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This phase 2 study investigated pevonedistat + azacitidine + venetoclax ( n  = 83) versus azacitidine + venetoclax ( n  = 81) in patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy. The study was stopped early following negative results from PANTHER, which evaluated pevonedistat in higher-risk myelodysplastic syndromes/chronic myelomonocytic leukemia or low-blast AML. Outcomes were analyzed up to the datacut. For pevonedistat + azacitidine + venetoclax versus azacitidine + venetoclax, the median follow-up was 8.44 versus 7.95 months; the complete remission (CR) rate was 45% versus 49%; composite CR (CCR; CR+CR with incomplete blood count recovery) was 77% versus 72%. There were no differences in event-free survival (primary endpoint; hazard ratio [HR]: 0.99; 95% confidence interval [CI]: 0.61-1.60; p  = 0.477) or overall survival (HR: 1.42; 95% CI: 0.82-2.49; p  = 0.896). In exploratory analyses in IDH -mutated AML, CCR rates were higher with pevonedistat + azacitidine + venetoclax versus azacitidine + venetoclax. Safety was similar between treatment arms. Efficacy/safety with azacitidine + venetoclax was consistent with the phase 3 VIALE-A study., Trial Registration: NCT04266795.

In order to improve the outcome observed with azacitidine (AZA) in higher-risk Myelodysplastic syndrome (MDS), its combination with other drugs in MDS must be evaluated. So far, no combination has not been shown to be more effective than AZA alone. AZA-PLUS was a phase II trial that, in a "pick a winner" approach, randomly assigned patients with higher-risk MDS, CMML and low blast count AML to: AZA; AZA plus lenalidomide; AZA plus Valproic Acid or AZA plus Idarubicin. 322 patients were included. After six cycles, 69 (21.4%) CR + PR were observed with no benefit from any combination. Median EFS and OS were 17.2 and 19.7 months in the whole cohort, respectively, with no difference across randomised arms. Infection and rates of hospitalisation during the first six cycles were higher in the AZA-LEN And AZA-IDA arm, related to increased myelosuppression. Factors associated with better response were IPSS, favourable or intermediate karyotype, haemoglobin, lower circulating blast count, fibrinogen level and lower LDH, while poorer survival was seen in therapy-related MDS and, in the case of TP53, PTPN11 or CSF3R mutation. The combinations used did not improve the outcome obtained with AZA alone. However, our "pick a winner" randomised strategy may remain useful with potentially more active drugs to be tested in combination with AZA., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The combination of ivosidenib - an inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) - and azacitidine showed encouraging clinical activity in a phase 1b trial involving patients with newly diagnosed IDH1 -mutated acute myeloid leukemia., Methods: In this phase 3 trial, we randomly assigned patients with newly diagnosed IDH1 -mutated acute myeloid leukemia who were ineligible for intensive induction chemotherapy to receive oral ivosidenib (500 mg once daily) and subcutaneous or intravenous azacitidine (75 mg per square meter of body-surface area for 7 days in 28-day cycles) or to receive matched placebo and azacitidine. The primary end point was event-free survival, defined as the time from randomization until treatment failure (i.e., the patient did not have complete remission by week 24), relapse from remission, or death from any cause, whichever occurred first., Results: The intention-to-treat population included 146 patients: 72 in the ivosidenib-and-azacitidine group and 74 in the placebo-and-azacitidine group. At a median follow-up of 12.4 months, event-free survival was significantly longer in the ivosidenib-and-azacitidine group than in the placebo-and-azacitidine group (hazard ratio for treatment failure, relapse from remission, or death, 0.33; 95% confidence interval [CI], 0.16 to 0.69; P = 0.002). The estimated probability that a patient would remain event-free at 12 months was 37% in the ivosidenib-and-azacitidine group and 12% in the placebo-and-azacitidine group. The median overall survival was 24.0 months with ivosidenib and azacitidine and 7.9 months with placebo and azacitidine (hazard ratio for death, 0.44; 95% CI, 0.27 to 0.73; P = 0.001). Common adverse events of grade 3 or higher included febrile neutropenia (28% with ivosidenib and azacitidine and 34% with placebo and azacitidine) and neutropenia (27% and 16%, respectively); the incidence of bleeding events of any grade was 41% and 29%, respectively. The incidence of infection of any grade was 28% with ivosidenib and azacitidine and 49% with placebo and azacitidine. Differentiation syndrome of any grade occurred in 14% of the patients receiving ivosidenib and azacitidine and 8% of those receiving placebo and azacitidine., Conclusions: Ivosidenib and azacitidine showed significant clinical benefit as compared with placebo and azacitidine in this difficult-to-treat population. Febrile neutropenia and infections were less frequent in the ivosidenib-and-azacitidine group than in the placebo-and-azacitidine group, whereas neutropenia and bleeding were more frequent in the ivosidenib-and-azacitidine group. (Funded by Agios Pharmaceuticals and Servier Pharmaceuticals; AGILE ClinicalTrials.gov number, NCT03173248.)., (Copyright © 2022 Massachusetts Medical Society.)

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.

Purpose: TP53 -mutated ( TP53m ) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions., Patients and Methods: This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R TP53m MDS and AML patients., Results: Fifty-two TP53m patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved TP53 next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset ( P < .01) and higher age ( P = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively., Conclusion: In this very high-risk population of TP53m MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone., Competing Interests: Thomas CluzeauConsulting or Advisory Role: Abbvie, Agios, Bristol-Myers Squibb, Jazz Pharmaceuticals, Novartis, Roche, Takeda, Syros PharmaceuticalsSpeakers' Bureau: Novartis, Amgen, Sanofi, Astellas PharmaTravel, Accommodations, Expenses: Bristol-Myers Squibb, Novartis, Pfizer, Sanofi Jacqueline Lehmann-CheConsulting or Advisory Role: AstraZeneca, Roche Pierre PeterlinConsulting or Advisory Role: Jazz Pharmaceuticals, Abbvie, Astellas Pharma, Daiichi Sankyo/Lilly Odile Beyne RauzyTravel, Accommodations, Expenses: Novartis Christian RecherConsulting or Advisory Role: Roche, Pfizer, Incyte, Novartis, Otsuka, Astellas Pharma, Daiichi Sankyo, Macrogenics, Janssen, Abbvie, Jazz Pharmaceuticals, Amgen, CelgeneResearch Funding: Abbvie, Roche, MaaT Pharma, Daiichi Sankyo, Agios, Chugai Pharma, Astellas Pharma, Jazz Pharmaceuticals, Novartis, Amgen, CelgeneTravel, Accommodations, Expenses: Gilead Sciences, Daiichi Sankyo, Novartis, Amgen, Celgene, Sanofi, Incyte Aspasia StamatoullasHonoraria: CelgeneConsulting or Advisory Role: TakedaTravel, Accommodations, Expenses: Pfizer Lise WillemsHonoraria: Abbvie, Janssen, Novartis Emmanuel RaffouxTravel, Accommodations, Expenses: Abbvie, Roche Bruno QuesnelResearch Funding: Daiichi Sankyo Europe GmbH Michael LoschiConsulting or Advisory Role: Astellas Pharma, Iqone, NovartisTravel, Accommodations, Expenses: Novartis/Pfizer, MSD Antoine F. CarpentierStock and Other Ownership Interests: AltevaxHonoraria: Gilead SciencesConsulting or Advisory Role: Bristol-Myers Squibb David A. SallmanConsulting or Advisory Role: Syndax, Novartis, Magenta Therapeutics, Kite Pharma, Intellia Therapeutics, Gilead Sciences, Bristol-Myers Squibb, Aprea AB, Abbvie, Celyad, AgiosSpeakers' Bureau: Bristol-Myers Squibb, Incyte, AgiosResearch Funding: Jazz Pharmaceuticals, CelgenePatents, Royalties, Other Intellectual Property: Intellectual Property Patent for LB-100 in MDS Rami KomrokjiStock and Other Ownership Interests: AbbvieConsulting or Advisory Role: Acceleron Pharma, Abbvie, Geron, Jazz Pharmaceuticals, Bristol-Myers Squibb, Incyte, NovartisSpeakers' Bureau: Bristol-Myers Squibb, Jazz PharmaceuticalsTravel, Accommodations, Expenses: Agios, Bristol-Myers Squibb, Jazz Pharmaceuticals, Incyte Lionel AdesResearch Funding: CelgeneHonoraria: Novartis, Silence Therapeutics, BerGenBio, Jazz Pharmaceuticals, Abbvie, Celgene Pierre FenauxHonoraria: CelgeneResearch Funding: CelgeneNo other potential conflicts of interest were reported.

Hypomethylating agents are a classical frontline low-intensity therapy for older patients with acute myeloid leukemia. Recently, TP53 gene mutations have been described as a potential predictive biomarker of better outcome in patients treated with a ten-day decitabine regimen., However, functional characteristics of TP53 mutant are heterogeneous, as reflected in multiple functional TP53 classifications and their impact in patients treated with azacitidine is less clear. We analyzed the therapeutic course and outcome of 279 patients treated with azacitidine between 2007 and 2016, prospectively enrolled in our regional healthcare network. By screening 224 of them, we detected TP53 mutations in 55 patients (24.6%), including 53 patients (96.4%) harboring high-risk cytogenetics. The identification of any TP53 mutation was associated with worse overall survival but not with response to azacitidine in the whole cohort and in the subgroup of patients with adverse karyotype. Stratification of patients according to three recent validated functional classifications did not allow the identification of TP53 mutated patients who could benefit from azacitidine. Systematic TP53 mutant classification will deserve further exploration in the setting of patients treated with conventional therapy and in the emerging field of therapies targeting TP53 pathway., Competing Interests: Christian Recher has received research funding from Celgene, unrelated to this study. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high-risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic subgroup. We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cytogenetics, and absence of prior treatment with intensive chemotherapy had a better outcome. 27 patients were allo-transplanted and achieved a 21-month median OS. Balanced 3q21 translocations were associated with a better response rate and overall survival. Outcome of patients with isolated EVI-1 overexpression was comparable to that of patients with chromosome 3q lesions. Thus, AML/MDS patients with 3q abnormalities appear to be a heterogeneous group in their response to AZA, and AZA may represent a suitable option in particular as a bridge to allogeneic transplantation., (© 2015 Wiley Periodicals, Inc.)

The prognosis of patients older than 50 with relapsed or refractory AML is dismal. Azacitidine has been investigated in older AML patients. Here we report the outcome of 130 patients older than 50 years included in a multicenter patient named program of azacitidine after relapse (n=67) or induction failure (n=63) of intensive chemotherapy. Median age was 67 years, cytogenetic risk was high in 28% and performance status ≥2 in 15% of cases. Most (72%) patients received azacitidine at the standard schedule (75mg/m(2)/d, 7 days/month) for a median of 4 courses. The overall response rate was 17% (CR: 10%, CRi: 7%). Median overall survival was 8.4 months. Achievement of CR/CRi was associated with prolonged survival (P=0.0001), whereas hematological improvement according to MDS criteria, achieved in 36% of patients with resistant disease, did not improve survival. In multivariate analysis, high risk cytogenetics (P=0.022) and peripheral blasts >10% (P<0.0001) at onset of azacitidine were independently predictive of poor prognosis. Combining these two factors, we identified a subgroup of 48% of patients with intermediate risk cytogenetics and peripheral blasts ≤10% and a median OS of 11.3 months. These results warrant further investigation of azacitidine-based regimens in this subgroup of patients., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Limited data are available on azacitidine (AZA) treatment and its prognostic factors in acute myeloid leukemia (AML). One hundred and forty-nine previously untreated AML patients considered ineligible for intensive chemotherapy received AZA in a compassionate patient-named program. AML diagnosis was de novo, post-myelodysplastic syndromes (MDS), post-MPN, and therapy-related AML in 51, 55, 13, and 30 patients, respectively. Median age was 74 years, median white blood cell count (WBC) was 3.2 × 10⁹ /L and 58% of the patients had ≥ 30% marrow blasts. Cytogenetics was adverse in 60 patients. Patients received AZA for a median of five cycles (range 1-31). Response rate (including complete remission/CR with incomplete recovery/partial remission) was 27.5% after a median of three cycles (initial response), and 33% at any time (best response). Only adverse cytogenetics predicted poorer response. Median overall survival (OS) was 9.4 months. Two-year OS was 51% in responders and 10% in non-responders (P<0.0001). Adverse cytogenetics, WBC >15 × 10⁹ /L and ECOG-PS ≥ 2 predicted poorer OS, while age and marrow blast percentage had no impact. Using MDS IWG 2006 response criteria, among patients with stable disease, those with hematological improvement had no significant survival benefit in a 7 months landmark analysis. Outcomes observed in this high-risk AML population treated with AZA deserve comparison with those of patients treated intensively in prospective studies., (Copyright © 2013 Wiley Periodicals, Inc.)

Hydroxyurea is the standard therapy of chronic myelomonocytic leukemia (CMML) presenting with advanced myeloproliferative and/or myelodysplastic features. Response to hypomethylating agents has been reported in heterogeneous series of CMML. We conducted a phase 2 trial of decitabine (DAC) in 39 patients with advanced CMML defined according to a previous trial. Median number of DAC cycles was 10 (range, 1-24). Overall response rate was 38% with 4 complete responses (10%), 8 marrow responses (21%), and 3 stable diseases with hematologic improvement (8%). Eighteen patients (46%) demonstrated stable disease without hematologic improvement, and 6 (15%) progressed to acute leukemia. With a median follow-up of 23 months, overall survival was 48% at 2 years. Mutations in ASXL1, TET2, AML1, NRAS, KRAS, CBL, FLT3, and janus kinase 2 (JAK2) genes, and hypermethylation of the promoter of the tumor suppressor gene TIF1γ, did not predict response or survival on DAC therapy. Lower CJUN and CMYB gene expression levels independently predicted improved overall survival. This trial confirmed DAC efficacy in approximately 40% of CMML patients with advanced myeloproliferative or myelodysplastic features and suggested that CJUN and CMYB expression could be potential biomarkers in this setting. This trial is registered at EudraCT (eudract.ema.europa.eu) as #2008-000470-21 and www.clinicaltrials.gov as #NCT01098084.

Purpose: Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience primary or secondary treatment failure. The outcome of these patients has not yet been described., Patients and Methods: Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program)., Results: The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care., Conclusion: Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population.

Prognostic factors for response and survival in higher-risk myelodysplastic syndrome patients treated with azacitidine (AZA) remain largely unknown. Two hundred eighty-two consecutive high or intermediate-2 risk myelodysplastic syndrome patients received AZA in a compassionate, patient-named program. Diagnosis was RA/RARS/RCMD in 4%, RAEB-1 in 20%, RAEB-2 in 54%, and RAEB-t (AML with 21%-30% marrow blasts) in 22%. Cytogenetic risk was good in 31%, intermediate in 17%, and poor in 47%. Patients received AZA for a median of 6 cycles (1-52). Previous low-dose cytosine arabinoside treatment (P = .009), bone marrow blasts > 15% (P = .004), and abnormal karyotype (P = .03) independently predicted lower response rates. Complex karyotype predicted shorter responses (P = .0003). Performance status ≥ 2, intermediate- and poor-risk cytogenetics, presence of circulating blasts, and red blood cell transfusion dependency ≥ 4 units/8 weeks (all P < 10(-4)) independently predicted poorer overall survival (OS). A prognostic score based on those factors discriminated 3 risk groups with median OS not reached, 15.0 and 6.1 months, respectively (P < 10(-4)). This prognostic score was validated in an independent set of patients receiving AZA in the AZA-001 trial (P = .003). Achievement of hematological improvement in patients who did not obtain complete or partial remission was associated with improved OS (P < 10(-4)). In conclusion, routine tests can identify subgroups of patients with distinct prognosis with AZA treatment.

PurposeTo 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 methodsWe 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.ResultsPatients (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.ConclusionsIn 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.