as monotherapy or combination under individual request when the potential benefit outweighed the risk. Methods: This was a non-interventional, multi-country, retrospective chart review in eligible pts with Ph+ ALL aged ≥18 who were refractory/resistant or intolerant to available Tx and who received ≥1 dose of ASC within the MAP. Index date (date of first ASC administration) occurred between 1 March 2019 and 30 June 2023. Existing data were extracted from index date up to 13 months (mo), or until discontinuation, death or last visit, whichever occurred first. The primary endpoint was complete hematologic remission (CR) and CR with incomplete count recovery (CRi) anytime in the first 3 mo of Tx based on peripheral blood assessments. Results: A total of 37 pts were enrolled. At Tx start, 25 pts (67.6%) received ASC as monotherapy. Median ASC dose intensity was 400 mg/day (range 71.6–400.0). Overall, 23 pts (62.2%) achieved CR/CRi within 3 months (95% CI: 44.8, 77.5). Median duration of response was 7.4 mo. Median overall survival was 7.7 mo. Nineteen pts were assessed for minimal residual disease (MRD) at time of CR/CRi and 7 (36.8%) were MRD-. Of the 13 pts with T315I mutation, 10 achieved CR or CRi at any time during follow-up. Thirty-three pts (89.2%) permanently discontinued ASC; reasons for permanent discontinuation included disease progression (n=16) and adverse events (AEs, n=5). Any-grade Tx-emergent AEs were reported in 73.0% (Grade ≥3, 56.8%) of pts; the most common any-grade AE was neutropenia (21.6%). No new safety signals were observed. Most deaths (22/28) were Ph+ ALL related. Conclusions: Adults with Ph+ ALL that was relapsed, resistant/refractory or intolerant to previous Tx achieved high rates of CR/CRi with ASC as monotherapy or in combination with chemotherapy/immunotherapy, despite most pts being heavily pretreated and/or harboring poor prognosis markers (Table). The safety profile was consistent with previous studies. Results, while positive, should be cautiously interpreted given the retrospective nature of the study and heterogenous population. Pt baseline characteristics. Pts N=37 Median age (range), years 53 (19─84) Disease status (bone marrow blasts), %≥5%<5%Unknown 67.624.38.1 Prior treatment lines, %123≥4 2.732.421.643.2 Ponatinib pretreatment, % 94.6 T315I mutation, % 35.1 Reason for starting ASC, %RelapseSpecific mutationsResistanceIntoleranceOther 67.627.024.318.913.5

ABSTRACT:The use of chimeric antigen receptor (CAR) T-cell therapy is increasing for adult B-cell acute lymphoblastic leukemia (B-ALL), with 3 CD19 CAR T-cell products commercially available. Several key clinical questions related to best practices for CAR T-cell administration in this population exist, and limited prospective randomized trials have been conducted to fill these knowledge gaps. Thus, to help guide clinical practice, we conducted a modified Delphi study to develop and validate consensus recommendations on the administration of commercially available CAR T-cell therapy for adults with B-ALL. Consensus panelists (n = 9) included principal investigators (PIs) from Real World Outcomes Collaborative of CAR T-Cell Therapy in Adult ALL (ROCCA) consortium sites and were selected based on expertise and CAR T-cell center volume. Final panel consensus recommendations were distributed for rating by the remaining PIs from ROCCA consortium sites, which served as the validation group (n = 27). Consensus topics included patient selection, bridging and pre-CAR T-cell leukemia staging, lymphodepletion, and CAR T-cell treatment setting, specific toxicity prevention and management, post-CAR T-cell response assessment and disease monitoring, and the role of consolidation and/or maintenance therapies after CAR T-cell therapy. Initially, 58 recommendation statements were evaluated for consensus. After 2 panel meetings, a total of 34 statements achieved consensus rating among the expert panel. After rating by the validation group, all but 1 recommendation statement continued to meet consensus, for a total of 33 consensus recommendation statements on the administration of CAR T-cell therapy in adult B-ALL.

ABSTRACT:In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.

Previous studies have demonstrated that social determinants of health (SDOH) are associated with overall survival (OS) in patients with acute myeloid leukemia (AML). Their interaction with the European LeukemiaNet (ELN) 2022 genetic risk criteria remains unclear. We evaluated the impact of SDOH, measured by the national Area Deprivation Index (nADI) and categorized as low (<=50; more advantaged) vs. high (>50; less advantaged), in 365 patients with newly diagnosed AML treated with intensive chemotherapy. Among ELN favorable (n=115) and adverse (n=166) risk groups, overall survival was similar for high and low nADI groups. Conversely, in intermediate risk patients (n=84), overall survival was higher for more advantaged patients (median 33 vs. 17 months, p=0.04), which persisted in multivariable analysis adjusted for age, race, sex, and hematopoietic cell transplantation as a time-varying covariate (HR 3.09, 95% confidence interval [CI] 1.3-7.34, p=0.01). In this intermediate risk group, response and transplantation rates did not differ by nADI group. Among patients consolidated with transplantation (59/84, 70%), survival was prolonged for more advantaged patients, although not significantly (2-year OS: 69% and 58%; p=0.069), which appeared to be mediated by a higher relapse rate (3-year cumulative incidence of 35% and 69%, p=0.06) rather than non-relapse mortality (20% and 19%, p=0.8). In conclusion, for patients with AML treated with intensive chemotherapy, more advantaged SDOH was associated with improved overall survival solely in the ELN intermediate risk group. This improvement appeared to be mediated by lower post-transplant relapse.

ABSTRACT:Risk stratification in myelodysplastic syndromes (MDS) is essential for clinical decision-making, yet the optimal approach to estimate risk for patients undergoing allogeneic stem cell transplantation (alloHSCT) remains uncertain. Whether dynamic changes in risk between diagnosis and post-hypomethylating agent (HMA) therapy improve prognostic accuracy beyond baseline evaluation has not been established. We retrospectively studied 176 HMA-treated patients who underwent alloHSCT, applying the Molecular International Prognostic Scoring System (IPSS-M) at both diagnosis and before transplant. The primary end point was 4-year progression-free survival (PFS). Overall, dynamic assessment did not improve prognostic performance compared with baseline evaluation. For 4-year PFS, C-indices at diagnosis vs at alloHSCT were 0.6406 vs 0.6377 (P = .82). Patients with worsening risk after HMA experienced notably inferior outcomes, whereas those with apparent improvement fared no better than patients with unchanged risk (4-year PFS: 50%, 50%, and 31% for improved, unchanged, and worsening risk, respectively). Apparent IPSS-M improvement before alloHSCT yielded no gains in survival and no reduction in relapse relative to unchanged risk, a pattern consistent among TP53 wild-type patients. Moreover, clearance of TP53 mutations after HMA therapy did not translate into improved posttransplant outcomes. In summary, dynamic reassessment with IPSS-M before alloHSCT offers no prognostic advantage over baseline evaluation at diagnosis in HMA-treated patients with MDS. Accordingly, risk reduction should not be regarded as a therapeutic goal or trial end point, whereas risk progression constitutes an adverse marker that may inform incorporation of posttransplant maintenance strategies or intensified conditioning regimens to improve survival.

While TP53 mutations in myeloproliferative neoplasms (MPN) are associated with an increased risk of leukemic transformation, not all patients carrying a TP53 mutation progress. To better risk-stratify MPN patients with TP53 mutations, we analyzed data from 1540 patients treated at four specialized cancer centers. Among them, 1429 had wildtype TP53 and 111 had mutations in the TP53 gene. At first MPN diagnosis, 32% had polycythemia vera, 39% had essential thrombocythemia, and 25% had primary myelofibrosis. Among all MPN patients with TP53 mutations, presence of fibrosis in the bone marrow (hazard ratio (HR): 3.84, 95% CI: 1.98-7.43), multi-hit TP53 mutation status (HR: 2.74, 95% confidence interval (CI): 1.52-4.97), and higher PHANTM score (HR: 1.87, 95% CI: 1.02-3.42) were associated with worse OS in a multivariable analysis. Based on these variables, we developed a risk model to identify TP53-mutated MPN patients who are at high risk for inferior OS. Median OS from time of TP53 detection was 0.5 years in high-risk patients, compared to 2.3 years for patients with intermediate risk and 6.3 years for patients with low risk. This scoring system may help refine risk stratification for chronic phase MPN patients harboring TP53 aberrations.

BACKGROUND:Blinatumomab, a bispecific CD19 × CD3 antibody is effective for the treatment of B-cell acute lymphoblastic leukemia (ALL). Because of its immune toxicities, namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the US Food and Drug Administration (FDA) recommends preemptive hospitalization for the initiation of cycle 1 (C1) and cycle 2 (C2). The necessity of this approach is unclear. METHODS:The authors conducted a retrospective cohort study among all patients treated with blinatumomab between 2012 and 2025 at two academic cancer centers: Memorial Sloan Kettering Cancer Center (MSK) and Dana-Farber Cancer Institute (DFCI). RESULTS:For C1, only nine of 308 (3%) patients initiated outpatient (OP) treatment. A total of 184 of 308 (60%) initiated C2: At DFCI, 10 of 83 (12%) initiated C2 OP and at MSK, and 74 of 101 (88%) initiated C2 OP. Demographic and clinical characteristics were similar between patients initiating C2 inpatient versus OP. No patients who initiated C2 (0 of 184) had Gr3+ CRS (across all cycles) and only two (1%) had Gr3+ ICANS; both were inpatient for C2. Of 84 patients treated without preemptive hospitalization for C2, 16 of 84 (19%) required hospitalization at some point during the cycle, largely for infections (50%). CONCLUSIONS:OP administration of C2 of blinatumomab can be administered safely with no unexpected, severe, or life-threatening toxicities. The ability to safely manage treatment without preemptive hospitalization may support the patient experience and limit costs of care.

Clonal mature plasmacytoid dendritic cell proliferations (MPDCP) are a recently recognized entity in the WHO fifth edition, but their pathologic spectrum remains poorly characterized. Cases with extensive MPDCP in the bone marrow (BM) are rare and can exhibit overlapping features with blastic plasmacytoid dendritic cell neoplasm (BPDCN). We compared clinicopathologic and genomic features of 11 patients with myeloid neoplasm-associated MPDCP to 5 patients with secondary BPDCN arising from clonally-related myeloid neoplasms. MPDCP exhibited variable degrees of BM involvement (5% to 50%) and architectural patterns, were uniformly positive for CD123, CD4, TCF4, and IRF8, variably positive for TCL1 (7/11), CD5 (7/11), and CD7 (2/11), and negative for SOX4, CD56, and TdT. MPDCP skin involvement was rare (1/11), with no CNS involvement. MPDCP heralded myeloid disease progression in a subset of patients, with increased blasts or progression to AML (4/11). In contrast, secondary BPDCN was uniformly positive for SOX4 and TCL1, with frequent CD56 (4/5) and subset/weak TdT (3/4). All BPDCN patients had characteristic skin lesions, and a subset with CNS involvement (2/5). The underlying myeloid neoplasms associated with MPDCP or BPDCN were enriched in TET2 , SRSF2 , ASXL1 , RUNX1 , and RAS pathway mutations. While karyotypic abnormalities were uncommon in MPDCP, all BPDCN showed chromosomal structural abnormalities and copy number variants, including deletions of 3p, 9p, and 12p. Our findings expand the histopathologic, immunophenotypic, and genetic characterization of MPDCP, and highlight pathologic features that distinguish it from BPDCN. Utilization of SOX4 immunohistochemistry, combined with careful clinical and molecular correlation, can aid in resolving these diagnostic challenges.

Table S2: Treatment dose-levels. For cycle 1, venetoclax dosing followed a ramp-up from days 1 to 3 and navitoclax dosing began on day 3 only if platelets remained ≥10 × 109/L (platelet transfusions allowed thereafter).

Table S6: All treatment emergent adverse events by dose level regardless of individual attribution.

Somatic mutations in RNA splicing regulators, including the serine/arginine-rich protein SRSF2, are frequently observed in myeloid malignancies. Using mouse models and primary human samples, we investigated the impact of SRSF2 mutations on erythropoiesis. We found reduced erythropoiesis in Srsf2P95H versus wild-type mice upon stress-induced erythropoiesis and identified that SRSF2 mutations correlate with reduced hemoglobin in JAK2-mutant patients with myeloproliferative neoplasms (MPN). Consistent with this, Jak2V617F-Srsf2P95H versus Jak2V617F mice displayed reduced red blood cell counts and erythroid precursor frequencies. RNA-sequencing on erythroid precursors showed reduced expression of heme metabolism and mitotic spindle-related genes, and increased expression of mTORC1 signaling in Srsf2P95H versus wild-type cells. RNA splicing analyses on the same cells and on human patient samples identified aberrant FYN splicing in SRSF2mut cells, with increased aberrant FYNB over normal FYNT transcripts. FYNB, but not FYNT, expression resulted in reduced erythroid differentiation and increased phosphorylation of mTORC1 downstream target S6. Additionally, increased S6 phosphorylation was confirmed in primary Srsf2P95H erythroid cells. mTORC1 pathway inhibition using rapamycin normalized FYNB- and Srsf2P95H-induced impaired erythropoiesis and significantly increased erythroid colony formation of SRSF2-mutant myelodysplastic neoplasm (MDS) bone marrow cells. Our data reveal targetable molecular mechanisms of impaired erythropoiesis in SRSF2-mutant cells.

Abstract Purpose: The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective treatment for most subtypes of acute myeloid leukemia (AML), but it is less effective for other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate antiapoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies. We conducted a phase I study (NCT05455294) of dose-escalated navitoclax added to venetoclax and decitabine for subjects with advanced myeloid malignancies. Patients and Methods: Eligible patients had a diagnosis of (i) secondary or therapy-related AML, (ii) accelerated- or blast-phase myelofibrosis (AP/BP-MF), (iii) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or (iv) relapsed/refractory (R/R) MDS with excess blasts. In 28-day cycles, subjects received navitoclax doses of 25 or 50 mg/day given for days 3 to 14 during cycle 1 and days 1 to 14 in subsequent cycles, target venetoclax doses of 400 mg/day given for days 1 to 14 or days 1 to 21 depending on the myeloid malignancy subtype, and decitabine doses of 20 mg/m2/day given for days 1 to 5. Results: Sixteen subjects were enrolled. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (44%). No clinically significant bleeding was observed. One dose-limiting toxicity of delayed neutrophil recovery occurred. Among 15 evaluable subjects, the overall objective response rate was 60% (9/15). The recommended phase II dose was decitabine 20 mg/m2 days 1 to 5, venetoclax 400 mg/day days 1 to 14, and navitoclax 50 mg/day days 1 to 14 for AP-MF, MDS/MPN, and R/R MDS, respectively. Correlative studies indicate preserved immature platelet fractions despite on-target reduction of mature platelets, a reduction in disease-associated monocytes in subjects with monocytic disease, and higher myeloblast dependence on BCL-2 and BCL-xL in responding subjects. Conclusions: Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.