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Verner-Morrison syndrome, characterized by diarrhea, hypokalemia, and hypochlorhydria, is caused most commonly by vasoactive intestinal polypeptide-secreting islet cell tumors of the pancreas. Verner-Morrison syndrome has not been described as a paraneoplastic syndrome in non-small cell lung cancer. We describe a 38-year-old man with metastatic non-small cell lung cancer of large cell carcinoma with neuroendocrine differentiation who presented with bone metastasis and intractable secretory diarrhea that was unresponsive to pharmacological treatment, including octreotide. Laboratory evaluation indicated elevated serum calcitonin and vasoactive intestinal polypeptide levels. Chemotherapy resulted in a transient response in the patient's diarrhea and neuroendocrine markers. The patient did not respond to further therapy and died 5 months after onset of back pain. To our knowledge, this is the first published case of large cell carcinoma with neuroendocrine differentiation associated with treatment-responsive paraneoplastic Verner-Morrison syndrome. [ABSTRACT FROM AUTHOR]

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.)

Background: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission., Methods: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1 -negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point., Results: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group., Conclusions: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.)., (Copyright © 2024 Massachusetts Medical Society.)

Hematologic malignancies disproportionately affect older adults. Hematopoietic cell transplantation (HCT) is potentially curative, but poor overall survival (OS) has limited its use in older adults. Fried's frailty phenotype (FFP) is a geriatric assessment tool that combines objective and subjective performance measures: gait speed, grip strength, activity level, exhaustion, and weight loss. People meeting ≥3 criteria are classified as frail; 1 or 2 criteria, as pre-frail; and 0 criteria, as fit. To evaluate the association of pre-HCT FFP with post-HCT outcomes, we assessed FFP prior to conditioning for 280 HCT recipients age ≥60 years with acute leukemia or a myeloid neoplasm at 3 institutions. When analyzing survival by age group, patients age ≥70 years had inferior OS compared to patients age 60 to 69 years (P = .002), with corresponding OS estimates of 38.9% (95% confidence interval [CI], 27.8% to 49.9%) and 59.3% (95% CI, 51.9% to 65.9%). Nonrelapse mortality (NRM) also was significantly higher in the older patients (P = .0005); the 2-year cumulative incidences of NRM were 38.5% (95% CI, 27.5% to 49.2%) and 17.2% (95% CI, 12.3% to 22.8%), for older and younger recipients, respectively. The cumulative incidences of relapse did not differ by age group (P = .3435). Roughly one-third (35.5%) of the patients were fit, 57.5% were pre-frail, and 7.5% were frail, with corresponding 2-year OS estimates of 68.4% (95% CI, 57.9% to 76.8%), 45.5% (95% CI, 37.4% to 53.2%), and 45.8% (95% CI, 23.4% to 65.8%) (P = .013). FFP was not significantly associated with NRM, but being frail or pre-frail was associated with a higher rate of disease-related deaths (33.3% and 27.3%, respectively, compared with 17.4% for fit patients; P = .043). In univariate modeling of restricted mean survival time with a 3-year horizon (RMST&#95;3y), the factors that were significantly associated were FFP, age, Karnofsky Performance Status (KPS), Disease Risk Index (DRI), and HCT-specific Comorbidity Index (HCT-CI). Of those factors, only FFP (P = .006), age (P = .006), KPS (P = .004), and DRI (P = .005) were significantly associated in multivariate modeling of RMST&#95;3y. Estimates of RMST&#95;3y were computed and 5 risk-groups were created with survival ranging from 31.4 months for those who were age 60 to 69 years, fit, had KPS 90 to 100, and low/intermediate-risk DRI compared to 10.5 months for those who had high-risk features for all the evaluated factors. In univariate and multivariate analyses for restricted mean time to relapse with a 3-year horizon (RMRT&#95;3y), FFP (pre-frail versus fit, P = .007; frail versus fit, P = .061) and DRI (P = .001) were the only significant factors. Predicted RMRT&#95;3y was longest (30.6 months) for those who were fit and had low/intermediate-risk DRI scores and shortest (19.1 months) for those who were frail and had high-risk or very high-risk DRI scores. Both age and FFP impact survival after HCT. Incorporation of FFP into pre-HCT evaluations may improve decision-making and counseling regarding HCT risk for older adults. Our findings support future trials designed to reverse frailty, such as pre-HCT supervised exercise programs, and correlative analyses to unravel the connection of frailty and relapse to generate future targets for intervention. Finally, exploration of novel HCT platforms to reduce relapse in pre-frail and frail patients, as well as reduce NRM in adults age >70 years, are warranted., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Purpose: Gilteritinib is a type 1 FLT3 inhibitor active as monotherapy for relapsed or refractory FLT3 -mutated AML. We investigated the safety, tolerability, and efficacy of gilteritinib incorporated into intensive induction and consolidation chemotherapy, and as maintenance therapy for adult patients with newly diagnosed, non-favorable-risk AML., Methods: In this phase IB study (2215-CL-0103; ClinicalTrials.gov identifier: NCT02236013), 103 participants were screened and 80 were allocated to treatment. The study was divided into four parts: dose escalation, dose expansion, investigation of alternate anthracycline and gilteritinib schedule, and continuous gilteritinib during consolidation., Results: After dose escalation, 120 mg gilteritinib once daily was chosen for further study. There were 58 participants evaluable for response at this dose, 36 of whom harbored FLT3 mutations. For participants with FLT3 -mutated AML, the composite complete response (CRc) rate was 89% (83% were conventional complete responses), all achieved after a single induction cycle. The median overall survival time was 46.1 months. Gilteritinib was well-tolerated in this context although the median time to count recovery during induction was approximately 40 days. Longer time-to-count recovery was associated with higher trough levels of gilteritinib, which, in turn, were associated with azole use. The recommended regimen is gilteritinib at a dose of 120 mg once daily from days 4 to 17 or 8 to 21 of a 7 + 3 induction with either idarubicin or daunorubicin and from day 1 continuously with high-dose cytarabine consolidation. Maintenance therapy with gilteritinib was well-tolerated., Conclusion: These results demonstrated the safety and tolerability of gilteritinib incorporated into an induction and consolidation chemotherapy regimen, and as single-agent maintenance therapy for patients with newly diagnosed FLT3 -mutant AML. The data herein provide an important framework for the design of randomized trials comparing gilteritinib with other FLT3 inhibitors.

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.)

Intensive chemotherapy with cytarabine and anthracycline (7&3) remains the standard therapy for patients medically fit for induction, but the assessment of fitness remains controversial. Venetoclax and hypomethylating agent (ven/HMA) combination therapy has improved outcomes in unfit patients but no prospective study has assessed ven/HMA versus 7&3 as initial therapy in older, fit patients. Given no studies and expectation of ven/HMA use in patients outside of trial criteria, we evaluated retrospective outcomes among newly diagnosed patients. A nationwide electronic health record (EHR)-derived database and the University of Pennsylvania EHR identified 312 patients receiving 7&3 and 488 receiving ven/HMA who were 60-75 years old without history of organ failure. Ven/HMA patients were older and more likely to have secondary AML, adverse cytogenetics, and adverse mutations. Median overall survival (OS) for patients receiving intensive chemotherapy was 22 versus 10 months for ven/HMA (HR 0.53, 95% CI 0.40-0.60). Controlling for measured baseline characteristic imbalances reduced survival advantage by half (HR 0.71, 95% CI 0.53-0.94). A sub-group of patients with equipoise, likelihood at least 30%-70% of receiving either treatment, had similar OS outcomes (HR 1.10, 95% CI 0.75-1.6). Regarding safety outcomes, 60-day mortality was higher for ven/HMA (15% vs. 6% at 60 days) despite higher documented infections and febrile neutropenia for 7&3. In this multicenter real-word dataset, patients selected for intensive chemotherapy had superior OS but a large group had similar outcomes with ven/HMA. Prospective randomized studies, controlling for both measured and unmeasured confounders, must confirm this outcome., (© 2023 Wiley Periodicals LLC.)

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes., (© 2023. The Author(s).)

Mivavotinib (TAK-659) is an investigational type 1 tyrosine kinase inhibitor with dual activity against spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 (FLT3). We conducted a phase Ib study to investigate the safety, tolerability, and efficacy of mivavotinib in patients with refractory and/or relapsed (R/R) acute myeloid leukemia (AML). Both daily (QD) and twice daily (BID) dosing regimens were evaluated. A total of 43 patients were enrolled, and there were 5 complete responses (4 with incomplete count recovery). In the QD dosing regimen, the maximum tolerated dose (MTD) was not reached up to 160 mg QD per protocol; 140 mg QD was identified as the recommended phase II dose. In the BID dosing regimen, the MTD was 60 mg BID. Thirty patients (70%) experienced a bleeding event on study; the majority were grades 1 or 2, were resolved without mivavotinib modification, and were not considered related to study treatment. Eleven patients (26%) experienced grade ≥3 bleeding events, which were observed most frequently with the 80 mg BID dose. We conducted platelet aggregation studies to investigate the potential role of mivavotinib-mediated SYK inhibition on platelet function. The bleeding events observed may have been the result of several confounding factors, including AML disease status, associated thrombocytopenia, and high doses of mivavotinib. Overall, these findings indicate that the activity of mivavotinib in R/R AML is modest. Furthermore, any future clinical investigation of this agent should be undertaken with caution, particularly in thrombocytopenic patients, due to the potential bleeding risk of SYK inhibition. ClinicalTrials.gov: NCT02323113.

Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n = 55) or refractory myelodysplastic syndrome (MDS; n = 12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P = .05) and 2-year OS (39% versus 70%; P = .04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

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.)

Acute myeloid leukemia (AML) secondary to antecedent hematologic disorder or prior therapeutics for cancer represent a diverse group of leukemias often associated with inferior outcomes. Conventional therapy with cytarabine-based chemotherapy has been the mainstay of care for the past 30 years with disappointing overall outcomes. Novel therapies, including liposomal cytarabine/daunorubicin, and venetoclax-based therapies have emerged as options in recent years based on studies showing improvement in outcomes over standard-of-care therapies. Despite these advances, mutations in TP53 are associated with inferior response to both therapies and represent an area of unmet clinical need. Novel strategies with immune-targeted therapies such as CD47 monoclonal antibodies appear active in early-phase studies, but randomized studies have yet to report outcomes leading to approval. Allogeneic transplant remains the only known curative therapy for many of these cases. Nonetheless, pretransplant high-risk molecular features of secondary AML are associated with inferior outcome despite transplantation. An optimal approach to secondary AML is yet to be determined., (Copyright © 2022 by The American Society of Hematology.)

After forty years of essentially unchanged treatment in acute myeloid leukemia (AML), innovation over the past five years has been rapid, with nine drug approvals from 2016 to 2021. Increased understanding of the molecular changes and genetic ontology of disease have led to targeting mutations in isocitrate dehydrogenase, FMS-like tyrosine kinase 3 ( FLT3 ), B-cell lymphoma 2 and hedgehog pathways. Yet outcomes remain variable; especially in defined molecular and genetic subgroups such as NPM1 (Nucleophosmin 1) mutations, 11q23/ KMT2A rearranged and TP53 mutations. Emerging therapies seek to address these unmet needs, and all three of these subgroups have promising new therapeutic approaches. Here, we will discuss the normal biological roles of menin in acute leukemia, notably in KMT2A translocations and NPM1 mutation, as well as current drug development. We will also explore how CD47 inhibition may move immunotherapy into front-line settings and unlock new treatment strategies in TP53 mutated disease. We will then consider how these new therapeutic advances may change the management of AML overall.

Objectives: Using individual patient-level data from the phase 3 VIALE-A trial, this study assessed the cost-effectiveness of venetoclax in combination with azacitidine compared with azacitidine monotherapy for patients newly diagnosed with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy, from a United States (US) third-party payer perspective., Methods: A partitioned survival model with a 28-day cycle and three health states (event-free survival (EFS), progressive/relapsed disease, and death) was developed to estimate costs and effectiveness of venetoclax + azacitidine versus azacitidine over a lifetime (25-year) horizon. Efficacy inputs (overall survival (OS), EFS, and complete remission (CR)/CR with incomplete marrow recovery (CRi) rate) were estimated using VIALE-A data. Best-fit parametric models per Akaike Information Criterion were used to extrapolate OS until reaching EFS and extrapolate EFS until Year 5. Within EFS, the time spent in CR/CRi was estimated by applying the CR/CRi rate to the EFS curve. Past Year 5, patients still in EFS were considered cured and to have the same mortality as the US general population. Mean time on treatment (ToT) for both regimens was based on the time observed in VIALE-A. Costs of drug acquisition, drug administration (initial and subsequent treatments), subsequent stem cell transplant procedures, adverse events (AEs), and healthcare resource utilization (HRU) associated with health states were obtained from the literature/public data and inflated to 2021 US dollars. Health state utilities were estimated using EuroQol-5 dimension-5 level data from VIALE-A; AE disutilities were obtained from the literature. Incremental cost-effectiveness ratios (ICERs) per life-year (LY) and quality-adjusted life-year (QALY) gained were estimated. Deterministic sensitivity analyses (DSA), scenario analyses, and probabilistic sensitivity analyses (PSA) were also performed., Results: Over a lifetime horizon, venetoclax + azacitidine versus azacitidine led to gains of 1.89 LYs (2.99 vs. 1.10, respectively) and 1.45 QALYs (2.30 vs. 0.84, respectively). Patients receiving venetoclax + azacitidine incurred higher total lifetime costs ($250,486 vs. $110,034 (azacitidine)). The ICERs for venetoclax + azacitidine versus azacitidine were estimated at $74,141 per LY and $96,579 per QALY gained. Results from the DSA and scenario analyses supported the base-case findings, with ICERs ranging from $60,718 to $138,554 per QALY gained. The results were most sensitive to varying the parameters for the venetoclax + azacitidine base-case EFS parametric function (Gompertz), followed by alternative approaches for ToT estimation, treatment costs of venetoclax + azacitidine, standard mortality rate value and ToT estimation, alternative sources to inform HRU, different cure modeling assumptions, and the parameters for the venetoclax + azacitidine base-case OS parametric function (log-normal). Results from the PSA showed that, compared with azacitidine, venetoclax + azacitidine was cost-effective in 99.9% of cases at a willingness-to-pay threshold of $150,000 per QALY., Conclusions: This analysis suggests that venetoclax + azacitidine offers a cost-effective strategy in the treatment of patients with newly diagnosed AML who are ineligible for intensive chemotherapy from a US third-party payer perspective., Trial Registration: ClinicalTrials.gov, NCT02993523. Date of registration: 15 December 2016., (© 2022. The Author(s).)

CPX-351 and venetoclax and azacitidine (ven/aza) are both indicated as initial therapy for acute myeloid leukemia (AML) in older adults. In the absence of prospective randomized comparisons of these regimens, we used retrospective observational data to evaluate various outcomes for patients with newly diagnosed AML receiving either CPX-351 (n = 217) or ven/aza (n = 439). This study used both a nationwide electronic health record (EHR)-derived de-identified database and the University of Pennsylvania EHR. Our study includes 217 patients who received CPX-351 and 439 who received ven/aza. Paitents receiving ven/aza were older, more likely to be treated in the community, and more likely to have a diagnosis of de novo acute myeloid leukemia. Other baseline covariates were not statistically significantly different between the groups. Median overall survival (OS) for all patients was 12 months and did not differ based on therapy (13 months for CPX-351 vs 11 months for ven/aza; hazard ratio, 0.88; 95% confidence interval, 0.71-1.08; P = .22). OS was similar across multiple sensitivity analyses. Regarding safety outcomes, early mortality was similar (10% vs 13% at 60 days). However, documented infections were higher with CPX-351 as were rates of febrile neutropenia. Hospital length of stay, including any admission before the next cycle of therapy, was more than twice as long for CPX-351. In this large multicenter real-world dataset, there was no statistically significant difference in OS. Prospective randomized studies with careful attention to side effects, quality of life, and impact on transplant outcomes are needed in these populations., (© 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.)

Limited treatment options exist for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Venetoclax (VEN) in combination with a hypomethylating agent (HMA) or low-dose cytarabine (LDAC) has been recently approved for treatment-naïve patients unfit for intensive induction. Limited data are available to characterize the efficacy of VEN combinations in R/R AML. We retrospectively analyzed 77 patients with a median of 1 prior therapy (range 0-5) treated with VEN combinations for R/R AML or AML secondary to myelodysplastic syndrome (MDS) progressing after HMA monotherapy. The median overall survival (OS) was 13.1 months (95% CI 9.2-15.1). The median progression-free survival (PFS) was 12 months (95% CI 8.2-15.4) with a median duration of response of 8.9 months (95% CI 5.7-13.9). Overall response rate (ORR) was 68% with a composite complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 53%. VEN combination therapy is efficacious in R/R AML and further prospective studies are warranted.

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with FLT3-mutant acute myeloid leukemia., 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). FLT3 mutation was analyzed centrally on pretreatment bone marrow aspirates., Results: In the biomarker evaluable population, FLT3 mutation was detected in 42 (15%) and 22 (19%) 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) for FLT3-mutant patients were 67%/36%, median duration of remission (DoR) was 17.3/5.0 months, and median OS was 12.5/8.6 months. The CRc rates among FLT3 wild-type patients were 67%/25%, median DoR 18.4/13.4 months, and median OS 14.7/10.1 months. In patients treated with venetoclax + azacitidine, CRc in patients with FLT3-ITD and FLT3-TKD was 63% and 77% and median OS was 9.9 and 19.2 months, and in comutated FLT3-ITD + NPM1 patients, CRc was 70%, median DoR was not reached, and median OS was 9.1 months. There were no unexpected toxicities in the venetoclax + azacitidine group., Conclusions: When treated with venetoclax + azacitidine, patients with FLT3 mutations and FLT3 wild-type had similar outcomes. Future analyses in larger patient populations may further define the impact of venetoclax + azacitidine in patients harboring FLT3-ITD. See related commentary by Perl and Vyas, p. 2719., (©2022 The Authors; Published by the American Association for Cancer Research.)

Introduction: Granulocyte colony-stimulating factor (G-CSF) hastens neutrophil engraftment and reduces infections after allogeneic hematopoietic cell transplant (alloHCT), yet the optimal start date is unknown. Additionally, concurrent G-CSF and methotrexate for graft-vs-host disease (GVHD) prophylaxis may potentiate myelosuppression, and prolonged G-CSF is costly. Our institution changed from day + 4 to day + 12 G-CSF initiation following reduced intensity (RIC) alloHCT with methotrexate GVHD prophylaxis., Methods: We retrospectively compared day + 4 and day + 12 G-CSF initiation after RIC alloHCT from 2017-2021. The primary endpoint was the time to neutrophil engraftment. Secondary endpoints included length of stay (LOS) and the time to platelet engraftment as well as the incidence of infectious events, acute GVHD (aGVHD), and mucositis., Results: Thirty-two patients were included in each group with similar baseline characteristics. We observed faster neutrophil engraftment (median 12 vs. 15 days, p = 0.01) and platelet engraftment (median 13 vs. 15 days, p = 0.026) with day + 4 vs. day + 12 G-CSF initiation. Median LOS was 23 days (range, 19-32) with day + 4 initiation vs. 24 days (21-30) with day + 12 (p = 0.046). The incidence of culture-negative febrile neutropenia (p = 0.12), any grade aGVHD (p = 0.58), and grade 2-4 mucositis (p = 0.8) were similar between groups., Conclusion: Compared to day + 4, day + 12 G-CSF initiation following RIC alloHCT had a longer time to neutrophil and platelet engraftment. Day + 12 initiation also resulted in longer LOS, which while statistically significant, was potentially of limited clinical significance. These findings are hypothesis generating.

Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups were analyzed using Kaplan-Meier and unadjusted log-rank analyses. VEN + AZA vs PBO + AZA patients had longer TTD in GHS/QoL (P = 0.066) and fatigue (P = 0.189), and significantly longer TTD in PF (P = 0.028) and HS-VAS (P < 0.001). VEN + LDAC vs PBO + LDAC patients had significantly longer TTD in GHS/QoL (P = 0.011), PF (P = 0.020), and fatigue (P = 0.004), and a trend in HS-VAS (P = 0.057). Approximately 43%, 35%, 32%, and 18% of patients treated with VEN + AZA, AZA + PBO, VEN + LDAC, or LDAC + PBO, respectively, saw improvements >MCT in GHS/QoL. Overall, VEN may positively impact HRQoL in patients with AML ineligible for intensive chemotherapy, leading to longer preservation of functioning and overall health status., (© 2022. The Author(s).)

Purpose: There is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD < 10 -3 in the VIALE-A trial., Methods: The patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as < 1 residual blast per 1,000 leukocytes (< 10 -3 or 0.1%) with an estimated analytic sensitivity of 0.0037%-0.0027%. CRc, duration of remission (DoR), event-free survival (EFS), and overall survival (OS) were assessed. A multivariate Cox regression analysis identified prognostic factors associated with OS., Results: One hundred sixty-four of one hundred ninety (86%) patients with CRc were evaluable for MRD. MRD < 10 -3 was achieved by 67 of 164 (41%), and 97 of 164 (59%) had MRD ≥ 10 -3 . The median DoR, EFS, and OS were not reached in patients with CRc and MRD < 10 -3 , and the 12-month estimates for DoR, EFS, and OS in this group were 81.2%, 83.2%, and 94.0%. Among patients with CRc and MRD ≥ 10 -3 , the median DoR, EFS, and OS were 9.7, 10.6, and 18.7 months. Multivariate analysis showed that CRc with MRD < 10 -3 was a strong predictor of OS (adjusted hazard ratio = 0.285; 95% CI, 0.159 to 0.510; P < .001)., Conclusion: Patients who achieved CRc and MRD < 10 -3 with venetoclax and azacitidine had longer DoR, EFS, and OS, than responding patients with MRD ≥ 10 -3 ., Competing Interests: Keith W. PratzConsulting or Advisory Role: Astellas Pharma, Boston Biomedical, AbbVieResearch Funding: Agios (Inst), Millennium (Inst), AbbVie (Inst), Daiichi Sankyo (Inst) Brian A. JonasConsulting or Advisory Role: AbbVie, Jazz Pharmaceuticals, GlycoMimetics, Treadwell Therapeutics, Takeda, Genentech, Bristol Myers Squibb/Pfizer, PfizerResearch Funding: Daiichi Sankyo (Inst), AbbVie (Inst), Pharmacyclics (Inst), Genentech/Roche (Inst), Glycomimetics (Inst), Celgene (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Arog (Inst), Roche (Inst), Jazz Pharmaceuticals (Inst), Pfizer (Inst), Sigma-Tau (Inst), Forty Seven¸ Amgen (Inst), Immune-Onc Therapeutics (Inst), Loxo (Inst), Gilead/Forty Seven (Inst)Travel, Accommodations, Expenses: AbbVie Vinod PullarkatConsulting or Advisory Role: Novartis, Amgen, Pfizer, Jazz Pharmaceuticals, AbbVie/GenentechSpeakers' Bureau: Novartis, Amgen, Jazz Pharmaceuticals, AbbVie Christian RecherConsulting or Advisory Role: Celgene, Amgen, Novartis, Jazz Pharmaceuticals, AbbVie, Janssen, Astellas Pharma, MacroGenics¸ Daiichi Sankyo, Otsuka, Novartis¸ Incyte, Pfizer¸ Roche, TakedaResearch Funding: Celgene (Inst), Amgen (Inst), Jazz Pharmaceuticals (Inst), Astellas Pharma (Inst), Agios (Inst), Daiichi Sankyo (Inst), MaaT Pharma (Inst), Roche (Inst), AbbVie (Inst), Novartis (Inst), Chugai Pharma (Inst), IQVIA (Inst)Travel, Accommodations, Expenses: Incyte, Celgene, Sanofi, Amgen, Novartis, Daiichi Sankyo, Gilead Sciences Andre C. SchuhHonoraria: Celgene, Amgen, Pfizer, Novartis, Jazz PharmaceuticalsResearch Funding: Celgene, Amgen, Agios, Pfizer Michael J. ThirmanConsulting or Advisory Role: AstraZeneca, Genentech, AbbVie, Adaptive Biotechnologies, Celgene¸ PharmacyclicsResearch Funding: AbbVie (Inst), Syndax (Inst), Merck (Inst), TG Therapeutics (Inst) Jacqueline S. GarciaConsulting or Advisory Role: AbbVie, Takeda, Astellas PharmaResearch Funding: AbbVie (Inst), Pfizer (Inst), Genentech/Roche (Inst), Lilly (Inst), AstraZeneca (Inst), Prelude Therapeutics (Inst) Courtney D. DiNardoThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Leadership: Notable LabsStock and Other Ownership Interests: Notable LabsHonoraria: Agios, Celgene, AbbVie, Jazz Pharmaceuticals, Daiichi Sankyo, Novartis, TakedaConsulting or Advisory Role: Celgene, Agios, AbbVieResearch Funding: AbbVie, Agios, Celgene, Daiichi Sankyo Vladimir VorobyevConsulting or Advisory Role: AstraZeneca, Janssen Oncology, Sanofi, Novartis, BeiGene, Roche, AbbVie, Takeda, Gilead SciencesSpeakers' Bureau: AbbVie, AstraZeneca, Amgen, BioCad, Janssen, Sanofi, Takeda¸ Novartis, BeiGeneTravel, Accommodations, Expenses: AstraZeneca Nicola S. FracchiollaConsulting or Advisory Role: Amgen, Jazz Pharmaceuticals, Incyte, AbbVieTravel, Accommodations, Expenses: Pfizer Su-Peng YehHonoraria: Novartis, Bristol Myers Squibb, Janssen¸ Takeda, AbbVie, Amgen, Sanofi, Bayer, Astellas PharmaConsulting or Advisory Role: AbbVie, Sanofi, Novartis, Pfizer, Chugai Pharma Jun Ho JangSpeakers' Bureau: Novartis Muhit OzcanResearch Funding: Janssen, Celgene, Takeda, Bayer, Merck, Archigen Biotech, Roche, AbbVie, Acerta Pharma/AstraZeneca Kazuhito YamamotoHonoraria: Kyowa Hakko Kirin, Takeda¸ Janssen, Bristol Myers Squibb, Celgene, Sumitomo Dainippon, Ono Pharmaceutical, Chugai Pharma, Novartis, Otsuka, Mundipharma, Eisai, MSD, Meiji Seika Kaisha, Sanofi, Nippon Shinyaku, AbbVie, GlaxoSmithKline, SymBio Pharmaceuticals, Micron, Daiichi SankyoConsulting or Advisory Role: Ono Pharmaceutical, Meiji Seika Kaisha, Chugai Pharma, Bristol Myers Squibb, Kyowa Hakko Kirin, Takeda, Celgene, HUYA Bioscience International, Stemline Therapeutics, Eisai, Janssen, AstraZeneca¸ Daiichi Sankyo, AbbVie,Research Funding: Chugai Pharma (Inst), Novartis (Inst), ARIAD (Inst), Takeda (Inst), Gilead Sciences (Inst), AbbVie (Inst), Ono Pharmaceutical (Inst), Celgene (Inst), Solasia Pharma (Inst), MSD (Inst), Eisai (Inst), Zenyaku Kogyo (Inst), Bayer (Inst), SymBio Pharmaceuticals (Inst), AstraZeneca (Inst), Incyte (Inst), Mundipharma (Inst), Yakult Pharmaceutical (Inst) Arpad IllesConsulting or Advisory Role: Janssen, Takeda, Novartis, Pfizer, Roche, CelgeneResearch Funding: Takeda, Seattle GeneticsTravel, Accommodations, Expenses: Novartis, Janssen, Pfizer, Roche Ying ZhouStock and Other Ownership Interests: AbbVie Monique DailEmployment: Genentech/RocheStock and Other Ownership Interests: Roche/Genentech Brenda ChylaEmployment: AbbVieStock and Other Ownership Interests: AbbVie Jalaja PotluriEmployment: AbbVieStock and Other Ownership Interests: AbbVie Hartmut DöhnerConsulting or Advisory Role: AbbVie, Agios¸ Amgen, Astellas Pharma, Celgene, Jazz Pharmaceuticals, Janssen Oncology, Novartis, AstraZeneca, Berlin-Chemie, GEMoaB, Bristol Myers Squibb/Celgene, Gilead Sciences, SyndaxResearch Funding: Arog, Amgen, Bristol Myers Squibb, Novartis, Pfizer, Jazz Pharmaceuticals, AbbVie, Kronos BioNo other potential conflicts of interest were reported.

Background: The phase 3 VIALE-A trial (NCT02993523) reported that venetoclax-azacitidine significantly prolonged overall survival compared with placebo-azacitidine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Herein, efficacy and safety of venetoclax-azacitidine are analyzed in the Japanese subgroup of VIALE-A patients., Methods: Eligible Japanese patients were randomized 2:1 to venetoclax-azacitidine (N = 24) or placebo-azacitidine (N = 13). Primary endpoints for Japan were overall survival and complete response (CR) + CR with incomplete hematologic recovery (CRi). Venetoclax (target dose 400 mg) was given orally once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously on Days 1-7 of each 28-day cycle., Results: Median follow-up was 16.3 months (range, 1.0-20.3). Median overall survival was not reached with venetoclax-azacitidine (hazard ratio 0.409 and 95% confidence interval: 0.151, 1.109); overall survival estimate was higher with venetoclax-azacitidine than placebo-azacitidine at 12 (67 and 46%) and 18 months (57 and 31%), respectively. CR and CRi rates were 67% with venetoclax-azacitidine and 15% with placebo-azacitidine. Most common any-grade adverse events were febrile neutropenia (79 and 39%), thrombocytopenia (54 and 77%), constipation (54 and 54%) and decreased appetite (54 and 38%) in the venetoclax-azacitidine and placebo-azacitidine arms, respectively. Only 1 patient in the venetoclax-azacitidine arm, and no patients in the placebo-azacitidine arm, had grade 4 febrile neutropenia that led to treatment discontinuation., Conclusions: This Japanese subgroup analysis of VIALE-A demonstrates comparable safety and efficacy outcomes compared with the global study and supports venetoclax-azacitidine as first-line standard-of-care for Japanese treatment-naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: Therapeutic outcomes for acute myeloid leukemia patients with Fms-like tyrosine kinase 3 (FLT3) mutations have improved substantially since the discovery of small molecule tyrosine kinase inhibitors. Today, use of FLT3 inhibitors is standard in frontline intensive chemotherapy as well as patients with relapsed or refractory acute myeloid leukemia and FLT3 mutations and increasingly used as for prolonged remission maintenance posttransplant and/or postconsolidation. Yet, FLT3 inhibitors alone are not curative, and best outcomes are seen when the drugs are used as part of combination regimens. Optimizing therapy for patients with FLT3 mutations remains a work in progress. Overall, modern therapeutic approaches generate cure rates for this group at levels that argue against considering these mutations adverse risk. Still, such survivals require intensive therapy and often transplant. Therefore, efforts are underway to determine if lower toxicity regimens can attain comparable outcomes, at least for patients responding optimally. This review will review the various FLT3 inhibitors that are approved or in development, highlight the areas where they have been shown to add value, and identify areas where their use remains controversial., Competing Interests: Conflicts of Interest and Source of Funding: A.E.P. has received honoraria or consulting fees from AbbVie, Astellas, Daiichi Sankyo, Genentech, Novartis, and Arog and grants or research support (to institution) from AbbVie, Astellas, Daiichi Sankyo, Novartis, and FujiFilm. K.W.P. has received honoraria of consultancy fees from AbbVie, Astellas, Boston BioMedical, Bristol Myers Squibb, Novartis, Jazz Pharmaceuticals, and Celgene and institutional research funding from AbbVie, Astellas, Agios, Daiichi Sankyo, and Millennium., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1-21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL., Experimental Design: Adults ≥60 years with ND ALL/ABL or ≥21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m 2 /day IV for 5 days, days 3-7) (Arm A). Adults aged 40-59 years with ND ALL/ABL or age ≥21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy., Results: Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32 %; it was 50 % for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined., Conclusion: Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted., (Copyright © 2021. Published by Elsevier Ltd.)

Although inhibitors of the kinases CHK1, ATR, and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines in vitro , including TP53 -null acute myeloid leukemia (AML) and BCR/ABL-positive acute lymphoid leukemia (ALL), and inhibits leukemic colony formation in clinical AML samples ex vivo . In further studies, downregulation or inhibition of CHK1 triggered signaling in sensitive human acute leukemia cell lines that involved CDK2 activation followed by AP1-dependent TNF transactivation, TNFα production, and engagement of a TNFR1- and BID-dependent apoptotic pathway. AML lines that were intrinsically resistant to CHK1 inhibition exhibited high CHK1 expression and were sensitized by CHK1 downregulation. Signaling through this same CDK2-AP1- TNF cytotoxic pathway was also initiated by ATR or WEE1 inhibitors in vitro and during CHK1 inhibitor treatment of AML xenografts in vivo . Collectively, these observations not only identify new contributors to the antileukemic cell action of CHK1, ATR, and WEE1 inhibitors, but also delineate a previously undescribed pathway leading from aberrant CDK2 activation to death ligand-induced killing that can potentially be exploited for acute leukemia treatment. SIGNIFICANCE: This study demonstrates that replication checkpoint inhibitors can kill AML cells through a pathway involving AP1-mediated TNF gene activation and subsequent TP53-independent, TNFα-induced apoptosis, which can potentially be exploited clinically., (©2021 American Association for Cancer Research.)

The FMS-like tyrosine kinase 3 (FLT-3) is the most frequently mutated gene in acute myeloid leukemia (AML), a high-risk feature, and now the target of tyrosine kinase inhibitors (TKIs), which are approved and in development. The most common mutation is the internal tandem duplication (ITD). We present a novel mutation, FLT-3/Q575Δ, identified in a patient with AML through next-generation sequencing (NGS). This mutation is activating, drives downstream signaling comparable to FLT-3/ITD, and can be targeted using available FLT-3 TKIs. We present the results of a systematic analysis that identified Y572Δ, E573Δ, and S574Δ as similarly activating and targetable deletions located in the FLT-3 juxtamembrane domain (JMD). These mutations target key residues in the JMD involved in the interactions within FLT-3 that regulate its activation. Our results suggest a new class of FLT-3 mutations that may have an impact on patient care and highlight the increasing importance of a systematic understanding of FLT-3 mutations other than ITD. It is likely that, as NGS becomes more commonly used in the diagnosis of patients with AML, these and other activating mutations will be discovered with increasing frequency., (© 2021 by The American Society of Hematology.)

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708., (© 2021 by The American Society of Hematology.)

Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes., (© 2020 by The American Society of Hematology.)

Background: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study., Methods: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival., Results: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively., Conclusions: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.)., (Copyright © 2020 Massachusetts Medical Society.)

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m 2 /day IV continuous infusion days 1-3, daunorubicin 45 mg/m 2 IV days 1-3, etoposide 400 mg/m 2 IV days 8-10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4 + and CD8 + peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4 + and CD8 + T cells.

FLT3-ITD-mutated acute myeloid leukemia (AML) remains a therapeutic challenge. FLT3 inhibition in the setting of minimal residual disease and a new immune system via allogeneic transplantation offers a promise of improved survival for these patients. We performed a prospective study of patients with FLT3-ITD AML undergoing allogeneic transplant that was conducted to evaluate the safety, tolerability, and outcome of sorafenib administered peritransplant. Sorafenib dosing was individualized, starting at 200 mg twice a day (BID), and titrated based on tolerability or toxicities until a tolerable dose was identified. Forty-four patients, with a median age of 52 years, undergoing allogeneic transplant were started on sorafenib in the peritransplant period (21 pretransplant). The median duration of post-transplant follow-up was 27.6 months (range, 5.2 to 60.4). Overall survival was 76% at both 24 and 36 months. Event-free survival at 24 and 36 months was 74% and 64%, respectively. Ten patients died in the post-transplant period, with 6 deaths due to relapsed leukemia and 4 from transplant-associated toxicity. Tolerable doses ranged from 200 mg every other day to 400 mg BID with similar exposure. Correlative studies evaluating FLT3 inhibition via a plasma inhibitory activity assay showed consistent inhibition of FLT3 at all tolerability-determined dosing levels. Sorafenib is well tolerated in the peritransplant setting irrespective of the conditioning intensity or the donor source. Our findings indicate that sorafenib dosing can be individualized in the post-transplantation setting according to patient tolerability. This approach results in effective in vivo FLT3 inhibition and yields encouraging survival results., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: Defective homologous recombination (HR) has been reported in multiple myeloid disorders, suggesting a shared dysregulated pathway in these diverse malignancies. Because targeting HR-defective cancers with PARP inhibition (PARPi) has yielded clinical benefit, improved understanding of HR defects is needed to implement this treatment modality., Experimental Design: We used an ex vivo irradiation-based assay to evaluate HR repair, HR gene promoter methylation, and mRNA expression in primary myeloid neoplastic cells. In vitro BRCA1 gene silencing was achieved to determine the consequences on HR repair, sensitivity to PARPi, and expression of miR-155, an oncogenic miRNA., Results: Impaired HR repair was frequently detected in myeloid neoplasm samples (9/21, 43%) and was linked to promoter methylation-mediated transcriptional repression of BRCA1 , which was not observed for other members of the HR pathway ( BRCA2, ATM, ATR, FANC-A ). In vitro BRCA1 knockdown increased sensitivity to PARP inhibition, and BRCA1 expression is inversely correlated with miR-155 expression, a finding reproduced in vitro with BRCA1 knockdown. Increased miR-155 was associated with PU.1 and SHIP1 repression, known myeloid differentiation factors that are frequently downregulated during leukemic transformation., Conclusions: This study demonstrates frequent defective HR, associated with BRCA1 epigenetic silencing, in a broad range of myeloid neoplasms. The increased prevalence of BRCA1 promoter methylation, resulting in repressed BRCA1 , may have an additional role in leukemogenesis by increasing miR-155 expression, which then inhibits transcription factors associated with normal myeloid differentiation. Further study of HR defects may facilitate the identification of HR-defective myeloid neoplasms sensitive to PARPi., (©2019 American Association for Cancer Research.)

CPX-351 is a liposomally encapsulated 5:1 molar ratio of cytarabine and daunorubicin that recently received regulatory approval for the treatment of therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes based on improved overall survival compared to standard cytarabine/daunorubicin therapy. Checkpoint kinase 1 (CHK1), which is activated by DNA damage and replication stress, diminishes sensitivity to cytarabine and anthracyclines as single agents, suggesting that CHK1 inhibitors might increase the effectiveness of CPX-351. The present studies show that CPX-351 activates CHK1 as well as the S and G2/M cell cycle checkpoints. Conversely, CHK1 inhibition diminishes the cell cycle effects of CPX-351. Moreover, CHK1 knockdown or addition of a CHK1 inhibitor such as MK-8776, rabusertib or prexasertib enhances CPX-351-induced apoptosis in multiple TP53-null and TP53-wildtype AML cell lines. Likewise, CHK1 inhibition increases the antiproliferative effect of CPX-351 on primary AML specimens ex vivo, offering the possibility that CPX-351 may be well suited to combine with CHK1-targeted agents.

To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re-induction chemotherapy. They were randomized to the following regimens: carboplatin-topotecan (CT), each by continuous infusion for 5 days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S-MEC). The primary objective was attainment of a complete remission (CR). A Simon two-stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared with 55 years for the CT arm and the S-MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%-35%), 28% in the FLAM arm (10/36, 90% CI, 16%-43%), and 16% in the S-MEC arm (3/19, 90% CI, 4%-36%). There were nine treatment-related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients., (© 2018 Wiley Periodicals, Inc.)

Sorafenib administered at the approved dose continuously is not tolerated long-term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (E max ) model. Sorafenib could inhibit FLT3-ITD activity by 100% with an IC 50 of 69.3 ng/mL and ERK activity by 84% with an IC 50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure-response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3-ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML., (© 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Novel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline-based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single-agent activity in relapsed or refractory (R/R) AML. This phase 1, open-label, sequential group dose-escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML). Nineteen patients unselected for FLT3 mutational status received one of three quizartinib dihydrochloride dose levels (DL): 60 mg/d for 7 days (DL1; n = 6), 60 mg/d for 14 days (DL2; n = 7), and 40 mg/d for 14 days (DL-1; n = 6); administered orally starting on day 4 of chemotherapy. Median age was 43.8 years. Ten patients completed induction and consolidation. Three patients experienced dose-limiting toxicities (DLTs): 2 at DL2 (1 pericardial effusion; 1 febrile neutropenia, decreased platelet count, and QT prolongation); 1 at DL-1 (pericarditis). Maximum tolerated dose (MTD) was identified as DL-1. Most common grade 3/4 adverse events were febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), and anemia (26%). There were no apparent additional toxicities with addition of quizartinib to chemotherapy although grade ≤1 QT prolongation was observed at MTD. Sixteen patients (84%) achieved a response; 14 (74%) composite complete response; 2 (11%) morphologic leukemia-free state. The phase 3 QuANTUM-First trial (NCT02668653) is further evaluating the effect of quizartinib plus SOC chemotherapy in ndAML FLT3-ITD mutated patients., (© 2017 Wiley Periodicals, Inc.)

Acute myeloid leukemia (AML) therapies are rapidly evolving with novel targeted therapies showing high-level responses in a notoriously difficult to treat group of patients - the elderly and unfit. This review will examine the outcomes of older AML patients (>60 years old) with conventional induction strategies, and published literature on risks of pursuit of induction. Low-intensity combination therapy response rates appear to be approaching that of induction regimens, and with lower toxicity, low-intensity therapy likely represents the future standard approach in this age group. Lastly, allogeneic transplant appears to have a role in increasing durable remissions regardless of age and should be considered in patients with limited comorbidities.

Background: Elderly patients (aged ≥65 years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study., Methods: Previously untreated patients aged 65 years and over with acute myeloid leukaemia who were ineligible for standard induction therapy were enrolled into this non-randomised, open-label, phase 1b study. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0-2 and either intermediate-risk or poor-risk cytogenetics. Patients were enrolled into one of three groups for the dose-escalation phase of this study: group A (venetoclax and intravenous decitabine 20 mg/m 2 [days 1-5 of each 28-day cycle]), group B (venetoclax and subcutaneous or intravenous azacitidine 75 mg/m 2 [days 1-7 of each 28-day cycle]), and group C (a venetoclax and decitabine substudy with the oral CYP3A inhibitor posaconazole, 300 mg twice on cycle 1, day 21, and 300 mg once daily from cycle 1, days 22-28, to assess its effect on venetoclax pharmacokinetics). Dose escalation followed a standard 3 + 3 design with at least three evaluable patients enrolled per cohort; daily target doses of venetoclax for groups A and B were 400 mg (cohort 1), 800 mg (cohorts 2 and 3), and 1200 mg (cohort 4), and 400 mg for group C. The primary endpoints were the safety and pharmacokinetics of venetoclax plus decitabine or azacitidine, and to determine the maximum tolerated dose and recommended phase 2 dose. Secondary endpoints included the preliminary anti-leukaemic activity of venetoclax with decitabine or azacitidine through the analysis of overall response, duration of response, and overall survival. We analysed safety, pharmacokinetics, and anti-leukaemic activity in all patients who received one or more venetoclax doses. The expansion phase of the study is ongoing but is closed to accrual. This trial is registered with ClinicalTrials.gov, number NCT02203773., Findings: 57 patients were enrolled in the study. 23 patients in group A and 22 patients in group B were enrolled between Nov 19, 2014, and Dec 15, 2015, and 12 patients in group C were enrolled between June 14, 2015, and Jan 16, 2016. As of data cutoff on June 15, 2016, the most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (27 [47%] of 57 patients; nine in group A, 13 in group B, and five in group C), febrile neutropenia (24 [42%] of 57; 11 in group A, ten in group B, and three in group C), and neutropenia (23 [40%] of 57; 12 in group A, eight in group B, and three in group C). The most common serious treatment-emergent adverse event in groups A and B was febrile neutropenia (seven [30%] of 23 patients vs seven [32%] of 22), whereas in group C it was lung infection (four [33%] of 12 patients). 49 (86%) of 57 patients had treatment-related adverse events; the most common in groups A and B included nausea (12 [52%] patients vs seven [32%] patients), fatigue (six [26%] patients vs seven [32%]), and decreased neutrophil count (six [26%] patients vs six [27%]), whereas in group C the most common were nausea (seven [58%] of 12 patients), leucopenia (six [50%]), vomiting (five [42%]), and decreased platelet count (five [42%]). The maximum tolerated dose was not reached. The recommended phase 2 dose was 400 mg once a day or 800 mg with an interrupted dosing schedule (safety expansion). In total, four (7%) of 57 patients had died within 30 days of the first venetoclax dose caused by sepsis (group B), bacteraemia (group A), lung infection (group C), and respiratory failure (group A). Tumour lysis syndrome was not observed. Decitabine and azacitidine did not substantially affect venetoclax exposures. Overall, 35 (61%; 95% CI 47·6-74·0) of 57 patients achieved complete remission or complete remission with incomplete marrow recovery. In groups A and B, 27 (60%; 95% CI 44·3-74·3) of 45 patients had complete remission or complete remission with incomplete marrow recovery., Interpretation: Venetoclax plus hypomethylating agent therapy seems to be a novel, well-tolerated regimen with promising activity in this underserved patient population. Evaluation of expansion cohorts is ongoing at 400 mg and 800 mg doses using both hypomethylating agent combinations., Funding: AbbVie and Genentech., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults, but there is limited information on survivors' quality of life (QOL) after remission., Objective: We piloted a survey exploring patient-reported outcomes for people with AML in first complete remission (CR1) to determine whether patients felt the survey is relevant to their well-being and to summarize patient characteristics., Design/measurements: Cross-sectional survey of a convenience sample of AML patients in CR1 assessing QOL and functioning (European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30 v 3.0), well-being (QOL-cancer survivor [QOL-CS]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue]), and anxiety and depression (hospital anxiety and depression scale [HADS]). The survey contained five open-ended questions., Results: Eighteen patients completed the survey. Most felt it was completely or mostly relevant (88.8%) in describing their QOL. Participants scored well on the EORTC QLQ-C30, fatigue being the most common symptom (83%).The FACIT-Fatigue mean score was 28.7 and median score was 33.5 (normal ≥30). Two scored in the abnormal range for anxiety and one for depression on the HADS. On the QOL-CS, participants scored more than 6 out of 10 in most domains, except the subscales of distress and fear., Conclusions: The survey content and length were appropriate. Patients reported ongoing fatigue, fears of future test results, getting a second cancer, and recurrence of cancer. Survivors experience ongoing symptoms, highlighting the importance of providers performing ongoing symptom and needs assessments.