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The isocitrate dehydrogenase enzyme 2 (IDH2) gene is mutated in ∼5% of patients with myelodysplastic syndrome (MDS). Enasidenib is an oral, selective, mutant IDH2 inhibitor approved for IDH2-mutated (mIDH2) relapsed/refractory acute myeloid leukemia. We designed a 2-arm multicenter study to evaluate safety and efficacy of (A) the combination of enasidenib with azacitidine for newly diagnosed mIDH2 MDS, and (B) enasidenib monotherapy for mIDH2 MDS after prior hypomethylating agent (HMA) therapy. Fifty patients with mIDH2 MDS enrolled: 27 in arm A and 23 in arm B. Median age of patients was 73 years. The most common adverse events were neutropenia (40%), nausea (36%), constipation (32%), and fatigue (26%). Hyperbilirubinemia from off-target UGT1A1 inhibition occurred in 14% of patients (8%; grades 3 and 4), and IDH-inhibitor–associated differentiation syndrome (IDH-DS) in 8 patients (16%). In the combination arm, the overall response rate (ORR: complete remission [CR] + marrow CR [mCR] + partial remission) was 74%, including 70% composite CR (CRc: CR + mCR). Median time to best response was 1 month (range, 1-4), and a median of 4 cycles was received (1-32). The median overall survival (OS) was 26 months (range, 14 to not reached). In the enasidenib monotherapy cohort after HMA failure, ORR and CRc were both 35% (n = 8), with 22% CR (n = 5). Median time to first response was 27 days, and time to best response was 4.6 months (2.7-7.6 months). A median of 7 cycles was received (range, 1-29), and the median OS was 20 months (range, 11 to not reached). Enasidenib is an effective treatment option for mIDH2 MDS, both in combination with azacitidine for treatment-naïve high-risk MDS, and as a single agent after prior HMA therapy. This trial is registered at www.clinicaltrials.gov as #NCT03383575.

Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in relapsed/refractory (R/R) settings are unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (first salvage, 56% vs 37%; P < .0001; second salvage, 33% vs 22%; P = .02; third salvage, 24% vs 14%; P = .02). However, NPM1 mutations had no impact on relapse-free survival (RFS) and overall survival (OS) with each salvage therapy with a median OS following salvage 1, 2 or 3 therapies in NPM1c vs NPM1wt of 7.8 vs 6.0; 5.3 vs 4.1; and 3.5 vs 3.6 months, respectively. Notably, the addition of venetoclax to salvage regimens in patients with NPM1c improved RFS and OS (median RFS, 15.8 vs 4.6 months; P = .05; median OS, 14.7 vs 5.9 months; P = .02). In conclusion, NPM1 mutational status has a minimal impact on prognosis in relapsed or refractory AML; therefore, novel treatment strategies are required to improve outcomes in this entity.

The safety and efficacy of combining the IDH1 inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO+VEN) +/- azacitidine (AZA; IVO+VEN+AZA) was evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n=31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO+VEN+AZA vs. IVO+VEN was 90% vs. 83%. Among MRD-evaluable patients (N=16) 63% attained MRD-negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N=14). Median EFS and OS were 36 (95% CI: 23-NR) and 42 (95% CI: 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked co-occurring mutations, anti-apoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.

We conducted a phase Ib/II multi-arm, parallel cohort study to simultaneously evaluate various immunotherapeutic agents and combinations in relapsed/refractory acute myeloid leukemia (AML). Overall, 50 patients were enrolled into one of 6 arms: (A) single agent PF-04518600 (OX40 agonist monoclonal antibody), (B) azacitidine + venetoclax + gemtuzumab ozogamicin (GO), (C) azacitidine + avelumab (anti-PD-L1 monoclonal antibody) + GO, (D) azacitidine + venetoclax + avelumab, (E) azacitidine + avelumab + PF-04518600, and (F) glasdegib + GO. Among all regimens evaluated, azacitidine + venetoclax + GO appeared most promising. In this arm, the CR/CRi rates among venetoclax-naïve and prior venetoclax-exposed patients were 50% and 22%, respectively, and the 1-year OS rate was 31%. This study shows the feasibility of a conducting a multi-arm trial to efficiently and simultaneously evaluate novel therapies in AML, a needed strategy in light of the plethora of emerging therapies. This trial was registered at www.clinicaltrials.gov as NCT03390296.

Myeloproliferative neoplasms research has entered a dynamic and exciting era as we witness exponential growth of novel agents in advanced/early phase clinical trials for myelofibrosis (MF). Building on the success and pivotal role of ruxolitinib, many novel agents, spanning a wide range of mechanisms/targets (epigenetic regulation, apoptotic/intracellular signaling pathways, telomerase, bone marrow fibrosis) are in clinical development; several are studied in registrational trials and hold great potential to expand the therapeutic arsenal/shift the treatment paradigm if regulatory approval is granted. Insight into MF pathogenesis and its molecular underpinnings, preclinical studies demonstrating synergism of ruxolitinib with investigational agents, urgent unmet clinical needs (cytopenias, loss of response to JAK inhibitors); and progressive disease fueled the rapid rise of innovative therapeutics. New strategies include pairing ruxolitinib with erythroid maturation agents to manage anemia (luspatercept), designing rational combinations with ruxolitinib to boost responses in both the frontline and suboptimal response settings (pelabresib, navitoclax, parsaclisib), treatment with non-JAK inhibitor monotherapy in the second-line setting (navtemadlin, imetelstat), novel JAK inhibitors tailored to subgroups with challenging unmet needs (momelotinib and pacritinib for anemia and thrombocytopenia, respectively); and agents potentially enhancing longevity (imetelstat). Beyond typical endpoints evaluated in MF clinical trials (spleen volume reduction ≥ 35%, total symptom score reduction ≥ 50%) thus far, emerging endpoints include overall survival, progression-free survival, transfusion independence, anemia benefits, bone marrow fibrosis and driver mutation allele burden reduction. Novel biomarkers and additional clinical features are being sought to assess new agents and tailor emerging therapies to appropriate patients. New strategies are needed to optimize the design of clinical trials comparing novel combinations to standard agent monotherapy.

The progress with intensive chemotherapy and supportive care measures has improved survival in patients with newly diagnosed acute myeloid leukemia (AML). Given the recent development of effective low intensity therapies, an optimal decision on the therapy intensity may improve survival through the avoidance of early mortality. We reviewed the outcome of 3728 patients with newly diagnosed AML who received intensive chemotherapy between August 1980 and May 2020. Intensive chemotherapy was defined as a cumulative cytarabine dose ≥ 700 mg/m2 during induction therapy. We divided the whole cohort into a training and validation group at a 3:1 ratio. The population was divided into a training (2790 patients) and a validation cohort (938 patients). The median age was 55 years (range, 15-99). Among them, 442 patients (12%) had core-binding factor AML. Binary logistic regression identified older age, worse performance status, hyperbilirubinemia, elevated creatinine, hyperuricemia, cytogenetic abnormalities other than CBF and -Y, and pneumonia as adverse prognostic factors for an early 4-week mortality. This risk classification for early mortality was verified in the validation cohort of patients. In the validation cohort of more recently treated patients from 2000 to 2017, the 4-week mortality rates with intensive chemotherapy were 2%, 14%, and 50% in the low-, high-, and very high-risk group, respectively. The mortality rates with low intensity therapies were 3%, 9%, and 20%, respectively. The risk classification guides treatment intensity by the assessment of age, frailty, organ dysfunction, cytogenetic abnormality, and infection to avoid early mortality.

PURPOSE Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML. MATERIALS AND METHODS The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML. RESULTS Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease–negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML. CONCLUSION Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation.

Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-α cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with ≥2 prior therapies and a median baseline platelet count of 52 × 103/μL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.1+). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.

Ruxolitinib (RUX) was the first JAK1/2 inhibitor approved for patients with advanced-phase myelofibrosis (MF) with a median therapy duration of about 3 years.We aimed to characterize the clinical features of patients treated with RUX for ≥3 years.Retrospective review of medical records of 131 patients presented to our institution between January 2000 and July 2020 who received RUX for ≥3 years.Major clinical features were reported by descriptive statistics. OS was analyzed using the Kaplan-Meier model. The Cox proportional hazard model (univariate, multivariate) was used for factors associated with OS.The median age of patients was 67 years (range, 31-84) and 56% were men. Fewer than 20% of patients had hemoglobin10 g/dL or platelets150×10Forty percent of patients who remained on RUX for ≥3 years were alive at 10 years since their therapy initiation. Age remains the major predictive factor of survival on long RUX therapy.

Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm driven by canonical gene mutations in JAK2, CALR or MPL in more than 80% of the cases. PMF cases that lack these canonical alterations are termed triple-negative PMF (TN-PMF). The pathologic and genetic characteristics of TN-PMF compared to conventional PMF with canonical driver mutations (DM-PMF) have not been well studied. We aim to identify clinicopathologic and molecular genetic differences between TN-PMF (n = 56) and DM-PMF (n = 89), all of which fulfilled the 2016 WHO diagnostic criteria for PMF. Compared to the control group, TN-PMF patients were more likely to have thrombocytopenia and less likely to have organomegaly. The bone marrow with TN-PMF showed fewer granulocytic elements and more frequent dyserythropoiesis. Cytogenetic analysis showed a higher incidence of trisomy 8. Targeted NGS revealed a lower frequency of ASXL1 mutations but an enrichment of ASXL1/SRSF2 co-mutations. Our findings demonstrated several clinicopathologic and molecular differences between TN-PMF and DM-PMF. These findings, particularly the observed mutation profile characterized by a higher frequency of ASXL1 and SRSF2 co-mutation, suggest that at least a subset of TN-PMF may be pathogenetically different from DM-PMF, with potential prognostic implications.

Background: Multiagent induction chemotherapy consisting of fludarabine, cytarabine, G-CSF, and idarubicin (FLAG-IDA) results in complete remission in ~ 85% of newly diagnosed patients with acute myeloid leukemia (ND-AML), yet 30-40% experience relapse. Combining the BCL-2 inhibitor venetoclax (VEN) with chemotherapy results in synergistic leukemic cell death, inferring FLAG-IDA+VEN may improve outcomes in ND-AML. Design: A phase 1b/2 study evaluating FLAG-IDA+VEN (Fig. 1A) in ND and relapsed/refractory (R/R) AML patients 18 years of age. Phase 1b results were previously reported (DiNardo, JCO 2021). The Phase 2 (P2) portion enrolled patients into two cohorts: ND and R/R-AML. ND-AML outcomes are reported herein. Objectives: The primary P2 objective is determination of overall activity of FLAG-IDA+VEN including overall response rate (ORR: CR+CRi+CRh+MLFS+PR). Secondary objectives include determination of overall survival (OS), event-free survival (EFS), duration of response (DOR), and biomarkers predictive of VEN sensitivity. Results: Forty-one patients with ND-AML (de novo AML: n=29, secondary AML [sAML]: n=7, therapy-related AML [tAML]: n=5) enrolled. Median age was 44 years (range 20-65). ELN risk was favorable, intermediate, and adverse in 20%, 37%, and 44% of patients. Common mutations included NRAS (29%; n=12), IDH2 (17%; n=7), RUNX1 (15%, n=6), and NPM1 (15%, n=6). TP53 mutations and KMT2A-rearrangements were identified in 10% (n=4) and 12% (n=5) of patients at diagnosis, respectively. The median number of treatment cycles received was 2 (range 1-6). The ORR was 98% (CR: n=30 [73%], CRh: n=5 [12%], CRi: n=1 [2%], MLFS: n=4 [10%]) and CRc (CR+CRh+CRi) rate was 88% (n=36). 92% of CRc patients attained MRD-negative status by flow cytometry. Median time to best response was 29 days (range 22-94). Sixty-six percent (n=27) of patients transitioned to allogeneic transplantation (HSCT) after a median of 3.8 (range 3.2-4.9) months. Median DOR was NR (95% CI: 17-NR). Median cycle length for cycles 1 and 2 were 31 and 41 days. Median time to count recovery (ANC 500 cells/mm 3 and platelet count 50,000 cells/mm 3) was longer following cycle 2 compared to cycle 1 (47 vs. 32 days, p-value < 0.001). Common adverse events included febrile neutropenia (39%; n=16), pneumonia (24%; n=10), and bacteremia (19%; n=8). No 30 or 60-day mortality occurred. Nine patients relapsed (ELN intermediate: N=3, adverse: N=6) including 100% of patients with baseline TP53 mutations (N= 4), and the one patient with inv(3). TP53 mutations were identifiable in 67% (n=6) of patients at relapse, including two patients without TP53 mutations at diagnosis. Four deaths have occurred, all in the setting of relapsed disease. With median follow up of 16 months, median OS and EFS are both NR, with 1-year OS and EFS rates of 96% and 77%, respectively (Fig. 1B). Patients with KMT2A rearrangements (n=5) and NPM1, IDH1, and/or IDH2 mutations (n=13) have experienced an 18-month survival rate of 100%. Patients with TP53 mutations at diagnosis have significantly inferior OS (24 months vs. NR, p-value: 0.03) and EFS (median EFS 8 months vs. NR, p-value A propensity score matched analysis compared to a historical cohort of patients receiving frontline FIA (fludarabine, idarubicin, cytarabine) induction (N=74) at our institution indicated FLAG-IDA+VEN was associated with improved median OS (NR vs. 47 months, p-value: 0.022), and a trend towards improved OS and EFS in patients not undergoing HSCT (FLAG-IDA+VEN vs. FAI median OS: 24 vs. 19 months, p-value: 0.09; median EFS: NR vs. 8 months, p-value: 0.064). On multivariate analysis, increased age and ELN risk group correlated with increased risk of death (age [HR 1.05, 95% CI: 1.02-1.09, p-value: 0.001]; ELN risk group [HR 1.92; 95% CI: 1.185-3.11, p-value: 0.008]), while decreased risk was observed based on treatment with FLAG-IDA+VEN vs. FIA (HR 0.28, 95% CI: 0.096-0.84, p-value: 0.02). Conclusions: FLAG-IDA+VEN induction and consolidation results in high MRD-negative CRc rates in ND-AML with an expected safety profile. Durable responses were observed at 12-months, with favorable outcomes compared to historical cohorts of intensive therapy. Patients with TP53 mutations treated with FLAG-IDA+VEN experience inferior outcomes compared to patients with wild-type TP53. Prospective randomized trials are warranted to confirm these results. Figure 1 Figure 1. Disclosures DiNardo: AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Takahashi: GSK: Consultancy; Celgene/BMS: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Kadia: Amgen: Other: Grant/research support; Liberum: Consultancy; Jazz: Consultancy; Ascentage: Other; Novartis: Consultancy; Cellonkos: Other; Sanofi-Aventis: Consultancy; Cure: Speakers Bureau; Dalichi Sankyo: Consultancy; Aglos: Consultancy; AstraZeneca: Other; AbbVie: Consultancy, Other: Grant/research support; BMS: Other: Grant/research support; Genentech: Consultancy, Other: Grant/research support; Pfizer: Consultancy, Other; Pulmotech: Other; Genfleet: Other; Astellas: Other. Daver: ImmunoGen: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Hanmi: Research Funding; Novimmune: Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Short: Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Astellas: Research Funding; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Novartis: Honoraria; Amgen: Consultancy, Honoraria. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Wang: Stemline Therapeutics: Honoraria. Borthakur: Astex: Research Funding; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Issa: Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding; Kura Oncology: Consultancy, Research Funding. Alvarado: Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Sun Pharma: Consultancy, Research Funding; FibroGen: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding. Pemmaraju: Springer Science + Business Media: Other; Roche Diagnostics: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Plexxicon: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; CareDx, Inc.: Consultancy; MustangBio: Consultancy, Other; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Jain: Genentech: Honoraria, Research Funding; Servier: Honoraria, Research Funding; TG Therapeutics: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Beigene: Honoraria; Fate Therapeutics: Research Funding; Incyte: Research Funding; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Janssen: Honoraria; Precision Biosciences: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Andreeff: Medicxi: Consultancy; AstraZeneca: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Senti-Bio: Consultancy; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; ONO Pharmaceuticals: Research Funding; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; Syndax: Consultancy; Glycomimetics: Consultancy; Aptose: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Karyopharm: Research Funding; Breast Cancer Research Foundation: Research Funding. Ravandi: Xencor: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Novartis: Honoraria; Prelude: Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Konopleva: Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Ascentage: Other: grant support, Research Funding; Cellectis: Other: grant support; Agios: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Stemline Therapeutics: Research Funding; KisoJi: Research Funding. Kantarjian: Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Astellas Health: Honoraria; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Jazz: Research Funding; Aptitude Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Astra Zeneca: Honoraria; Taiho Pharmaceutical Canada: Honoraria. OffLabel Disclosure: Will describe use of venetoclax in combination with FLAG-IDA induction and consolidation therapy in AML.

Background There are limited data on the clonal mechanisms underlying leukemogenesis, prognostic factors, and optimal therapy for atypical chronic myeloid leukemia (aCML). Methods The authors evaluated the clinicopathologic features, outcomes, and responses to therapy of 65 patients with aCML. The median age was 67 years (range, 46-89 years). Results The most frequently mutated genes included ASXL1 (83%), SRSF2 (68%), and SETBP1 (58%). Mutations in SETBP1, SRSF2, TET2, and GATA2 appeared at variant allele frequencies (VAFs) greater than 40%, whereas other RAS pathway mutations were more likely to appear at low VAFs. The acquisition of new, previously undetectable mutations at transformation was observed in 63% of the evaluable patients, with the most common involving signaling pathway mutations. Hypomethylating agents (HMAs) were associated with the highest response rates but with a short duration of response (median, 2.7 months). Therapy with ruxolitinib was not associated with clinically significant responses as a single agent or in combination with an HMA. Allogeneic stem cell transplantation was the only therapy associated with improved outcomes (hazard ratio, 0.144; 95% CI, 0.035-0.593; P = .007). Age, platelet counts, bone marrow blast percentages, and serum lactate dehydrogenase (LDH) levels were independent predictors of survival and were integrated in a multivariable model that allowed the prediction of 1- and 3-year survival. Conclusions aCML is characterized by high frequencies of ASXL1, SRSF2, and SETBP1 mutations and is associated with a high risk of acute myeloid leukemia transformation. Response and survival outcomes with current therapies remain poor. The incorporation of age, platelet counts, bone marrow blast percentages, and LDH levels can allow survival prediction, and allogeneic stem cell transplantation should be considered for all eligible patients.