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The ELN 2024 risk-stratification guidelines for patients with acute myeloid leukemia receiving hypomethylating agents combined with venetoclax were recently published. This analysis demonstrates re-classification and incorporation of new gene mutations in the present model can further improve and individualize prognostication., (Copyright © 2024 American Society of Hematology.)

Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. Although venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and nonresponsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate an active metabolic (i.e., OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance. Significance: We identify increased utilization of mitochondrial calcium as a distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy., (©2024 American Association for Cancer Research.)

The advent of molecularly targeted therapeutics has transformed the management of patients with acute myeloid leukemia (AML). Particularly for individuals unfit for intensive chemotherapy, lower intensity therapies (LIT) incorporating small molecules have significantly improved patient outcomes. With BCL2, IDH1, IDH2, and FLT3 inhibitors widely used for relapsed AML, combination regimens are now utilized in the frontline. Expansion of these targeted LIT combinations, along with development of novel agents including menin inhibitors, exemplifies the promise of precision medicine. Further understanding of molecular drivers of leukemic transformation and mechanisms of relapse will continue to advance frontline treatment options for patients with AML., (© 2024 Wiley Periodicals LLC.)

Despite the concurrent use of haploidentical cord (HCT) and dual cord (DCT) stem cell transplant approaches for over a decade, there have been few comparisons of their outcomes. Our objective in this study is to assess for differences in the outcomes and adverse effects associated with HCTs versus DCTs. Here we report a retrospective analysis of HCTs and DCTs at our institution. From October 2012 to October 2022, 70 HCT and 133 DCT transplants were performed following 50 mg/kg of IV cyclophosphamide, 150 mg/m 2 of IV fludarabine, 10 mg/kg of IV thiotepa, and 4 Gy total body irradiation conditioning. With a median follow-up of 3.6 years among survivors, there was no difference in overall survival (OS) (3 years OS 65% DCT versus 63% HCT, P = 1) or relapse-free survival (3 years RFS 62% DCT versus 64% HCT, P = .97) for all patients. Time to neutrophil recovery was faster in HCT recipients (median 17 versus 22 days, P = .021), with no difference in platelet recovery to 20,000/μL (P = .12). Median hospitalization for HCT recipients was 20 days versus 24 days for DCT recipients (P < .0001). Engraftment syndrome treated with steroids occurred in 47/133 (35%) DCT recipients versus 42/70 (60%) HCT recipients (odds ratios 0.37, P value=.001). There was a significant increase in grade 3 to 4 acute graft-versus-host disease (aGVHD) in haplo-cord recipients (P = .007), but no difference in grade 2 to 4 aGVHD (P = .11), all chronic GVHD (cGVHD) (P = .9), or moderate-severe cGVHD (P = .3). Our outcomes demonstrate faster engraftment and shorter hospitalization in HCTs relative to DCTs, but more engraftment syndrome and higher grade 3 to 4 aGVHD. When both are options, these factors should guide the choice between HCTs and DCTs., (Copyright © 2024. Published by Elsevier Inc.)

European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems were based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. Here, pooled analysis of patients in the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to 2017 and 2022 ELN risk classifications. A bioinformatic algorithm derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on median overall survival (OS). 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. When classified by ELN 2017 or 2022 prognostic criteria, most patients had adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). While outcomes with venetoclax-azacitidine were improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine; the mutational status of TP53, FLT3-ITD, NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% CI, 20.2 to 32.7], 12.1 months [95% CI, 7.3 to 15.2], and 5.5 months [95% CI, 2.8 to 7.6], respectively). ELN prognostic classifiers do not provide clinically meaningful risk stratification of OS outcomes for patients with AML treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows classification of these patients into three risk groups with distinct differences in median OS., (Copyright © 2024 American Society of Hematology.)

The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due at least in part to drug resistance of leukemia stem cells (LSCs). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors (TKIs) can eradicate bpCML LSCs. In this report, we employed preclinical models of bpCML to investigate the efficacy and underlying mechanism of LSC-targeting with venetoclax/TKI combinations. Transcriptional analysis of LSCs exposed to venetoclax and dasatinib revealed upregulation of genes involved in lysosomal biology, in particular lysosomal acid lipase A (LIPA), a regulator of free fatty acids. Metabolomic analysis confirmed increased levels of free fatty acids in response to venetoclax/dasatinib. Pre-treatment of leukemia cells with bafilomycin, a specific lysosome inhibitor, or genetic perturbation of LIPA, resulted in increased sensitivity of leukemia cells toward venetoclax/dasatinib, implicating LIPA in treatment resistance. Importantly, venetoclax/dasatinib treatment does not affect normal stem cell function, suggestive of a leukemia-specific response. These results demonstrate that venetoclax/dasatinib is an LSCselective regimen in bpCML and that disrupting LIPA and fatty acid transport enhances venetoclax/dasatinib response in targeting LSCs, providing a rationale for exploring lysosomal disruption as an adjunct therapeutic strategy to prolong disease remission.

Predictors for response to intensive therapy in AML have focused on baseline factors: percent leukemic blasts in marrow, cytogenetic/molecular genetic abnormalities, and presence of secondary AML. Non-baseline dynamic factors, occurring after induction but before response, may be useful for decisions related to salvage chemotherapy. We hypothesized white blood cell (WBC) count nadir after induction may be a real time indicator of treatment efficacy. We also examined whether time to stem cell transplant (SCT) or baseline molecular genetic abnormalities are associated with a low nadir. Data showed WBC nadir = 0 was a negative predictor for response to intensive induction and was correlated with reduced overall survival and progression free survival. Patients with WBC nadir = 0 did not have a significantly longer time to SCT, and none of the mutations increased the likelihood of reaching WBC nadir = 0. WBC nadir may be a useful real-time monitor in AML patients receiving intensive induction chemotherapy.

Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic value for broadscale molecular MRD after ven/aza treatment is less clear. We aimed to determine the utility of retrospective assessment using multi-gene molecular MRD by droplet digital polymerase chain reaction (ddPCR). We found this approach correlates with outcomes in a cohort of patients receiving frontline ven/aza for AML. The predictive value of ddPCR MRD persisted when NPM1 mutations were removed from analysis, as well as after adjustment for the impact of stem cell transplant on outcomes. Late achievement of MRD negativity, including after SCT, was still associated with superior outcomes compared to persistently detectable MRD. We further explored the impact of ven/aza on the burden of different classes of mutations, and identified the persistence of splicing factor mutations, commonly associated with MDS, as a consistent finding after ven/aza treatment. These data add to our understanding of the effects of ven/aza on AML disease biology and provide details on molecular depth of remission that can guide prospective trials in the future.

Background: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies., Patients and Methods: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle., Results: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway., Conclusion: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations., Competing Interests: Disclosure MYK is a consultant for AbbVie, Inc., Genentech, Inc., and F. Hoffmann La-Roche; is an advisory board member for F. Hoffmann La-Roche; holds shares from Reata Pharmaceuticals; has received honoraria from Amgen, AbbVie, Inc., and Genentech, Inc.; and has received research funding from AbbVie, Inc., Genentech, Inc., Eli Lilly, Cellectis, Calithera, Stemline, Threshold, Flexus Biosciences, Novartis, Ablynx, and Agios. MD, MO, JW, WH, DD, and HH are employees of Genentech, Inc. and may hold Roche stock or stock options. NGD has received research funding from Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Inc., Astellas, Daiichi Sankyo, AbbVie, Inc., Hanmi, Trovagene, Fate Therapeutics, Amgen, Novimmune, GlycoMimetics, Trillium, Kite Pharma, Aptose, Shattuck Labs, KAHR, ArcellX, Sanofi, Sumitomo, and ImmunoGen; and has served in a consulting or advisory role for Daiichi Sankyo, Bristol-Myers Squibb, Arog Pharmaceuticals, Pfizer, Novartis, Jazz Pharmaceuticals, Celgene, AbbVie, Inc., Astellas, Genentech, Inc., Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck Labs, ArcellX, Kite Pharma, Sumitomo, Caribou Biosciences, Sanofi, Rigel, Aptose, KURA, GlycoMimetics, and Agios. JSG has received research funding (for trials) from AbbVie, Inc., Genentech, Inc., Pfizer, Prelude, and AstraZeneca; and has served on advisory boards for AbbVie, Inc., Astellas, Bristol-Myers Squibb and Servier. BAJ is a consultant/advisor for AbbVie, Inc., Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Inc., Gilead, GlycoMimetics, Jazz Pharmaceuticals, Kymera, Pfizer, Rigel, Servier, and Takeda; protocol steering committee for GlycoMimetics; data monitoring committee for Gilead; travel reimbursement/support from Rigel; and research funding to his institution from AbbVie, Inc., Amgen, Arog Pharmaceuticals, Aptose, BMS, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma Therapeutics, Forty-Seven, Genentech, Inc./Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz Pharmaceuticals, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, and Treadwell. KWLY is a consultant for Astex, Bristol-Myers Squibb/Celgene, F. Hoffmann-La Roche, Novartis, Otsuka, Paladin, Pfizer, Shattuck Labs, Taiho, and Takeda; has received honorarium from AbbVie, Inc. and Novartis; and has received research funding from Astex, Forma Therapeutics, F. Hoffmann-La Roche, Genentech, Inc., Geron, Janssen, Jazz Pharmaceuticals, MedImmune, Novartis, Onconova, and Tolero. KRK, NV, SP, AT, AP, PF, and GV declare no competing financial interests. SA reports non-financial support from Roche/Genentech, Inc. during the conduct of the study; and has received personal fees from Roche Canada, Pfizer, Bristol-Myers Squibb, Palladin, and Lundbeck outside of the submitted work. GJR consulted for AbbVie, Inc., Amgen, Argenx, AstraZeneca, Bluebird Bio, Blueprint Medicines, Bristol-Myers Squibb, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses Pharma, GlaxoSmithKline, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Novartis, Pfizer, Roche, Syndax, Takeda (IRC Chair), and Telix Pharma; and has received research funding from Janssen. DAP has received research funding from AbbVie, Inc. and has served as a consultant or advisory board member for AbbVie, Inc. and Genentech, Inc. JMB consulted for AbbVie, Inc., Bristol-Myers Squibb, Astex, Pfizer, Astellas, Taiho, and Jazz Pharmaceuticals. BLP has received research funding from Ambit Biosciences, Genentech, Inc., F. Hoffmann-La Roche, Jazz Pharmaceuticals, Novartis, Pfizer, and Cornerstone Pharmaceuticals; and is a consultant for Cornerstone Pharmaceuticals. RLO has received research support for trials from Astellas, Pfizer, Genentech, Inc., Daiichi Sankyo, and Cellectis; and consulted for AbbVie, Inc., Astellas, and Actinium. GM is a consultant for AbbVie, Inc., Celgene, Roche, Janssen, Astellas, Pfizer, and Incyte. W-JH is a former employee of Genentech, Inc. and may hold Roche stock; and is a current employee of Prelude Therapeutics. MGO is an employee of F. Hoffmann-La Roche and may hold stock or stock options. MA consulted for Amgen, AstraZeneca, Daiichi Sankyo, Syndax, GlycoMimetics, Oncoceutics, and Aptose; has received research funding from F. Hoffmann-La Roche, AstraZeneca, Amgen, Daiichi Sankyo, Jazz Pharmaceuticals, GlycoMimetics; and holds stock from Reata, Oncoceutics/Chimerix and Aptose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Myelodysplastic neoplasm (MDS) is a hematopoietic stem cell disorder that may evolve into acute myeloid leukemia. Fatal infection is among the most common cause of death in MDS patients, likely due to myeloid cell cytopenia and dysfunction in these patients. Mutations in genes that encode components of the spliceosome represent the most common class of somatically acquired mutations in MDS patients. To determine the molecular underpinnings of the host defense defects in MDS patients, we investigated the MDS-associated spliceosome mutation U2AF1-S34F using a transgenic mouse model that expresses this mutant gene. We found that U2AF1-S34F causes a profound host defense defect in these mice, likely by inducing a significant neutrophil chemotaxis defect. Studies in human neutrophils suggest that this effect of U2AF1-S34F likely extends to MDS patients as well. RNA-seq analysis suggests that the expression of multiple genes that mediate cell migration are affected by this spliceosome mutation and therefore are likely drivers of this neutrophil dysfunction., (© 2023. The Author(s).)

Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: i) higher doses of venetoclax are tolerable and more effective, and ii) azacitidine can be discontinued after deep remissions. Forty-two newly diagnosed AML patients were enrolled in the investigator-initiated High Dose Discontinuation Azacitidine+Venetoclax (HiDDAV) Study (clinicaltrials gov. Identifier: NCT03466294). Patients received one to three "induction" cycles of venetoclax 600 mg daily with azacitidine. Responders received MRD-positive or MRDnegative "maintenance" arms: azacitidine with 400 mg venetoclax or 400 mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400 mg venetoclax. The overall response rate was 66.7%; the duration of response (DOR), event-free survival (EFS) and overall survival were 12.9, 7.8 and 9.8 months, respectively. The MRD negativity rate was 64.3% by flow cytometry and 25.0% when also measured by droplet digital polymerase chain recation. MRD-negative patients by flow cytometry had improved DOR and EFS; more stringent measures of MRD negativity were not associated with improved OS, DOR or EFS. Using MRD to guide azacitidine discontinuation did not lead to improved DOR, EFS or OS compared to patients who discontinued azacitidine without MRD guidance. Within the context of this study design, venetoclax doses >400 mg with azacitidine were well tolerated but not associated with discernible clinical improvement, and MRD may not assist in recommendations to discontinue azacitidine. Other strategies to optimize, and for some patients, de-intensify, venetoclax+azacitidine regimens are needed.

The BCL2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia stem cell (LSC), which we designate as monocytic LSC (m-LSC), that is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC). The m-LSC is distinguished by a unique immunophenotype (CD34-, CD4+, CD11b-, CD14-, CD36-), unique transcriptional state, reliance on purine metabolism, and selective sensitivity to cladribine. Critically, in some instances, m-LSC and p-LSC subtypes can co-reside in the same patient with AML and simultaneously contribute to overall tumor biology. Thus, our findings demonstrate that LSC heterogeneity has direct clinical significance and highlight the need to distinguish and target m-LSCs as a means to improve clinical outcomes with venetoclax-based regimens., Significance: These studies identify and characterize a new type of human acute myeloid LSC that is responsible for monocytic disease progression in patients with AML treated with venetoclax-based regimens. Our studies describe the phenotype, molecular properties, and drug sensitivities of this unique LSC subclass. This article is featured in Selected Articles from This Issue, p. 1949., (©2023 American Association for Cancer Research.)

Objectives: Dysregulation of BCL-2 family members has been reported in acute lymphocytic leukemia (ALL), with various BH3-dependencies of the leukemic clone. We conducted a multicenter retrospective cohort of patients with relapsed/refractory B or T ALL, with ven-chemotherapy or ven-navitoclax combinations, to assess efficacy and safety., Methods: Seventeen patients were included in the analysis, median age was 32 years, with 6 B-ALL and 11 T-ALL patients. Nine patients received venetoclax combined with chemotherapy, and 13 patients received venetoclax in combination with navitoclax, vincristine and asparaginase, of which 5 were already exposed to venetoclax in previous lines., Results: ORR was 55% and 46% among the ven-chemotherapy and the ven-navitoclax-chemotherapy, respectively. Most of the responders proceeded to an allogenic bone marrow transplant in both cohorts. The most common adverse effects of the ven-navitoclax combination were infectious complications and hepatotoxicity., Conclusions: Our data demonstrated the possible efficacy of ven-chemotherapy and ven-navitoclax in r/r ALL with moderate toxicity., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

The existence of two acute myeloid leukaemia classification systems-one put forth by WHO and one by the International Consensus Classification in 2022-is concerning. Although both systems appropriately move towards genomic disease definitions and reduced emphasis on blast enumeration, there are consequential disagreements between the two systems on what constitutes a diagnosis of acute myeloid leukaemia. This fundamental problem threatens the ability of heath-care providers to diagnose acute myeloid leukaemia, communicate with patients and other health-care providers, and deliver appropriate and consistent management strategies for patients with the condition. Clinical trial eligibility, standardised response assessments, and eventual drug development and regulatory pathways might also be negatively affected by the discrepancies. In this Viewpoint, we review the merits and limitations of both classification systems and illustrate how the coexistence, as well as application of both systems is an undue challenge to patients, clinicians, hematopathologists, sponsors of research, and regulators. Lastly, we emphasise the urgency and propose a roadmap, by which the two divergent classification systems can be harmonised., Competing Interests: Declaration of interests RMS has served in a consulting or advisory role for Bristol Myers Squibb, Curio Science, Gilead Sciences, and Sciences, Servier, and Rigel. ND has received research funding from Daiichi Sankyo, Bristol Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi Sankyo, AbbVie, Hanmi, Trovagene, Fate Therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen. ND has served in a consulting or advisory role for Daiichi-Sankyo, Bristol Myers Squibb, Arog, Pfizer, Novartis, Jazz Pharmaceuticals, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. JKA has received institutional research funding from AbbVie, Agios, ALX Oncology, Amgen, Amphivena, Aprea AB, Aptose Biosciences, Astellas Pharma, BioSight, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cyclacel, Fujifilm, Immunogen, Kartos Therapeutics, Kura Oncology, Loxo, Pfizer, and Telios; has served in a consulting or advisory role for AbbVie, Astellas Pharma, BioSight, Bluebird Bio, Curio, Gilead, Kura Oncology, Kymera, Stemline Therapeutics, and Syros; and has served on a data monitoring committee for GlycoMimetics. DAP has served as a consultant or advisor for AbbVie, Novartis, Karyopharm, Syndax, Jazz, Syros, Bristol Myers Squibb, BeiGene, Bergen Bio, Arcellx, Genentech, Immunogen, AstraZeneca, Kura, Ryvu, Magenta, Qihan, Zentalis, Medivir, Hibercell, Link, Daiichi Sankyo, Schrodinger, Aptevo, Rigel, Sumitomo, Adicet, Gilead, and Oncoverity; he has received research funding from AbbVie, Karyopharm, Teva, and Bristol Myers Squibb. TB has served as a consultant or advisor for Pfizer and Takeda. VRB reports participating in safety monitoring committee for protagonist. VRB receives consulting fees from Imugene, research funding from AbbVie, Pfizer, Incyte, Jazz Pharmaceuticals, and National Marrow Donor Program, and provided drug from Chimerix for a trial. AdlFB received research funding from Janssen-Cilag, Novartis, BTG Pharmaceuticals, and AbbVie; has served on advisory boards for Abbvie, Astellas, Bristol Meyers Squibb, Curis, Daiichi Sankyo, Incyte, Immunogen, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Servier. AdlFB has received speakers' fees from Abbvie, Astellas, Celgene-BMS, Daiichi Sankyo, Incyte, Janssen Cilag, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Servier. HEC received research funding from Celgene and has served as a consultant or advisor for Bristol Myers Squibb, Jazz Pharmaceuticals, Novartis, Daiichi, Genentech and Stemline. She has received speakers fees from Jazz, Novartis, BMS and Stemline; she has been on Data Safety Monitoring Board Committees for AbbVie, ASTEX, Syndax, and Takeda. FEC has received institutional research funding from Celgene, Bristol Myers Squib, Amgen, Fibrogen, Sumitomo Pharma Oncology, and AbbVie, and is a consultant for the Association of Community Cancer Centers. ATF has received research funding from Celgene, AbbVie, and Servier, and has served in a consulting or advisory role for Genentech, Celgene, Foghorn, Kite, Morphosys, AbbVie, Takeda, Ipsen, Forma, Amgen, Novartis, Astellas, Immunogen, Mablytics, EnClear, Orum, PureTech, Pfizer, Daiichi Sankyo, Minovia, Rigel, and Servier. IG has received research funding from Merck, Amgen, Gilead, Incyte, and Genentech, and has served as a consultant and advisor for Immunogen, Bristol Meyer Squibb, Amgen, ClearView, Curio, and Nkarta. MRG has stock ownership in Medtronic, received research support from Incyte and Jannsen, and received consulting fees from AbbVie, Amgen, Astellas, Blueprint Medicines, Bristol Myers Squibb, Cardinal Health, CTI BioPharma, Daiichi Sankyo, Gamida Cell, Genentech, Gilead, GSK, Sierra Oncology, Incyte, Invitae, Jazz, Karius, Novartis, Ono Pharmaceutical, Pfizer, Pharmacosmos, Premier, Servier, and Stemline Therapeutics. BAJ has served as a consultant and advisor for AbbVie, Bristol Meyers Squibb, Daiichi Sankyo, Genentech, Gilead, GlycoMimetics, Jazz, Kymera, Pfizer, Rigel, Servier, and Takeda; was on the protocol steering committee for GlycoMimetics, data monitoring committee for Gilead; and received travel reimbursement and [ support from AbbVie and Rigel; BAJ received institutional research funding from AbbVie, Amgen, Aptose, AROG, Bristol Meyers Squibb, Celgene, Daiichi Sankyo, F Hoffmann-La Roche, Forma, Forty Seven, Genentech, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, and Treadwell. GNM has received research funding from Bristol Meyers Squibb, Celgene, Glycomimetics, Forty Seven, Jazz, Astex, Syndax, Immune Onc, and Immunogen; has served as a consultant and advisor for AbbVie, Agios, Macrogenics and Pfizer, and has served on a scientific advisory committee for Abbvie, Agios, Astellas, Bristol Myers Squibb, Forty Seven, Genentech, and Stemline. JM has received institutional research funding from Incyte, Novartis, Bristol Meyers Squibb, CTI Bio, Geron, AbbVie, Kartos, and PharmaEssentia, and has received consulting fees from Bristol Meyers Squibb Incyte, Novartis, Roche, CTI Bio, Geron, Kartos, GSK, MorphoSys, PharmaEssentia, Imago, and Galecto. LCM has received institutional research funding from Jazz Pharmaceuticals, has served in a consulting or advisory role for AbbVie, Curio Science, Celgene Corp, Sierra Oncology, and Nkarta; has received honoraria from the American Society of Hematology, the American Board of Internal Medicine, and the Society of Hematologic Oncology; received royalties from Wintrobe's Publishing; and has served as an expert witness for Incyte Corporation. ASM has served in a consulting or advisory role for AbbVie, Servier, Syndax Pharmaceuticals, Bristol Meyers Squibb, Astellas, Rigel, Zentalis, and Ryvu Therapeutics; has served on a data monitoring safety committee for Jazz Pharmaceuticals, Daiichi Sankyo, and Foghorn Therapeutics; and has served as a medical monitor for the Leukemia and Lymphoma Society Beat AML Study. OP has served in a consulting or advisory role for Scopio Labs, Sysmex America, and F Hoffman-La Roche. KWP Research funding from AbbVie, Agios, Daiichi Sankyo, Millennium; was an advisory board member for AbbVie, Astellas, AstraZeneca, Boston BioMedical, Bristol Myers Squibb, Celgene, Novartis, Roche, Jazz Pharmaceuticals, and Servier. MAS has served on advisory boards for Bristol Meyers Squibb, Novartis, Kurome, and Gilead. CCS has received research funding from AbbVie, Bristol Myers Squibb, Erasca, Revolution Medicines, and Zentalis, and has served on a board of advisory committee for Astellas Pharma, Daichi Sanyko, and Genentech. MSt served on the advisory board for Novartis, Kymera, Sierra Oncology, GSK, and Rigel; consulted for Boston Consulting and Dedham group and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options. MSu receives industry research support from Amgen, Bristol Myers Squibb, Gilead, Janssen, Miltenyi Biotec, Morphosys, Novartis, Roche, Seattle Genetics, and Takeda; serves as a consultant and advisor to AvenCell, CDR-Life, Ichnos Sciences, Incyte Biosciences, Janssen, Molecular Partners, and Takeda; and serves on the speakers' bureau at Amgen, AstraZeneca, Bristol Meyers Squibb, Gilead, GSK, Janssen, Novartis, Pfizer, Roche, and Takeda. GLU served in a consulting role for Novartis and Jazz. MTV received compensation for being a speakers from AbbVie, Bristol Myers Squibb, Astellas, Jazz, Novartis, and Servier; has served in a consulting or advisory role for Jazz and Syros Pharmaceuticals. RBW received laboratory research grants and clinical trial support from Amgen, Aptevo, Celgene, ImmunoGen, Janssen, Jazz Pharmaceuticals, Kura, MacroGenics, and Pfizer; has ownership interests in Amphivena; and served in a consulting role to AbbVie, Adicet, Amphivena, BerGenBio, Bristol Myers Squibb, GlaxoSmithKline, ImmunoGen, Kura, and Orum. ESW has served in a consulting and advisory role for AbbVie, Astellas, Bristol Meyers Squibb, Daiichi Sankyo, Genentech, Gilead, GlaxoSmithKline, Janssen, Jazz, Kite, Kura, Novartis, NuProbe, Pfizer, Rigel, Sellas, and Sumitomo Pharma; has received speaking fees from AbbVie, Astellas, Dava Oncology, Kura Oncology, Novartis, and Pfizer; has served on a data monitoring committee for Abbvie and Gilead; and has served on a research committee for Gilead. JFZ has received honoraria from AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Gilead, Immunogen, Servier, and Shattuck Labs; has served as a consultant for AbbVie, Foghorn, Gilead and Servier; and has received research funding from AbbVie, Arog, Astex, Gilead, Jazz, Merck, Shattuck Labs, Stemline, Sumitomo Dainippon Pharma, and Takeda. AZ has served in a consulting or advisory role for AbbVie, Astellas, Jannsen, Novartis, and Pfizer, and received honoraria from AbbVie, Astellas, Jannsen, Novartis, and Takeda. AMZ has served in a consulting or advisory role for AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, AstraZeneca, BeyondSpring, Boehringer Ingelheim, Cardiff Oncology, Bristol Meyers Squibb, Daiichi Sankyo, Epizyme, Genentech, Gilead, Kura, Incyte, Ionis, Loxo Oncology, Janssen, Novartis; served on clinical trial committees for AbbVie, BioCryst, Bristol Meyers Squibb, Geron, Gilead, Kura, Loxo Oncology, Novartis; has received research funding from AbbVie, Acceleron, ADC Therapeutics, Amgen, Aprea, Astex, Boehringer Ingelheim, Cardiff Oncology, Bristol Meyers Squibb, Incyte, Jasper, Jazz, Novartis, and Pfizer. JPB, RSK, SdB, PD, RD, ND, SDF, MK, TLL, PM, and ACS declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Relapse is the most common cause of mortality in acute myeloid leukemia (AML) patients after allogeneic stem cell transplant (SCT). Post-SCT maintenance strategies that prevent relapse are desirable but must be well tolerated and convenient to administer. We hypothesized single agent venetoclax (ven) may be an effective maintenance therapy among high relapse risk patients. Between February 2019 and December 2021, we administered post-SCT ven maintenance to 49 AML patients at high-risk for relapse as a prospectively defined off-label practice at our institution. Ven was planned to be administered until 1-year post-SCT. While temporary interruptions were common (67.3% of all patients), of those with >1 year follow up, 22/25 (88%) completed the full year of planned therapy. Cytopenias (40.8%) and gastrointestinal adverse events (34.7%) were the most common toxicities. At 1-year post-SCT, overall survival (OS) and relapse-free survival (RFS) were 70% and 67% respectively. Our experience demonstrates single agent ven is a safe, tolerable, and feasible maintenance therapy that may improve RFS and OS in high relapse risk post-SCT patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Hematopoietic stem cell transplantation (HCT) is indicated for patients with higher-risk (HR) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Age, performance status, patient frailty, comorbidities, and nonclinical factors (eg, cost, distance to site) are all recognized as important clinical factors that can influence HCT referral patterns and patient outcomes; however, the proportion of eligible patients referred for HCT in routine clinical practice is largely unknown. This study aimed to assess patterns of consideration for HCT among patients with HR-MDS and AML enrolled in the Connect® Myeloid Disease Registry at community/government (CO/GOV)- or academic (AC)-based sites, as well as to identify factors associated with rates of transplantation referral. We assessed patterns of consideration for and completion of HCT in patients with HR-MDS and AML enrolled between December 12, 2013, and March 6, 2020, in the Connect Myeloid Disease Registry at 164 CO/GOV and AC sites. Registry sites recorded whether patients were considered for transplantation at baseline and at each follow-up visit. The following answers were possible: "considered potentially eligible," "not considered potentially eligible," or "not assessed." Sites also recorded whether patients subsequently underwent HCT at each follow-up visit. Rates of consideration for HCT between CO/GOV and AC sites were compared using multivariable logistic regression analysis with covariates for age and comorbidity. Among the 778 patients with HR-MDS or AML enrolled in the Connect Myeloid Disease Registry, patients at CO/GOV sites were less likely to be considered potentially eligible for HCT than patients at AC sites (27.9% versus 43.9%; P < .0001). Multivariable logistic regression analysis with factors for age (<65 versus ≥65 years) and ACE-27 comorbidity grade (<2 versus ≥2) showed that patients at CO/GOV sites were significantly less likely than those at AC sites to be considered potentially eligible for HCT (odds ratio, 1.6, 95% confidence interval, 1.1 to 2.4; P = .0155). Among patients considered eligible for HCT, 45.1% (65 of 144) of those at CO/GOV sites and 35.7% (41 of 115) of those at AC sites underwent transplantation (P = .12). Approximately one-half of all patients at CO/GOV (50.1%) and AC (45.4%) sites were not considered potentially eligible for HCT; the most common reasons were age at CO/GOV sites (71.5%) and comorbidities at AC sites (52.1%). Across all sites, 17.4% of patients were reported as not assessed (and thus not considered) for HCT by their treating physician (20.7% at CO/GOV sites and 10.7% at AC sites; P = .0005). These findings suggest that many patients with HR-MDS and AML who may be candidates for HCT are not receiving assessment or consideration for transplantation in clinical practice. In addition, treatment at CO/GOV sites and age remain significant barriers to ensuring that all potentially eligible patients are assessed for HCT., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479)., Patients and Methods: Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once-weekly or once-every-2-week maintenance dose. Azacitidine 75 mg/m 2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and complete remission (CR) rate., Results: Ninety-five patients were treated. Revised International Prognostic Scoring System risk was intermediate/high/very high in 27%, 52%, and 21%, respectively. Fifty-nine (62%) had poor-risk cytogenetics and 25 (26%) had TP53 mutation. The most common treatment-emergent adverse effects included constipation (68%), thrombocytopenia (55%), and anemia (52%). Median hemoglobin change from baseline to first postdose assessment was -0.7 g/dL (range, -3.1 to +2.4). CR rate and overall response rate were 33% and 75%, respectively. Median time to response, duration of CR, duration of overall response, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Median overall survival (OS) was not reached with 17.1-month follow-up. In TP53 -mutant patients, 40% achieved CR with median OS of 16.3 months. Thirty-four patients (36%) had allogeneic stem-cell transplant with 77% 2-year OS., Conclusion: Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with TP53 mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ClinicalTrials.gov identifier: NCT04313881 [ENHANCE]).

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Intensive chemotherapy (IC) is commonly used to achieve remission in patients with acute myeloid leukemia (AML). Venetoclax plus azacitidine (VEN-AZA) is FDA-approved to treat patients with AML aged ≥ 75 years or who are ineligible for IC. This retrospective analysis used de-identified electronic health records from the US-based Flatiron Health database from patients diagnosed 11/21/2018 to 10/31/2021 to compare treatment outcomes with VEN-AZA vs. IC. Patients were 1:1 propensity score-matched ([Formula: see text]). Assessments included rates of complete remission (CR) and hematopoietic stem cell transplant (HSCT), overall survival (OS), and relapse-free survival (RFS). CR and HSCT rates were higher with IC than with VEN-AZA (60.9% vs. 44.2% [P = 0.006] and 18.1% vs. 8.0% [P = 0.012], respectively). Median OS was 17.7 months in patients treated with IC and 11.3 months with VEN-AZA without censoring (P = 0.278) and 13.7 vs. 10.6 months, respectively, with censoring at HSCT (P = 0.584). Median RFS was 12.0 months in patients treated with IC vs. 9.5 months with VEN-AZA without censoring (P = 0.431) and 6.4 vs. 7.4 months, respectively, with censoring at HSCT (P = 0.444). No OS or RFS differences observed between the two arms reached statistical significance. Randomized controlled trials comparing the two approaches are warranted, as are novel approaches to reduce relapse rates following CR., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In the year 2021, there were three new Food and Drug Administration approvals for all leukemia types: asciminib (Scemblix) for chronic myeloid leukemia, brexucabtagene autoleucel (Tecartus) for relapsed/refractory B-cell acute lymphocytic leukemia, and asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) for acute lymphocytic leukemia. This is down from 2017-2018 when eight new therapies were approved for acute myeloid leukemia alone. However, this decrease from prior years does not imply that little progress was made in our understanding or treatment of leukemias in 2021. Asciminib and brexucabtagene autoleucel, in particular, are representative of major developing trends. Asciminib, a targeted therapy, is only one of many drugs in development that are products of a bedside-to-bench approach fueled by new sequencing and other genetic technologies that have greatly increased our understanding of the biology behind hematologic diseases. Brexucabtagene autoleucel, an adoptive cell therapy, is the newest of several similar treatments for B cell-associated neoplasms, and it is representative of a massive push to develop novel immunotherapies for a broad range of hematologic malignancies. This commentary reviews the development of asciminib and brexucabtagene autoleucel and describes other major advances in the associated fields of targeted therapy and immunotherapy for leukemias., (© 2022 American Cancer Society.)

This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with incomplete platelet count recovery) rate was 26.0% and morphologic leukemia-free state (MLFS) rate was 12%. For anticipated recommended phase 2 doses (venetoclax 600 mg + idasanutlin 150 mg; venetoclax 600 mg + idasanutlin 200 mg), the combined CRc rate was 34.3% and the MLFS rate was 14.3%. Pretreatment IDH1/2 and RUNX1 mutations were associated with higher CRc rates (50.0% and 45.0%, respectively). CRc rate in patients with TP53 mutations was 20.0%, with responses noted among those with co-occurring IDH and RUNX1 mutations. In 12 out of 36 evaluable patients, 25 emergent TP53 mutations were observed; 22 were present at baseline with low TP53 variant allele frequency (median 0.0095% [range, 0.0006-0.4]). Venetoclax-idasanutlin showed manageable safety and encouraging efficacy in unfit patients with R/R AML. IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were preexisting. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations. This trial was registered at www.clinicaltrials.gov as #NCT02670044., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Molibresib is a selective, small molecule inhibitor of the bromodomain and extra-terminal (BET) protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851)., Patients and Methods: Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), Non-Hodgkin lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T-cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR)., Results: There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg daily (for MDS) and 60 mg daily (for CTCL) were selected. Most common Grade 3+ adverse events included thrombocytopenia (37%), anemia (15%), and febrile neutropenia (15%). Six patients achieved complete responses [3 in Part 1 (2 AML, 1 NHL), 3 in Part 2 (MDS)], and 7 patients achieved partial responses [6 in Part 1 (4 AML, 2 NHL), 1 in Part 2 (MDS)]. The ORRs for Part 1, Part 2, and the total study population were 10% [95% confidence interval (CI), 4.8-18.7], 25% (95% CI, 7.3-52.4), and 13% (95% CI, 6.9-20.6), respectively., Conclusions: While antitumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted., (©2022 The Authors; Published by the American Association for Cancer Research.)

Patients with relapsed/refractory (R/R) higher-risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) after failing hypomethylating agent (HMA) treatment. There is no standard of care for patients after HMA therapy failure; hence, there is a critical need for effective therapeutic strategies. Herein, we present the safety and efficacy of venetoclax + azacitidine in patients with R/R MDS. This phase 1b, open-label, multicenter study enrolled patients ≥18 years. Patients were treated with escalating doses of oral venetoclax: 100, 200, or 400 mg daily for 14 days every 28-day cycle. Azacitidine was administered on Days 1-7 every cycle at 75 mg/m 2 /day intravenously/subcutaneously. Responses were assessed per modified 2006 International Working Group (IWG) criteria. Forty-four patients (male 86%, median age 74 years) received venetoclax + azacitidine treatment. Median follow-up was 21.2 months. Hematological adverse events of Grade ≥ 3 included febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%). Pneumonia (23%) was the most common Grade ≥ 3 infection. Marrow responses were seen including complete remission (CR, n = 3, 7%) and marrow CR (mCR, n = 14, 32%); 36% (16/44) achieved transfusion independence (TI) for RBCs and/or platelets, and 43% (6/14) with mCR achieved hematological improvement (HI). The median time to CR/mCR was 1.2 months, and the median duration of response for CR + mCR was 8.6 months. Median OS was 12.6 months. Venetoclax + azacitidine shows activity in patients with R/R MDS following prior HMA therapy failure and provides clinically meaningful benefits, including HI and TI, and encouraging OS., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Acute myeloid leukemia (AML) is an aggressive hematological malignancy for whom most patients a hematopoietic stem cell transplant (HSCT) is the only curative treatment modality. Intensive chemotherapy has been the first-line treatment for AML for many years but has significant morbidity and mortality in elderly patients and those with comorbidities, who constitute the majority of patients with this disease. Since 2017, multiple new lower intensity therapies have been approved for the treatment of AML. Their advantages include decreased hematological and non-hematological side effects, lower rates of infections and the ability to be given in an outpatient setting. For HSCT, reduced intensity conditioning (RIC) regimens have improved for older and comorbid patients, allowing potent graft vs. tumor effects with lower toxicity profiles, resulting in the expansion of this therapy to more patients. More studies are required to improve and refine lower intensity regimens as well as RIC, as they are increasingly utilized in AML treatment.

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt., Patients and Methods: We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1-28) + azacitidine (75 mg/m2 days 1-7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally., Results: Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared with patients with poor-risk cytogenetics (n = 56) receiving azacitidine alone (TP53wt = 22; TP53mut = 18).For poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and TP53wt.For poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively.For poor-risk cytogenetics + TP53mut patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt patients., Conclusions: In poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients. See related commentary by Green and Zeidner, p. 5235., (©2022 The Authors; Published by the American Association for Cancer Research.)

The advances and progress in the understanding and management of acute leukemia and myelodysplasia continue to occur at an exponential rate. While this has led to more therapy options, clinicians and researchers are now facing more challenges in terms of clinical decision-making and more unanswered questions. This paper has outlined some conundrums in acute leukemia and myelodysplasia, and the efforts that are underway to address these., (Copyright © 2022. Published by Elsevier Ltd.)

Allogeneic hematopoietic stem cell transplantation (SCT) after a patient with acute myeloid leukemia (AML) achieves a remission from intensive chemotherapy (IC) is given with curative intent. Recently, venetoclax-based regimens have become the standard of care for patients with newly diagnosed AML who are unfit for IC. If these patients achieve remission, they may also be considered for potentially curative consolidation with SCT. There are limited data comparing outcomes after SCT with these different induction strategies. The purpose of the current study was to evaluate depth of remission before SCT and outcomes after SCT in adults with nonrelapsed/refractory AML receiving pre-SCT therapy with either venetoclax/azacitidine (ven/aza) or IC. This was a retrospective, single-institution analysis of 169 patients receiving SCT in first remission after IC or ven/aza. Patient demographics and AML risk features were collected, as well as pre-SCT measurable residual disease (MRD) assessed by flow cytometry and molecular methods. Relapse, transplantation-related mortality, incidence of acute and chronic graft-versus-host-disease (GVHD), and death from any cause were also recorded. Descriptive and survival statistics were applied to these data to compare IC and ven/aza groups. Cox proportional hazard models were used for univariate and multivariate analyses. We demonstrate that despite differences in baseline factors between these groups, outcomes were similar. Relapse-free and overall survival, as well as cumulative incidences of transplantation-related mortality, relapse, and acute and chronic GVHD were comparable between groups. Exploring survival in younger (<65 years) versus older (≥65 years) patients by treatment group did not alter these results. Finally, although pre-SCT MRD by flow cytometry was significantly predictive of post-SCT relapse and survival in the IC + SCT patients, it was not significantly predictive of relapse and survival in the ven/aza + SCT patients. Although these findings require prospective validation in a larger cohort of patients, they suggest that ven/aza followed by SCT is a reasonable management strategy for transplantation candidates at any age., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Acute myeloid leukemia (AML) is associated with poor prognosis, particularly in elderly patients with comorbidities. Combining azacitidine (AZA) with BCL-2 inhibitor venetoclax (VEN) demonstrated significant improvement in outcomes for newly-diagnosed AML patients compared to AZA alone. However, this regimen is myelosuppressive, and the incidence of invasive fungal infections (IFIs) and impact of antifungal prophylaxis are not well defined., Methods: This retrospective cohort study evaluated newly-diagnosed AML patients treated with VEN/AZA at the University of Colorado Hospital from January 2014 to August 2020. Patients with history of prior IFI were excluded. Primary outcome was IFI incidence during VEN/AZA therapy. χ 2 and Fisher exact tests assessed the impact of patient demographics, AML-specific risk factors, and receipt of antifungal prophylaxis on IFI incidence., Results: 144 VEN/AZA-treated AML patients were included in the study. 25 (17%) patients developed IFI: 8% (n = 2) "proven," 24% (n = 6) "probable," and 68% (n = 17) "possible" per European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium criteria. There was no statistically significant association between IFI incidence with age, sex, or European LeukemiaNet classification. 10 patients received antifungal prophylaxis; none developed IFI. IFI incidence rate per 1000 patient-days was greatest 0-9 days after starting VEN/AZA, at 8.39., Conclusions: Incidence of "proven" and "probable" IFI in our VEN/AZA-treated AML cohort was 5.6%, in-line with incidence rates reported by recent similar studies. Furthermore, IFI incidence decreased as days from starting VEN/AZA therapy increased., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML., Competing Interests: Declaration of interests C.E.T. receives research support from Notable Labs and serves as a scientific liaison for AstraZeneca. J.E.M. receives research funding from Gilead Pharmaceutical and serves on a scientific advisory board for Ionis Pharmaceuticals. M.W.D. serves on the advisory boards and/or as a consultant for Novartis, Incyte, and BMS and receives research funding from BMS and Gilead. C.S.H. receives research funding from Sellas. T.L.L. consults for Jazz Pharmaceuticals and receives research funding from Tolero, Gilead, Prescient, Ono, Bio-Path, Mateon, Genentech/Roche, Trovagene, AbbVie, Pfizer, Celgene, Imago, Astellas, Karyopharm, Seattle Genetics, and Incyte. D.A.P. receives research funding from Pfizer and Agios and served on advisory boards for Pfizer, Celyad, Agios, Celgene, AbbVie, Argenx, Takeda, and Servier. B.J.D. serves on the advisory boards for Aileron Therapeutics, Aptose, Blueprint Medicines, Cepheid, EnLiven Therapeutics, Gilead, GRAIL, Iterion Therapeutics, Nemucore Medical Innovations, the Novartis CML Molecular Monitoring Steering Committee, Recludix Pharma, the RUNX1 Research Program, ALLCRON Pharma, VB Therapeutics, Vincerx Pharma, and the Board of Directors for Amgen, and receives research funding from EnLiven and Recludix. B.J.D. is principal investigator or co-investigator on Novartis, BMS, and Pfizer clinical trials. His institution, OHSU, has contracts with these companies to pay for patient costs, nurse and data manager salaries, and institutional overhead, but he does not derive salary, nor does his laboratory receive funds, from these contracts. J.W.T. has received research support from Acerta, Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Kronos, Meryx, Petra, Schrodinger, Seattle Genetics, Syros, Takeda, and Tolero and serves on the advisory board for Recludix Pharma. The authors certify that all compounds tested in this study were chosen without input from any of our industry partners. A subset of findings from this manuscript have been included in a pending patent application., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The clinical benefit of adding venetoclax (VEN) to hypomethylating agents or low-dose cytarabine in older and/or unfit patients with newly diagnosed acute myeloid leukemia (AML) has been confirmed in phase 3 studies. With the increased uptake of VEN-based therapies for patients with AML, a pertinent question is whether treatment can be safely ceased among patients who have achieved sustained remission. We hypothesized that a proportion of patients opting to cease therapy may benefit from a treatment-free remission (TFR) period without indefinite treatment. We report the retrospective outcomes of 29 patients in remission for a minimum of 12 months on VEN-based therapy, with 55% continuing therapy until disease progression and 45% electively ceasing treatment (STOP). With follow-up exceeding 5 years, we observed a median TFR lasting 45.8 months among the STOP cohort, with >50% of patients still in sustained remission at the data cutoff. The risk of relapse and duration of relapse-free and overall survival were similar between the 2 cohorts. Factors favoring sustained TFR within the cohort included NPM1 and/or IDH2 mutation at diagnosis, complete remission without measurable residual disease, and at least 12 months of VEN-based combination therapy prior to treatment cessation., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: 21q22 amplification is a rare cytogenetic aberration in acute myeloid leukemia (AML). So far, the cytogenomic and molecular features and clinical correlation of 21q22 amplification in AML have not been well-characterized., Case Presentation: Here, we describe a case series of three AML patients with amplified 21q22 identified by fluorescence in situ hybridization using a RUNX1 probe. Two of these patients presented with therapy-related AML (t-AML) secondary to chemotherapy, while the third had de novo AML. There was one case each of FAB M0, M1 and M4. Morphologic evidence of dysplasia was identified in both t-AML cases. Phenotypic abnormalities of the myeloblasts were frequently observed. Extra copies of 21q22 were present on chromosome 21 and at least one other chromosome in two cases. Two showed a highly complex karyotype. Microarray analysis of 21q22 amplification in one case demonstrated alternating levels of high copy number gain split within the RUNX1 locus at 21q22. The same patient also had mutated TP53. Two patients died at 1.5 and 11 months post-treatment, while the third elected palliative care and died within 2 weeks., Conclusions: Our results provide further evidence that 21q22 amplification in AML is associated with complex karyotypes, TP53 aberrations, and poor outcomes. Furthermore, we demonstrate that 21q22 amplification is not always intrachromosomally localized to chromosome 21 and could be a result of structural aberrations involving 21q22 and other chromosomes., (© 2022. The Author(s).)

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML)., Patients and Methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1-28) and azacitidine (75 mg/m2; days 1-7/28-day cycle)., Results: In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group., Conclusions: Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut. See related commentary by Perl and Vyas, p. 2719., (©2022 The Authors; Published by the American Association for Cancer Research.)

The Food and Drug Administration Oncology Center of Excellence initiated Project 2025 to develop 5-year goals in specific areas of oncology drug development. This meeting, in October 2020, brought together a panel of regulators and academic experts in acute myeloid leukemia (AML) to discuss opportunities to maximize the success that has recently occurred in AML drug development. The panel discussed challenges and opportunities in clinical trial design and novel endpoints, and outlined key considerations for drug development to facilitate continued growth in the field., (©2021 American Association for Cancer Research.)

Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, we curated 1547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 acute myeloid leukemia (AML) patients (13.6%) in 34 genes, including 6.39% (25/391) of patients harboring P/LP variants in genes considered clinically actionable (tier 1). 41.5% of the 53 patients with P/LP variants were in genes associated with the DNA damage response. The most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, and SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, 6 patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in silico approach that applies ACMG curation in an automated manner using the tool for assessment and (TAPES) prioritization in exome studies, which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families., (© 2022 by The American Society of Hematology.)

We present primary results from the phase 1b GO29754 study evaluating the safety and tolerability of atezolizumab, a programmed death-ligand 1 inhibitor, alone and in combination with azacitidine, a hypomethylating agent (HMA), in patients with relapsed/refractory (R/R) or HMA-naïve myelodysplastic syndrome (MDS). Patients with R/R MDS received atezolizumab for 12 months (cohort A) or atezolizumab plus azacitidine for 6 cycles followed by atezolizumab as maintenance for 8 cycles (cohort B). Patients with HMA-naïve MDS received atezolizumab plus azacitidine until loss of clinical benefit (cohort C). Safety, activity, and exploratory end points were investigated. Forty-six patients were enrolled and received treatment (cohort A, n = 11; cohort B, n = 14; cohort C, n = 21). All patients experienced ≥1 adverse event (AE) on study, and all patients discontinued atezolizumab. In cohort A, 7 patients (63.6%) died, and no patients responded. In cohort B, 8 patients (57.1%) discontinued azacitidine, 11 (78.6%) died, and 2 (14.3%) responded. In cohort C, all 21 patients discontinued azacitidine, 13 died (61.9%), and 13 (61.9%) responded. The study was terminated by the sponsor before completion of recruitment because of the unexpected high early death rate in cohort C (6 [46.2%] of 13 deaths were due to AEs and occurred within the first 4 treatment cycles.). The high death rate and poor efficacy observed in this study do not support a favorable risk-benefit profile for atezolizumab as a single agent or in combination with azacitidine in R/R or HMA-naïve MDS. This trial was registered at www.clinicaltrials.gov as #NCT02508870., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The combination of venetoclax (ven) and azacitidine (aza) has resulted in high response rates in the upfront treatment of AML in patients age > 75 and patients unfit for intensive chemotherapy. Given the poor historical outcomes in patients age ≥ 60 treated with induction chemotherapy, ven/aza has become our institutional preference for the initial treatment of non-core binding factor (CBF) AML patients age ≥ 60. The benefit of allogeneic stem cell transplant (SCT) in patients who achieve response to ven/aza is uncertain. We report outcomes of SCT-eligible patients treated at our center. Between 1/2015 and 1/2020, 119 newly diagnosed non-CBF AML patients age ≥ 60 received ven/aza as initial therapy. 21 patients underwent SCT; 31 additional patients were potentially SCT eligible but deferred SCT. Overall survival (OS) was significantly greater among SCT patients (median survival not reached) versus potentially SCT eligible patients not undergoing SCT (median 518 days) (p = 0.01). Our data suggest that ven/aza followed by SCT in newly diagnosed AML patients older than ≥ 60 results in excellent outcomes and likely improves outcomes over maintenance therapy. Ongoing investigation will further refine the optimal timing of and selection of patients for SCT based on prognostic disease features and response assessments., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Acute myeloid leukemia (AML) is characterized by the presence of leukemia stem cells (LSCs), and failure to fully eradicate this population contributes to disease persistence/relapse. Prior studies have characterized metabolic vulnerabilities of LSCs, which demonstrate preferential reliance on oxidative phosphorylation (OXPHOS) for energy metabolism and survival. In the present study, using both genetic and pharmacologic strategies in primary human AML specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates OXPHOS in LSCs. STAT3 regulates AML-specific expression of MYC, which in turn controls transcription of the neutral amino acid transporter gene SLC1A5. We show that genetic inhibition of MYC or SLC1A5 acts to phenocopy the impairment of OXPHOS observed with STAT3 inhibition, thereby establishing this axis as a regulatory mechanism linking STAT3 to energy metabolism. Inhibition of SLC1A5 reduces intracellular levels of glutamine, glutathione, and multiple tricarboxylic acid (TCA) cycle metabolites, leading to reduced TCA cycle activity and inhibition of OXPHOS. Based on these findings, we used a novel small molecule STAT3 inhibitor, which binds STAT3 and disrupts STAT3-DNA, to evaluate the biological role of STAT3. We show that STAT3 inhibition selectively leads to cell death in AML stem and progenitor cells derived from newly diagnosed patients and patients who have experienced relapse while sparing normal hematopoietic cells. Together, these findings establish a STAT3-mediated mechanism that controls energy metabolism and survival in primitive AML cells., (© 2022 by The American Society of Hematology.)

Venetoclax (ven) plus azacitidine (aza) is the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (IC). Some patients who are IC candidates instead receive ven/aza. We retrospectively analyzed patients with newly diagnosed AML who received ven/aza (n = 143) or IC (n = 149) to compare outcomes, seek variables that could predict response to 1 therapy or the other, and ascertain whether treatment recommendations could be refined. The response rates were 76.9% for ven/aza and 70.5% for IC. The median overall survival (OS) was 884 days for IC compared with 483 days for ven/aza (P = .0020). A propensity-matched cohort was used to compare outcomes in the setting of equivalent baseline variables, and when matched for age, biological risk, and transplantation, the median OS was 705 days for IC compared with not reached for ven/aza (P = .0667). Variables that favored response to ven/aza over IC included older age, secondary AML, and RUNX1 mutations. AML M5 favored response to IC over ven/aza. In the propensity-matched cohort analyzing OS, older age, adverse risk, and RUNX1 mutations favored ven/aza over IC, whereas intermediate risk favored IC over ven/aza. In conclusion, patients receiving IC have improved OS compared with those receiving ven/aza. However, in a propensity-matched cohort of patients with equivalent baseline factors, there was a trend toward favorable OS for ven/aza. Specific variables, such as RUNX1 mutations, reported here for the first time, can be identified that favor ven/aza or IC, helping to guide treatment decisions for patients who may be eligible candidates for either therapy., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The use of venetoclax in combination with hypomethylating agents (HMA) has changed the paradigm for the treatment of acute myeloid leukemia (AML) in elderly patients and those unfit for intensive chemotherapy. A phase 3 study has shown superior response rates and improved overall survival for patients treated with venetoclax + azacitidine compared with the previous standard of care, azacitidine alone. This success has led to multiple exciting follow-up studies, including investigations related to the discovery of predictors of response, relapse, and the mechanism of action of this therapy. While venetoclax + HMA has shown significant benefit in elderly patients unfit for chemotherapy, further questions remain as to how this therapy can be expanded into other populations including relapsed or refractory patients and younger newly diagnosed patients with adverse risk features. In this article, we discuss the clinical outcomes of AML with venetoclax + HMA, established and potential predictors of response to this regimen, its mechanisms of action, and speculate on the future of venetoclax + HMA therapy in AML., (Copyright © 2021 Elsevier Inc. All rights reserved.)