Received: 31 October 2022
`
`Revised: 10 January 2023
`
`Accepted: 12 January 2023
`
`DOI: 10.1002/ajh.26847
`
`C O R R E S P O N D E N C E
`
`Long-term survival with oral azacitidine for patients with acute
`myeloid leukemia in first remission after chemotherapy:
`Updated results from the randomized, placebo-controlled,
`phase 3 QUAZAR AML-001 trial
`
`To the Editor:
`Despite recent therapeutic advances, outcomes remain poor for older
`patients with acute myeloid leukemia (AML). For patients in the USA
`diagnosed with AML between 2010–2017, the 5-year overall survival
`(OS) rate was 22% for patients aged 60–69 years, and only 5% for
`those aged ≥70 years.1 Survival outcomes are influenced by patient-
`and disease-related factors, including age, comorbidities, cytogenetic
`abnormalities, gene mutations, and persistence of leukemic cells after
`intensive chemotherapy (IC)
`(i.e., measurable residual disease
`[MRD]).2,3 For patients with AML in remission, hematopoietic stem
`cell transplantation (HSCT)
`is often the only potentially curative
`option, but many patients are not candidates for HSCT due to
`advanced age, poor performance status, comorbidities, patient prefer-
`ence, or favorable AML European Leukemia Net risk, particularly in
`younger patients. Thus, there is a need for effective maintenance
`therapies to prolong survival among HSCT-ineligible patients in com-
`plete remission.
`In the randomized, double-blind, phase 3 QUAZAR AML-001 trial,
`oral azacitidine (Oral-AZA) significantly prolonged OS and relapse-free
`survival (RFS) versus placebo in patients ≥55 years with AML in first
`remission after IC who were not HSCT candidates.4 At the July 2019
`primary data cutoff, with a median follow-up time of 41.2 months,
`approximately one-quarter of all patients were alive and in survival
`follow-up. Here, we present updated OS outcomes (data cutoff March
`2022) with the median follow-up time now 55.5 months and investi-
`gate clinical and biological variables predictive of long-term survival,
`defined here as survival ≥3 years from randomization, in patients trea-
`ted with Oral-AZA or placebo.
`The study design was described in detail in Wei et al.4 Briefly,
`patients aged ≥55 years with intermediate-or poor-risk cytogenetics at
`diagnosis who achieved first complete remission (CR) or CR with
`incomplete blood count recovery (CRi) with IC, were randomized 1:1 to
`receive Oral-AZA 300-mg or placebo once-daily for 14 days in
`repeated 28-day cycles. Patients in the Oral-AZA arm could continue
`treatment
`in an optional open-label extension phase after
`trial
`
`unblinding (Figure S1). The primary endpoint was OS, defined as the
`time from randomization until death. Patients who withdrew consent
`or were lost to follow-up were then censored for OS. OS was estimated
`by Kaplan–Meier methods and compared between treatment groups
`by stratified log-rank test. NPM1 and FLT3 gene mutations(mut) were
`assessed locally at diagnosis for most patients; post-IC MRD status was
`assessed centrally at study screening by multiparameter flow cytome-
`try.5,6 During study therapy, surveillance bone marrow monitoring for
`hematologic remission and MRD status was performed every 3 cycles
`from cycles 3–24, then every 6 cycles or as clinically indicated. For
`patients MRD+ at baseline (≥0.1%), MRD response was defined as
`achieving MRD negativity (<0.1%) at ≥2 consecutive assessments dur-
`ing study.
`In all, 472 patients were randomized to Oral-AZA (n = 238) or
`placebo (n = 234). At diagnosis, 86% of patients had intermediate-risk
`cytogenetics, 29% had NPM1mut, and 14% had FLT3mut (Table S1).4–6
`Median age was 68 (range 55–86) years and 47% of patients were
`MRD+ at screening.
`(median follow-up
`the primary data cutoff
`Median OS at
`41.2 months) was 24.7 versus 14.8 months with Oral-AZA versus pla-
`cebo, respectively (p < .001); estimated 2-year survival rates were
`50.6% versus 37.1% (difference [Δ] +13.5%; 95% confidence interval
`[CI], +4.5% to +22.5%).4 Over one-fourth of randomized patients
`(26.5%) were being followed for survival and censored for OS, includ-
`ing 71 patients still receiving Oral-AZA (n = 45) or placebo (n = 26)
`(Figure S2). After unblinding, 39 (16%) patients continued receiving
`Oral-AZA in an optional extension phase and 6 patients discontinued
`(3 withdrew consent, 2 relapsed, and 1 died). Patients still receiving
`placebo at unblinding had treatment discontinued and were followed
`for OS. After the primary data cutoff, patients not receiving active
`therapy (including patients who discontinued Oral-AZA during the
`extension phase) were followed for OS for up to 12 months.
`At the updated March 2022 cutoff, median study follow-up was
`55.5 months and 25 (11%) patients were receiving Oral-AZA mainte-
`nance in the extension phase (Figure S2). Overall, 54 (23%) patients in
`
`This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
`medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
`© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.
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`CORRESPONDENCE
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`E85
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`Kaplan–Meier estimated overall survival by treatment arm as of March 2022. CI, confidence interval; HR, hazard ratio; mo,
`F I G U R E 1
`months; Oral-AZA, oral azacitidine; OS, overall survival; PBO, placebo.
`
`the Oral-AZA arm had received ≥36 treatment cycles (3 years), and
`34 (14%) had received ≥60 cycles. Median OS in each arm at the
`updated cutoff remained unchanged from the primary analysis, but
`the Kaplan–Meier curves for Oral-AZA and placebo remained sepa-
`rated through 80 months from randomization (Figure 1). Estimated
`3-year survival rates in the Oral-AZA and placebo arms were 37.4%
`and 27.9%, respectively (Δ +9.5% with Oral-AZA [95%CI +0.9% to
`+18.1%]); 5-year survival rates were 26.5% versus 20.1% (Δ +6.3%
`[95%CI 2.1% to +14.7%]).
`To assess clinical and biological variables predictive of long-term
`survival, patients were separated into two subgroups: the “Long-term
`Survivors” (LTS) cohort comprised patients known to have survived
`≥3 years from randomization, whereas the “Non-LTS” cohort included
`patients who died, were lost to follow-up, or withdrew consent before
`3 years. The LTS cohort comprised 30% (140/472) of all patients,
`including 35% (83/238) and 24% (57/234) of patients in the Oral-AZA
`and placebo arms, respectively. Compared with the Non-LTS group,
`patients in the LTS cohort were more likely to have intermediate-risk
`cytogenetics (95% vs. 82%, respectively) and NPM1mut (45% vs. 22%) at
`diagnosis, and less likely to be MRD+ at screening (34% vs. 53%)
`(Table S2). Use of consolidation chemotherapy and number of consoli-
`dation cycles were generally similar between the LTS and Non-LTS
`cohorts. Baseline demographic and disease characteristics were largely
`balanced between treatment arms within each LTS-defined cohort.
`Patients in the Oral-AZA arm who were LTS received a median of
`47 treatment cycles, compared with 8 cycles in the Non-LTS cohort. In
`the placebo arm, patients in the LTS cohort and the Non-LTS cohort
`received a median of 34 cycles and 5 cycles, respectively.
`In post-hoc univariate analyses, intermediate-risk cytogenetics and
`NPM1mut at diagnosis were each significantly correlated with long-term
`(≥3 years from randomization) survival within each treatment arm
`
`(Figure S3). No significant relationship was found between prior consoli-
`dation and long-term survival within either arm. In the placebo arm, there
`was a trend for greater long-term survival in patients who received 2–3
`prior consolidation cycles versus no consolidation but this association
`was not significant after adjusting for multiple testing (p = .161). As may
`be expected,
`longer randomized treatment duration was significantly
`associated with long-term survival in both arms. Baseline MRD status
`was positively associated with long-term survival in the placebo arm but
`not the Oral-AZA arm (Figure S3). Overall, 37% (38/103) of baseline
`MRD+ patients in the Oral-AZA arm achieved MRD response
`(i.e., conversion from MRD+ at baseline to MRD–), compared with 19%
`(22/116) of patients in the placebo arm (odds ratio 2.50 [95%CI 1.35–
`4.61]).6 MRD response on study was significantly associated with supe-
`rior long-term survival in both arms. While acknowledging the potential
`for lead-time bias by including MRD response in these survival analyses
`(i.e., longer survival may have allowed for more time to achieve MRD
`response), most (Oral-AZA, 76% [29/38]; placebo, 95% [21/22]) MRD
`responses occurred ≤6 months from randomization,6 whereas long-term
`survival required that a patient survive ≥3 years from randomization. Fif-
`teen patients (6%) in the Oral-AZA arm underwent HSCT within 3 years
`from randomization, including 6 who discontinued treatment while in
`first remission to receive HSCT, compared with 32 (14%) in the placebo
`arm (all of whom had relapsed); in univariate analyses, subsequent HSCT
`was significantly associated with long-term survival only in the placebo
`arm (Figure S3).
`A post-hoc multivariable logistic regression analysis was per-
`formed to identify baseline characteristics independently associated
`with long-term survival and assess the independent treatment effect
`of Oral-AZA when adjusting for other covariates. The model included
`randomized treatment arm (Oral-AZA vs. placebo), NPM1 status
`vs. NPM1wt)
`(NPM1mut
`at diagnosis,
`cytogenetic
`risk
`(poor
`
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`
`CORRESPONDENCE
`
`intermediate) at diagnosis, MRD status (MRD+ vs. MRD–) at
`vs.
`screening, and absolute neutrophil count (continuous variable) at
`screening. After controlling for other covariates, Oral-AZA remained
`significantly and independently predictive of long-term survival, as
`intermediate-risk cytogenetics, and baseline MRD–
`were NPM1mut,
`status at screening (Table S3).
`These updated data demonstrate the long-term survival benefit of
`Oral-AZA for patients in first remission after IC. With additional survival
`follow-up, Oral-AZA showed sustained OS improvement versus pla-
`cebo for over 5 years from randomization, and improved absolute
`3-and 5-year OS rates versus placebo by 9.5% and 6.3%, respectively.
`Nearly one-fourth (23%) of patients randomized to Oral-AZA received
`≥36 cycles (3 years) of treatment, with 11% (25/238) of patients still
`receiving Oral-AZA at the updated cutoff, supporting the feasibility and
`tolerability of
`long-term maintenance therapy with Oral-AZA. As
`expected, intermediate cytogenetic risk status (vs. poor) and presence
`of NPM1mut (vs. NPM1wt) at diagnosis were each significantly associ-
`ated with long-term survival (≥3 years from randomization) in both uni-
`variate and multivariable analyses. While significant in the overall
`population in multivariate analysis, baseline MRD status was only sig-
`nificantly predictive of superior long-term survival within the placebo
`arm in univariate analyses, suggesting that Oral-AZA may increase the
`likelihood of long-term survival by partially mitigating the adverse prog-
`nostic effect of post-IC MRD positivity, as evidenced by the two-fold
`higher rate of conversion from MRD positive to negative status during
`Oral-AZA therapy. For patients MRD+ at screening, achievement of
`MRD status on study was significantly correlated with long-term sur-
`vival in both arms. When controlling for key prognostic pretreatment
`covariates, Oral-AZA remained significantly predictive of long-term sur-
`vival compared with placebo. In conclusion, these updated findings
`demonstrate the feasibility and sustained long-term clinical benefit of
`Oral-AZA maintenance, now with over 4 years of median follow-up
`time for patients in remission after chemotherapy. Patients with AML
`completing intensive induction and consolidation therapy should there-
`fore be strongly considered for Oral-AZA maintenance, particularly
`those for whom HSCT may not be feasible or initially indicated, includ-
`ing patients with favorable risk NPM1 mutated disease.
`
`ACKNOWLEDGMENTS
`The authors thank the patients, families, investigators, staff, and clini-
`cal study teams who participated in the QUAZAR AML-001 trial. All
`authors contributed to and approved the manuscript for submission.
`Writing and editorial support were provided by Korin Albert, PhD, of
`Excerpta Medica, funded by Bristol Myers Squibb.
`
`CONFLICT OF INTEREST STATEMENT
`AHW has served on advisory boards for AbbVie, Agios, Amgen,
`Celgene/Bristol Myers Squibb, Gilead,
`Janssen, MacroGenics,
`Novartis, Pfizer, Roche, and Servier; has received research funding
`to his institution from AbbVie, Amgen, AstraZeneca, Celgene/Bristol
`Myers Squibb, Novartis, and Servier; has served on a speakers
`bureau for AbbVie, Celgene, and Novartis; and is eligible for royalty
`payments from the Walter and Eliza Hall
`Institute of Medical
`
`Research related to venetoclax. HDö has served in a consultancy
`position for AbbVie, Agios, Amgen, Astellas, Berlin-Chemie, Bristol
`Myers Squibb, Daiichi Sankyo, Gilead, Janssen, Jazz Pharmaceuticals,
`Novartis, Servier, and Syndax; reports receiving research funding
`from AbbVie, Agios, Amgen, Astellas, Bristol Myers Squibb, Jazz
`Pharmaceuticals, Kronos Bio, Novartis, and Pfizer; and reports
`receiving honoraria from AbbVie, Agios, Amgen, Astellas, AstraZe-
`neca, Berlin-Chemie, Bristol Myers Squibb, Daiichi Sankyo, Gilead,
`Janssen, Jazz Pharmaceuticals, Novartis, Servier, and Syndax. HS has
`served on advisory committees for Bristol Myers Squibb. FR reports
`receiving research funding from Amgen, Astellas, Astex/Taiho,
`Biomea Fusion, Celgene/Bristol Myers Squibb, Prelude, Syros, and
`Xencor; and honoraria from AbbVie, Astellas, AstraZeneca, Celgene/
`Bristol Myers Squibb, Novartis, and Syros. PM has served in a con-
`sultancy position for Menarini/Stemline, Gilead, Otsuka, Kura Oncol-
`ogy, AbbVie, Bristol Myers Squibb, Novartis, Jazz Pharmaceuticals,
`BeiGene, Astellas, Pfizer,
`Incyte, Takeda, Ryvu, and Nerviano;
`reports receiving research funding from AbbVie, Bristol Myers
`Squibb, Jazz Pharmaceuticals, Menarini/Stemline, Novartis, Pfizer,
`and Takeda; and has served on a speakers bureau for AbbVie, Astel-
`las, Bristol Myers Squibb, Gilead, Jazz Pharmaceuticals, and Pfizer.
`HDo reports receiving honoraria from Incyte and Servier. DS reports
`receiving grants or contracts, honoraria, consulting fees, and travel
`support from AbbVie, Bristol Myers Squibb, Novartis, and Pfizer; and
`has served in a leadership role for the Belgian College for Reimburse-
`ment of Orphan Drugs. BS reports prior employment with Celgene/
`Bristol Myers Squibb. CLB reports prior employment and stock own-
`ership with Bristol Myers Squibb. TP and GZ report employment and
`stock ownership with Bristol Myers Squibb. AR and DM report
`employment, stock ownership, and patents with Bristol Myers
`Squibb. MU and WLS report employment with Bristol Myers Squibb.
`GJR reports receiving research support from Janssen and has served
`in an advisory position for AbbVie, Agios, Amgen, Astellas, AstraZe-
`neca, Bluebird Bio, Blueprint Medicines, Bristol Myers Squibb,
`Catamaran, Celgene, Glaxo SmithKline, Helsinn, Janssen, Jasper
`Therapeutics, Jazz Pharmaceuticals, Mesoblast, Novartis, Pfizer,
`Roche, Syndax, and Takeda (IRC Chair).
`
`DATA AVAILABILITY STATEMENT
`BMS policy on data sharing may be found at https://www.bms.com/
`researchers-and-partners/independent-research/data-sharing-
`request-process.html.
`
`PATIENT CONSENT STATEMENT
`All patients provided informed written consent. An independent data
`monitoring committee assessed study conduct and safety outcomes.
`
`, Hartmut Döhner 3, Hamid Sayar 4
`Andrew H. Wei 1,2
`,
`, Pau Montesinos 6, Hervé Dombret 7,8,
`Farhad Ravandi 5
`Dominik Selleslag 9, Kimmo Porkka 10, Jun-Ho Jang 11,
`Barry Skikne 12,13, C. L. Beach 13, Thomas Prebet 13, George Zhang 13,
`Alberto Risueño 14, Manuel Ugidos 14, Wendy L. See 13,
`Daniel Menezes 13, Gail J. Roboz 15,16
`
`

`

`CORRESPONDENCE
`
`E87
`
`1Department of Clinical Haematology, The Alfred Hospital, Melbourne,
`Victoria, Australia
`2Australian Centre for Blood Diseases, Monash University, Melbourne,
`Victoria, Australia
`3Ulm University Hospital, Ulm, Germany
`4Indiana University Cancer Center, Indianapolis, Indiana, USA
`5The University of Texas MD Anderson Cancer Center, Houston,
`Texas, USA
`6Hospital Universitario y Politécnico La Fe, Valencia, Spain
`7Hôpital Saint-Louis, Assistance Publique—Hôpitaux de Paris (AP-HP),
`Paris, France
`8Institut de Recherche Saint-Louis, Université Paris Cité, Paris, France
`9AZ Sint-Jan Brugge-Oostende AV, Bruges, Belgium
`10HUS Comprehensive Cancer Center, Hematology Research Unit
`Helsinki and iCAN Digital Precision Cancer Center Medicine Flagship,
`University of Helsinki, Helsinki, Finland
`11Samsung Medical Center, Sungkyunkwan University School of
`Medicine, Seoul, South Korea
`12University of Kansas Cancer Center, Kansas City, Kansas, USA
`13Bristol Myers Squibb, Summit, New Jersey, USA
`14BMS Center for Innovation and Translational Research Europe (CITRE,
`a Bristol-Myers Squibb Company), Seville, Spain
`15Weill Cornell Medicine, New York, New York, USA
`16New York Presbyterian Hospital, New York, New York, USA
`
`Correspondence
`Andrew H. Wei, Department of Clinical Haematology, Peter
`MacCallum Cancer Centre and Royal Melbourne Hospital,
`305 Grattan Street, Melbourne, VIC 3000, Australia.
`Email: andrew.wei@petermac.org
`
`The affiliations provided for the authors “Barry Skikne and CL Beach”
`were the affiliations at the time of study.
`
`ORCID
`Andrew H. Wei
`Hamid Sayar
`Farhad Ravandi
`
`https://orcid.org/0000-0002-7514-3298
`https://orcid.org/0000-0002-1047-8783
`https://orcid.org/0000-0002-7621-377X
`
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`
`SUPPORTING INFORMATION
`Additional supporting information can be found online in the Support-
`ing Information section at the end of this article.
`
`