Leukemia (2017) 31, 34–39
`© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0887-6924/17
`www.nature.com/leu
`
`ORIGINAL ARTICLE
`Maintenance therapy with decitabine in younger adults with
`acute myeloid leukemia in first remission: a phase 2 Cancer
`and Leukemia Group B Study (CALGB 10503)
`W Blum1, BL Sanford2, R Klisovic1, DJ DeAngelo3, G Uy4, BL Powell5, W Stock6, MR Baer7, JE Kolitz8, ES Wang9, E Hoke2, K Mrózek1,
`J Kohlschmidt1,2, CD Bloomfield1, S Geyer10, G Marcucci11 and RM Stone3, RA Larson6 for the Alliance for Clinical Trials in Oncology
`
`In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied
`decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete
`remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with
`hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would
`improve disease-free survival (DFS) for AML patients o60 years, who did not receive allogeneic stem cell transplantation in CR1.
`After blood count recovery from final consolidation, patients received decitabine at 20 mg/m2 intravenously daily for 4–5 days,
`every 6 weeks for eight cycles. One hundred and thirty-four patients received decitabine and 85 (63%) had favorable risk AML.
`The median number of cycles received was 7 (range: 1–8) and the primary reason for discontinuation was relapse. DFS at 1 year and
`3 years was 79% and 54%, respectively. These results are similar to the outcomes in the historical control comprising similar patients
`treated on recent CALGB trials. Thus, maintenance with decitabine provided no benefit overall. Standard use of decitabine
`maintenance in younger AML patients in CR1 is not warranted. This trial was registered at www.clinicaltrials.gov as NCT00416598.
`
`Leukemia (2017) 31, 34–39; doi:10.1038/leu.2016.252
`
`INTRODUCTION
`Although most patients with acute myeloid leukemia (AML)
`achieve remission with initial therapy, especially those aged o60
`years, the majority ultimately relapse and die of disease. Post-
`remission therapies such as transplantation or clinical trials with
`novel agents remain ongoing research priorities. The most
`effective post-remission therapy, allogeneic hematopoietic cell
`transplantation (alloHCT), provides a potentially lifelong graft-
`versus-leukemia effect for select patients. However, the toxicities
`may outweigh the benefits for patients in first remission, who
`have intermediate or
`favorable risk disease.
`In contrast
`to
`‘maintenance therapy’ has been traditionally
`transplantation,
`defined as prolonged but relatively low toxicity treatment. Long-
`term maintenance therapy with conventional cytotoxic drugs
`improves survival in acute lymphoblastic leukemia. However, with
`the notable exception of arsenic trioxide and retinoic acid in acute
`promyelocytic leukemia, no maintenance therapy has proven
`effective in AML.1–5 Given the lack of benefit observed when
`conventional cytotoxic drugs have been used as maintenance in
`AML, agents with alternative mechanisms of action are appealing
`for investigation in this area.
`Decitabine and azacitidine have epigenetic activities distinct
`from conventional chemotherapies.6 Although the relationship
`
`between drug-induced DNA demethylation and clinical response
`to these agents remains incompletely understood, both can
`induce and maintain clinical
`responses
`in myelodysplastic
`syndromes (MDS) and in AML.7–15 Both are now approved in the
`United States for treatment of patients with MDS and they are
`frequently used as single agents for older AML patients even
`outside of clinical trials. Critical to successful therapy with these
`azanucleosides is the administration of
`repetitive cycles of
`treatment at regular intervals (for example, 4–6 weeks), allowing
`efficient
`incorporation of drug into the newly synthesized
`nucleotides of myeloid blasts undergoing mitosis during each
`exposure. Such therapy is well tolerated.
`Given these findings, we hypothesized that hypomethylating
`agents would be ideal candidates to test as maintenance therapy
`in AML.
`Indeed, preliminary data with decitabine maintenance
`have provided promising, albeit
`inconclusive, evidence of
`benefit.15 Azacitidine or decitabine maintenance is now under
`study in several clinical trials (including after alloHCT). Further-
`more, based on very limited published data, post-remission
`therapy with a hypomethylating agent is commonly used in
`clinical practice. To determine whether long-term maintenance
`with decitabine was feasible and beneficial for younger adults
`with AML in first remission, we conducted a phase 2 trial within
`
`1Division of Hematology and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; 2The Alliance for Clinical Trials in Oncology Statistics and Data
`Center, Mayo Clinic, Rochester, MN, USA; 3Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; 4Department of Medicine, Washington University in
`St. Louis, St. Louis, MO, USA; 5Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA; 6Department of Medicine, University of Chicago, Chicago, IL,
`USA; 7Department of Medicine and Greenebaum Cancer Center University of Maryland, Baltimore, MD, USA; 8Hofstra North Shore-Long Island Jewish School of Medicine,
`Manhasset, NY, USA; 9Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA; 10Health Informatics Institute, University of South Florida, Tampa, FL, USA and
`11Gehr Family Leukemia Center, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. Correspondence: Dr W Blum, Division of Hematology and the Comprehensive
`Cancer Center, The Ohio State University, B312 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210, USA.
`E-mail: william.blum@osumc.edu
`Preliminary results of this manuscript were presented at the 54th Annual Meeting of the American Society of Hematology, Atlanta, GA, 9 December 2012.
`Received 8 April 2016; revised 14 June 2016; accepted 16 June 2016; accepted article preview online 13 September 2016; advance online publication, 7 October 2016
`
`CELGENE 2136
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`Decitabine maintenance in AML
`W Blum et al
`
`35
`
`the Cancer and Leukemia Group B (CALGB, now part of the
`Alliance for Clinical Trials in Oncology).
`
`PATIENTS AND METHODS
`Eligibility criteria and study design
`Patients were enrolled on CALGB study 10503 at the initial diagnosis of
`AML and received uniform induction and risk-adapted consolidation
`therapies. Eligible patients were adults aged ⩾ 15 and o60 years, with an
`unequivocal histologic diagnosis of non-M3 AML. Patients with myelodys-
`plastic features were eligible only if there was no evidence of MDS
`43 months before enrolment. Patients with therapy-related AML were
`eligible if free of their primary disease with no chemotherapy for at least
`2 years. No prior azacitidine or decitabine therapy was permitted. With the
`exception of including therapy-related AML patients in the current effort,
`these inclusion criteria were the same as in recent studies (with alternative
`investigational maintenance or observation) within CALGB for the same
`population. Patients registered to maintenance on those studies served as
`the historical reference group for the current, non-randomized study of
`decitabine maintenance. Written informed consent and approval by
`institutional review boards were required at each participating institution.
`
`Treatment: induction and consolidation
`Induction and risk-adapted consolidation therapies were identical to the
`standard treatment arms of the historical reference CALGB studies in this
`patient population. Induction used daunorubicin 90 mg/m2/day intrave-
`nously (IV) on days 1–3, etoposide 100 mg/m2/day IV on days 1–3 and
`IV on days 1–7 (‘3+3+7’).
`cytarabine 100 mg/m2/day continuous
`If necessary, a second induction course was given on a 2+2+5 schedule
`for those with persistent disease on day 14 (45% blasts and at least 20%
`cellular marrow). Post-remission consolidation chemotherapy was assigned
`depending on molecular and/or cytogenetic risk. Patients requiring
`alloHCT were removed from the study before receiving consolidation or
`maintenance, as feasible. Patients with core-binding factor (CBF) AML, that
`t(8;21)(q22;q22)/RUNX1-RUNX1T1 or
`is patients with either
`inv(16)
`(p13.1q22), or t(16;16)(p13.1;q22)/CBFB-MYH11 detected by cytogenetic
`and/or molecular methods,16 received three cycles of high-dose cytarabine
`(HIDAC, 3 gm/m2 over 3 h, every 12 h, on days 1, 3 and 5). All other
`patients underwent chemo-mobilization with HIDAC (2 gm/m2 every 12 h
`for 8 doses) with etoposide (10 mg/kg/day IV continuous infusion days
`1–4; total dose of 40 mg/kg) followed by filgrastim for collection of stem
`cells. These patients then received autologous hematopoietic stem cell
`transplantation (autoHCT) following high-dose busulfan and etoposide as
`previously described.17,18 Patients ineligible for autoHCT received two
`additional cycles of standard HIDAC consolidation following one cycle of
`HIDAC/etoposide.
`Disease evaluation time points and follow-up during maintenance
`included bone marrow aspiration and biopsy every 3–4 months for 1 year
`after completion of consolidation therapy, then every 6 months for 2 years.
`These same time points were also used as previously done in the historical
`control, which included patients who received investigational recombinant
`interleukin-2 (rIL-2) maintenance or observation during first complete
`remission (CR1) in prior CALGB trials.
`
`Maintenance: treatment with decitabine
`Patients remaining in CR after consolidation were scheduled to receive
`eight cycles of decitabine IV over 1 h at 20 mg/m2/day for 5 days, every
`6 weeks. To be eligible for maintenance, patients were required to have
`adequate recovery of neutrophils (41 × 109/l) and platelets (475 × 109/l)
`and be within 90 days of autoHCT or 60 days of last HIDAC, if no autoHCT.
`Patients were required to have blood count recovery (as noted above)
`before starting each subsequent cycle of decitabine as well. If necessary, a
`2-week delay before the next cycle of decitabine was permitted to allow
`count recovery. For grade 4 neutropenia lasting more than 2 weeks or
`grade 4 thrombocytopenia lasting more than 1 week after decitabine
`therapy, 1 day of treatment was deleted from the subsequent cycle.
`However, a minimum of 3 days of decitabine per cycle was required, in
`order
`to continue protocol
`therapy. The schedule of decitabine
`was shortened to 4 days for patients consolidated with autoHCT when
`pre-planned thresholds for prolonged neutropenia were exceeded after
`20 patients were treated. Patients consolidated with only HIDAC
`chemotherapy (no auto-HSCT) continued on the original 5-day/cycle
`treatment schedule.
`
`Criteria for response and toxicity
`CR was defined as bone marrow biopsy ⩾ 20% cellularity with o5% blasts
`at the time of hematologic recovery (neutrophils 41 × 109/l and platelets
`4100 × 109/l), following one or two cycles of induction. The NCI Common
`Toxicity Criteria (CTCAE 3.0) were used to grade adverse events.
`
`Quality control, quality assurance and auditing
`Patient registration, data collection and all statistical analyses were carried
`out by the Alliance for Clinical Trials in Oncology Statistics and Data Center.
`The medical records of 91% of patients receiving decitabine maintenance
`were audited (in addition, 26% of all other patients enrolled on CALGB
`10503 were audited); records from each participating institution were
`reviewed. Data quality was ensured by review of data by the Alliance
`Statistics and Data Center and by the study chairperson following Alliance
`policies.
`
`Cytogenetic and molecular analyses
`Pretreatment cytogenetic analyses were performed by the institutional
`cytogenetic laboratories and the results were confirmed by central
`karyotype review.19 For the karyotype to be classified as normal, ⩾ 20
`metaphase cells from bone marrow specimens subjected to short-term
`culture must have been analyzed.19 The presence or absence of
`FLT3-internal tandem duplication20,21 and mutations in the CEBPA22 and
`NPM1 (Becker et al.23) genes were evaluated centrally. The patients were
`categorized according to the European LeukemiaNet classification.24
`
`Statistical analysis
`The primary endpoint of the study was 1-year disease-free survival (DFS)
`for non-CBF AML patients who registered for decitabine maintenance
`therapy. DFS was defined as the time from documented CR to time of
`relapse or death. Overall survival (OS) was calculated as the time from
`study entry (that is, before induction treatment) to death from any cause.
`Event-free patients were censored at the time of their last follow-up.
`No interim analysis was planned. This study was designed with separate
`decision criteria for non-CBF AML patients and for CBF AML patients. Each
`of these subgroups was evaluated using phase 2 decision criteria that were
`calibrated to the historical reference group patients who were treated with
`the same induction and risk-adapted consolidation strategy as on prior
`CALGB trials for this patient population. The historical reference group
`comprised previous studies in this target population, which included a
`maintenance component, namely rIL-2 or observation. Additional follow-
`up data for the reference group (specifically from CALGB 19808) became
`available during the course of the current trial, allowing further calibration
`of study results relative to the reference group including consideration
`of European LeukemiaNet-risk group assignment. For
`the non-CBF
`AML patients, the statistical design required 75 patients registered to
`receive decitabine maintenance, to detect an increase of 0.15 in the true
`1-year DFS rate. Similarly, for the CBF AML patients, 32 patients were
`required to detect an increase of 0.20 in the 1-year DFS rate relative to the
`reference cohort. Designs for each group provided at least 90% power and
`assumed a type I error constraint of 10%.
`Patient characteristics were summarized using descriptive statistics.
`Comparisons of these characteristics between groups used either χ2-
`two-sample t-tests or one-way
`statistics for categorical variables or
`analyses of variance for continuous variables, or their nonparametric
`equivalents in the setting of non-normality and/or small subgroup
`numbers. DFS and OS were evaluated using the Kaplan–Meier method
`and differences between groups were assessed using log rank statistics.
`DFS and OS rates and specific time points were based on estimates from
`the DFS and OS distribution through Kaplan–Meier analyses.
`
`RESULTS
`Patient characteristics
`Five hundred and forty-six newly diagnosed AML patients enrolled
`upfront on CALGB 10503 from 23 January 2007 through 30 July
`2010. The median age was 48 years (range: 17–60) and the median
`12.6 × 109/l
`(range:
`presenting white
`blood
`count was
`0.3–380 × 109/l). Overall, 76% of patients achieved CR (414/546)
`and 32% of the CR patients (134/414) subsequently received the
`investigational maintenance. Reasons for patients who achieved
`
`© 2017 Macmillan Publishers Limited, part of Springer Nature.
`
`Leukemia (2017) 34 – 39
`
`

`

`36
`
`Decitabine maintenance in AML
`W Blum et al
`
`CR but did not ultimately receive the maintenance therapy
`included removal
`from study (especially for alloHCT), patient
`refusal, inadequate count recovery after consolidation, and early
`relapse among others (Table 1).
`Of the 134 patients who registered for maintenance, 46 (34%)
`had CBF AML of whom all had received consolidation with HIDAC.
`Among the remaining 88 patients, 74 had received consolidation
`with autoHCT and 14 had received HIDAC-based consolidation.
`The median time from initial study registration to initiation of
`maintenance therapy was 6.3 months (range: 4.6–11.0). Patients
`receiving decitabine had a median age of 45 years (range: 18–60)
`and presenting white blood count of 13.5 × 109/l
`(range:
`0.4–221 × 109/l). Patients who received maintenance were in the
`following European LeukemiaNet genetic risk groups: Favorable
`(63%), Intermediate-I (10%), Intermediate-II (12%), Adverse (7%)
`and unknown (7%). This risk group breakdown is quite similar to
`that in the most contemporary part of the historical reference
`group for which molecular data were available (CALGB 19808;
`Table 2). Likewise, clinical characteristics were well matched
`(Supplementary Table 1) between the study group and 19808.
`
`Feasibility
`Treatment with decitabine was well tolerated and generally well
`accepted by patients and physicians. A total of 770 cycles of
`decitabine were given; the median number of cycles given per
`patient was 7 (range: 1–8). Forty-six percent of patients received
`all eight planned cycles; relapse was the most common reason for
`treatment discontinuation. Seventy-five percent of patients
`received at least four cycles. Discontinuation due to patient
`refusal occurred in 13%. Grade 3 or higher adverse events are
`listed in Table 3 and are notable for the expected myelosuppres-
`sion. Serious complications resulting from myelosuppression were
`rare. Considering the total of all cycles administered, 59% of cycles
`(456/770) resulted in grade 3 or higher neutropenia, but only
`4% (28/770) had grade ⩾ 3 infection.
`
`Outcomes
`For the patients who received post-remission maintenance with
`decitabine, 1-year and 3-year DFS were 79% (95% confidence
`interval, 71–85%) and 54% (45–62%), and 1-year and 3-year OS
`were 96% (90–98%) and 68% (59–75%), respectively. The median
`follow-up for the study group with 95% confidence interval was
`
`Table 1. Reasons for study discontinuation prior to decitabine
`maintenance therapy for patients who achieved complete remission
`
`Treatment course
`
`Number
`
`% of CR
`patients
`
`Achieved CR, received maintenance
`Achieved CR, no maintenance
`
`134
`280
`
`32
`68
`
`Reasons for no maintenance
`Early relapse
`Withdrew for non-protocol therapy
`(alloHCT in CR1)
`Patient refused
`Unresolved toxicity after consolidation
`Ineligible due to low counts (post
`autoHCT)
`Death during consolidation
`Insurance denial
`Others
`
`29
`96 (86)
`
`7
`23 (21)
`
`44
`33
`38
`
`6
`4
`30
`
`11
`8
`9
`
`1
`o1
`7
`
`Abbreviations: alloHCT, allogeneic hematopoietic stem cell transplantation;
`autoHCT, autologous hematopoietic stem cell transplantation; CR1, first
`complete remission.
`
`56.7 months (18.5–not estimable). For CBF AML patients, 1-year
`DFS was 80% (66–89%); for non-CBF AML patients, 1-year DFS was
`78% (68–86%) (see Figure 1). The use of decitabine maintenance
`did not provide any apparent benefit for DFS or OS relative to the
`historical reference group, as a whole or within the CBF AML or
`non-CBF AML subsets, respectively. Likewise, the results with
`respect to DFS and OS from this study were virtually identical to
`those seen with comparable patients treated on the immediately
`preceding trial in this population CALGB 19808 (the only study in
`the historical control with adequate molecular characterization of
`FLT3, NPM1 and CEBPA; Supplementary Figure 1).
`
`DISCUSSION
`For AML patients in remission after intensive therapy, there are
`currently no compelling data to justify standard use of any long-
`term maintenance therapy. At least for conventional cytotoxic
`drugs, previous trials proved that prolonged low-dose main-
`tenance is not better than intensive therapy,25 yielding, at best, a
`modest improvement in DFS but not in OS.26 The likelihood of
`achieving a second remission is reduced when relapses occur
`while patients are receiving conventional maintenance therapy,
`suggesting the emergence of drug resistance. Thus, conventional
`maintenance therapy in AML has been largely abandoned due to
`lack of efficacy.
`Investigational use of drugs with alternative
`mechanisms of action remains of interest, but results have been
`disappointing with agents such as gemtuzumab ozogamicin27,28
`or, more recently, rIL-2 with or without histamine dihydrochloride.29–36
`One study with rIL-2/histamine dihydrochloride showed a statistically
`significant DFS benefit but no benefit for OS;35 however, a recent
`meta-analysis, plus a subsequent report of a randomized trial from the
`Alliance, further dampen enthusiasm for the use of rIL-2 in remission
`maintenance in AML.29,36
`Hypomethylating agents, namely decitabine and azacitidine,
`may be useful to maintain or deepen AML/MDS responses. In a
`randomized phase III study for higher risk MDS, prolonged therapy
`
`Table 2. Patient risk (by ELN classification) and clinical outcomes for
`CALGB 10503 patients receiving maintenance were similar to those
`from the most recent CALGB trial in this population with alternative
`maintenance therapy (19808a).
`
`Characteristic
`
`CALGB 10503 CALGB 19808 P-valueb
`
`ELN Genetic Group, number (%)c
`Favorable
`Intermediate-I
`Intermediate-II
`Adverse
`Unknown
`3-Year OS, %
`3-Year DFS, %
`
`85 (63)
`13 (10)
`16 (12)
`10 (7)
`10 (7)
`68
`54
`
`94 (44)
`28 (13)
`36 (17)
`10 (5)
`46 (21)
`61/68
`45/56
`
`0.07
`
`Abbreviations: DFS, disease-free survival; ELN, European LeukemiaNet;
`FLT3-ITD, FLT3-internal tandem duplication; OS, overall survival. aPatients
`randomized to observation/rhIL-2 maintenance.29 bP-value is from Fisher’s
`exact test (not including unknowns). cThe patients were categorized
`according to the ELN classification24 as follows: Favorable Genetic Group
`included patients with t(8;21) or
`inv(16)/t(16;16) and cytogenetically
`normal AML patients who harbored mutated CEBPA and/or mutated
`NPM1 without FLT3-ITD;
`Intermediate-I Group included the remaining
`cytogenetically normal AML patients who had wild-type CEBPA and
`mutated NPM1 with FLT3-ITD or wild-type NPM1 with or without FLT3-
`ITD; Intermediate-II Group included patients with t(9;11) and those with all
`other chromosome abnormalities that were not classified as Favorable or
`Adverse; and Adverse Group included patients with inv(3)/t(3;3), t(6;9), t
`(v;11)(v;q23), -5 or del(5q), -7, abn(17p) and complex karyotype with X3
`abnormalities.
`
`Leukemia (2017) 34 – 39
`
`© 2017 Macmillan Publishers Limited, part of Springer Nature.
`
`

`

`Decitabine maintenance in AML
`W Blum et al
`
`37
`
`included post-autoHCT patients who likely would not have
`tolerated a more intensive dose or more frequent schedule
`of decitabine maintenance therapy, at
`least
`in the early
`months following recovery from the transplant.
`It is possible,
`albeit unlikely,
`that an alternative dose, route or schedule
`of decitabine, or with different
`intensive induction or
`post-remission strategies before maintenance, would yield
`different results.
`There was a higher proportion of CBF AML patients who
`registered for maintenance therapy with decitabine than that in
`the previous rIL-2 maintenance trials conducted in the Alliance.
`Whether this difference in CBF AML patients was due to greater
`familiarity with and acceptance of decitabine (rather than rhIL-2)
`as maintenance for AML, or due to improved protocol compliance
`in successive investigational maintenance studies within the
`Group is unknown. Preliminary laboratory data showing a
`potential role for aberrant DNA methyltransferase activity in CBF
`AML37 and clinical cases of CBF AML that had achieved
`CR following treatment with single agent decitabine12 bolstered
`our hypothesis that this subset would benefit from decitabine and
`may have also contributed to more robust recruitment of CBF AML
`patients. Although the study was not powered to detect small
`differences in survival for CBF AML patients, there did not appear
`to be clinical benefit in this subset of patients from decitabine
`maintenance.
`These results do not extinguish hope that maintenance
`therapy with a hypomethylating agent might prove useful
`in
`selected patient populations.
`Included among these areas of
`ongoing research interest are patients who are older, post-
`alloHCT for high-risk AML, or perhaps, with unique molecular
`features. Several ongoing studies should help to address these
`questions. Most notably among these, Eastern Cooperative
`Oncology Group is evaluating decitabine maintenance in older
`AML patients after either clofarabine or daunorubicin-based
`induction (NCT01041703), the Bone Marrow Transplant Clinical
`Trials Network recently completed accrual
`for azacitidine
`maintenance after alloHCT for AML in first CR (NCT01168219)
`and another trial is currently exploring the use of oral azacitidine
`maintenance in older AML patients (NCT01757535), respectively.
`Each study will provide important data in this area. However,
`our results suggest that use of hypomethylating agents for
`prolonged maintenance,
`following remission achieved by
`conventional means and with intensive consolidation therapy,
`should remain investigational.
`
`CONFLICT OF INTEREST
`The authors declare no conflict of interest.
`
`ACKNOWLEDGEMENTS
`We thank patients and their families, collaborators and staff in the CALGB and
`Alliance member institutions/data center and the Alliance Leukemia Tissue Bank/Ms
`Donna Bucci. We also thank John C Byrd, MD, and the team in the Leukemia and
`Leukemia Correlative Science Committees for
`the Alliance for
`review of
`the
`manuscript and assistance with molecular data. This trial was sponsored by the
`NCI Cancer Therapy Evaluation Program. We gratefully acknowledge the enormous
`contributions to this study and to the field of medicine by our friend Dr Meir Wetzler
`(deceased February 2015). Research reported in this publication was supported by
`the National Cancer Institute of the National
`Institutes of Health under Award
`Numbers U10CA31946, U10CA33601 (to CALGB), U10CA180821 and U10CA180882
`(to the Alliance for Clinical Trials in Oncology), and NIH/NCI K23CA120708. Additional
`support was provided under CA140158, CA016058, CA180850, CA101140 and
`CA128377. The content is solely the responsibility of the authors and does not
`necessarily represent the official views of the National Institutes of Health.
`
`Table 3. Adverse events Grade 3 or higher among 132 patients
`receiving decitabine maintenance therapy
`
`Adverse eventa
`
`Grade 3
`
`Grade 4b
`
`Neutropenia
`Thrombocytopenia
`Anemia
`Febrile neutropenia
`Infection with oGrade 3 ANC
`Infection with ≥ Grade 3 ANC
`Fatiguea
`Paina
`ALTa
`Dyspnea*
`
`Number
`
`16
`43
`15
`13
`3
`9
`9
`7
`4
`4
`
`%
`
`12
`33
`11
`10
`2
`7
`7
`5
`3
`3
`
`Number
`
`103
`52
`0
`1
`0
`0
`0
`0
`0
`0
`
`%
`
`79
`40
`0
`1
`0
`0
`0
`0
`0
`0
`
`Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count.
`aNon-hematologic toxicities include all Grade 3+ toxicities occurring in at
`least 3% of patients. bNo Grade 5 events occurred during maintenance
`therapy without relapse of
`leukemia (for example, there was no fatal
`drug toxicity).
`
`DFS by CBF status
`
`+ Censor
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`proportion surviving
`
`0
`
`Favorable-
`Unfavorable-
`
`46
`88
`
`20
`
`31
`56
`
`60
`40
`time (months)
`number at risk
`12
`26
`19
`40
`
`80
`
`2
`2
`
`100
`
`0
`0
`
`Figure 1. DFS of patients with CBF AML (blue) or non-CBF AML (red),
`who received maintenance decitabine.
`
`low-dose azacitidine significantly improved
`with single-agent,
`OS compared with conventional care regimens, despite a low
`overall CR rate.9 Notably, a subset of patients with low blast
`count AML (20–30% blasts) had a survival benefit with
`prolonged azacitidine treatment (median survival, 24.5 versus
`16.0 months for conventional care regimens).10 Several sche-
`dules of prolonged therapy with low-dose decitabine have also
`shown promise for AML.11–15 A low incidence of treatment-
`related toxicity for these agents, beyond myelotoxicity, sup-
`ported their development into trials of frontline therapy for
`‘unfit’ older AML patients and into maintenance therapy for a
`range of patients and disease states. Accordingly, the federal
`website www.clinicaltrials.gov currently lists nearly 20 active
`clinical trials that employ some form of investigational maintenance
`therapy with a hypomethylating agent.
`Despite promise seen with decitabine maintenance in a small
`randomized study,15 our trial found no benefit to 1 year of
`maintenance therapy in younger patients with AML in first CR
`compared with a well-matched and uniformly treated historical
`control. A number of factors could have contributed to this
`negative result. It is possible that the efficacy of the drug was
`diminished by a suboptimal schedule or dose, but this study
`
`© 2017 Macmillan Publishers Limited, part of Springer Nature.
`
`Leukemia (2017) 34 – 39
`
`

`

`38
`
`Decitabine maintenance in AML
`W Blum et al
`
`AUTHOR CONTRIBUTIONS
`WB was the Study Chair of the clinical trial. RAL was the Chair of the Leukemia
`Committee for the Alliance (formerly CALGB). GM also assisted in the design of
`the study. WB, RK, DJD, GU, BLP, WS, MRB, JEK, ESW, GM, RMS and RAL enrolled
`patients, provided clinical management and facilitated the conduct of the
`study. SG, BLS and JK provided statistical support. EH and BLS managed the
`database. WB and RK audited the data case report forms. CDB provided support
`and oversight for molecular studies. KM assisted with data acquisition and
`interpretation, manuscript writing and formatting. All authors reviewed the
`results and approved manuscript submission.
`
`REFERENCES
`1 Champlin R, Jacobs A, Gale RP, Boccia R, Elashoff R, Foon K et al. Prolonged
`survival in acute myelogenous leukaemia without maintenance chemotherapy.
`Lancet 1984; 1: 894–896.
`2 Raza A, Preisler HD, Browman GP, Larson RA, Rustum YM, Goldberg J et al.
`Long-term outcome of patients with acute myelogenous leukemia: the role of
`maintenance therapy, consolidation therapy and the predictive value of two
`in vitro assays. Leuk Lymphoma 1993; 10: 57–66.
`Imbach P, Maurice P et al.
`3 Sauter C, Berchtold W, Fopp M, Gratwohl A,
`chemotherapy
`after
`early
`Acute myelogenous
`leukaemia: maintenance
`consolidation treatment does not prolong survival. Lancet 1984; 1: 379–382.
`4 Büchner T, Berdel WE, Schoch C, Haferlach T, Serve HL, Kienast J et al. Double
`induction containing either two courses or one course of high-dose cytarabine
`plus mitoxantrone and postremission therapy by either autologous stem-cell
`transplantation or by prolonged maintenance for acute myeloid leukemia. J Clin
`Oncol 2006; 24: 2480–2489.
`5 Büchner T, Hiddemann W, Berdel WE, Wörmann B, Schoch C, Fonatsch C et al.
`6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and
`mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged
`maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of
`intensive consolidation by sequential HAM in adult patients at all ages with
`de novo acute myeloid leukemia (AML): a randomized trial of the German
`AML Cooperative Group. J Clin Oncol 2003; 21: 4496–4504.
`6 Santini V, Kantarjian HM,
`Issa JP. Changes in DNA methylation in neoplasia:
`pathophysiology and therapeutic implications. Ann Intern Med 2001; 134:
`573–586.
`7 Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-
`Reissig R et al. Randomized controlled trial of azacitidine in patients with the
`myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin
`Oncol 2002; 20: 2429–2440.
`Issa J-PJ, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J et al.
`8 Kantarjian H,
`Decitabine improves patient outcomes in myelodysplastic syndromes: results of a
`phase III randomized study. Cancer 2006; 106: 1794–1803.
`9 Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A et al.
`Efficacy of azacitidine compared with that of conventional care regimens in the
`treatment of higher-risk myelodysplastic syndromes: a randomised, open-label,
`phase III study. Lancet Oncol 2009; 10: 223–232.
`10 Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U
`et al. Azacitidine prolongs overall survival compared with conventional care
`regimens in elderly patients with low bone marrow blast count acute myeloid
`leukemia. J Clin Oncol 2010; 28: 562–569.
`11 Issa J-PJ, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S et al. Phase 1
`study of low-dose prolonged exposure schedules of the hypomethylating agent
`5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 2004;
`103: 1635–1640.
`12 Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S et al.
`Clinical response and miR-29b predictive significance in older AML patients
`treated with a 10- day schedule of decitabine. Proc Natl Acad Sci USA 2010; 107:
`7473–7478.
`13 Cashen AF, Schiller GJ, O'Donnell MR, DiPersio JF. Multicenter, phase II study of
`decitabine for the first-line treatment of older patients with acute myeloid
`leukemia. J Clin Oncol 2010; 28: 556–561.
`14 Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J et al.
`Multicenter, randomized, open-label, phase III trial of decitabine versus patient
`choice, with physician advice, of either supportive care or low-dose cytarabine for
`the treatment of older patients with newly diagnosed acute myeloid