Regular Article
`
`CLINICAL TRIALS AND OBSERVATIONS
`
`Azacitidine maintenance after intensive chemotherapy
`improves DFS in older AML patients
`
`Gerwin Huls,1 Dana A. Chitu,2 Violaine Havelange,3 Mojca Jongen-Lavrencic,4 Arjan A. van de Loosdrecht,5 Bart J. Biemond,6 Harm Sinnige,7
`Beata Hodossy,8 Carlos Graux,9 Rien van Marwijk Kooy,10 Okke de Weerdt,11 Dimitri Breems,12 Saskia Klein,13 J ¨urgen Kuball,14
`Dries Deeren,15 Wim Terpstra,16 Marie-Christiane Vekemans,3 Gert J. Ossenkoppele,5 Edo Vellenga,1 Bob L ¨owenberg,4 and the
`Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON)
`
`1Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 2Department of Hematology, HOVON
`Data Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; 3Department of Hematology, Cliniques Universitaires St. Luc, Brussels, Belgium;
`4Department of Hematology, Erasmus MC, Rotterdam, The Netherlands; 5Department of Hematology, Amsterdam University Medical Center, VU University
`Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; 6Department of Hematology, Amsterdam University Medical Center, Academic
`Medical Center Amsterdam, Amsterdam, The Netherlands; 7Department of Hematology, Jeroen Bosch Hospital, Den Bosch, The Netherlands; 8Department of
`Hematology, Citadelle, Liege, Belgium; 9Department of Hematology, Universit ´e Catholique de Louvain, University Medical Center Catholic University of Leuven
`Namur, Yvoir, Belgium; 10Department of Hematology, Isala Hospital, Zwolle, The Netherlands; 11Department of Hematology, Antonius Hospital, Nieuwegein, The
`Netherlands; 12Department of Hematology, Hospital Network Antwerp (ZNA) Stuivenberg/Middelheim, Antwerp, Belgium; 13Department of Hematology, Meander
`Hospital Amersfoort, Amersfoort, The Netherlands; 14Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands; 15Department of
`Hematology, General Hospital Delta Roeselare, Roeselare, Belgium; and 16Department of Hematology, Our Dear Lady Hospital (OLVG), Amsterdam, The Netherlands
`
`K E Y P O I N T S
`
`l Azacitidine
`maintenance is
`feasible in intensively
`treated older patients
`with newly
`diagnosed AML.
`
`The prevention of relapse is the major therapeutic challenge in older patients with acute
`myeloid leukemia (AML) who have obtained a complete remission (CR) on intensive che-
`motherapy. In this randomized phase 3 study (HOVON97) in older patients (‡60 years) with
`AML or myelodysplastic syndrome with refractory anemia with excess of blasts, in CR/CR
`with incomplete hematologic recovery (CRi) after at least 2 cycles of intensive chemo-
`therapy, we assessed the value of azacitidine as postremission therapy with respect to
`disease-free survival (DFS; primary end point) and overall survival (OS; secondary end point).
`In total, 116 eligible patients were randomly (1:1) assigned to either observation (N 5 60)
`or azacitidine maintenance (N 5 56; 50 mg/m2, subcutaneously, days 1-5, every 4 weeks)
`until relapse, for a maximum of 12 cycles. Fifty-five patients received at least 1 cycle of
`azacitidine, 46 at least 4 cycles, and 35 at least 12 cycles. The maintenance treatment with
`azacitidine was feasible. DFS was significantly better for the azacitidine treatment group
`(logrank; P 5 .04), as well as after adjustment for poor-risk cytogenetic abnormalities at
`diagnosis and platelet count at randomization (as surrogate for CR vs CRi; Cox regression;
`hazard ratio, 0.62; 95% confidence interval, 0.41-0.95; P 5 .026). The 12-month DFS was
`estimated at 64% for the azacitidine group and 42% for the control group. OS did not differ between treatment groups,
`with and without censoring for allogeneic hematopoietic cell transplantation. Rescue treatment was used more often
`in the observation group (n 5 32) than in the azacitidine maintenance group (n 5 9). We conclude that azacitidine
`maintenance after CR/CRi after intensive chemotherapy is feasible and significantly improves DFS. The study is registered
`with The Netherlands Trial Registry (NTR1810) and EudraCT (2008-001290-15). (Blood. 2019;133(13):1457-1464)
`
`l Azacitidine
`maintenance, with
`adjustment for poor
`risk cytogenetic risk
`at diagnosis and
`platelet count at
`randomization,
`improves DFS.
`
`Introduction
`About 75% of patients with acute myeloid leukemia (AML) are
`60 years of age or older.1 After intensive chemotherapy, complete
`remission (CR) rates in the range of 40% to 55% are generally
`attained, resulting in median disease-free survival
`(DFS) of
`between 6 and 12 months.2-8 The prevention of relapse is the
`major therapeutic challenge in older patients with AML who
`are in CR after intensive chemotherapy. No postremission treat-
`ment to prevent relapse has been established and gener-
`ally accepted in this setting, except for the use of allogeneic
`
`hematopoietic cell transplantation (allo-HCT) for a selected group
`of relatively fit patients.9-11 Although there is a long-standing in-
`terest in maintenance therapies such as interleukin 2,12-14 low-
`dose cytarabine,15 and gemtuzumab ozogamicin16 after intensive
`induction treatment, the clinical benefits of such maintenance
`therapy have remained controversial.17
`
`Potential candidates for maintenance treatment include hypo-
`methylating agents such as decitabine and azacitidine, which
`have proven efficacy and limited extra medullary toxicity in older
`
`© 2019 by The American Society of Hematology
`
`CELGENE 2150
`APOTEX v. CELGENE
`IPR2023-00512
`
`blood® 28 MARCH 2019 | VOLUME 133, NUMBER 13 1457
`
`

`

`individuals.18-20 A small randomized study comparing decitabine
`(20 mg/m2 for 5 days every 4-8 weeks) with conventional care
`(observation, low-dose cytarabine or intensive chemotherapy)
`was prematurely discontinued without showing a lower relapse
`rate for the 20 patients in the decitabine group.21 A phase 2
`study exploring decitabine maintenance (20 mg/m2 for 4-5 days
`every 6 weeks for 8 cycles) in 134 younger patients with AML in
`CR1 did not show better DFS compared with historical controls
`(1- and 3-year DFS, 79% and 54%, respectively).22 Various other
`small studies involving small numbers of patients explored
`azacitidine maintenance, but did not yield any conclusive data
`on its usefulness.23,24
`
`Here we present the final analysis of the HOVON97 study. In this
`phase 3 study in older patients ($60 years) with AML or MDS-
`refractory anemia with excess of blasts, subjects in CR/CR with
`incomplete hematologic recovery (CRi) after at least 2 cycles of
`intensive chemotherapy were randomly assigned to receive
`either azacitidine as postremission therapy or no further treat-
`ment (observation). The aim was to assess the value of main-
`tenance treatment with respect to DFS (primary end point) and
`overall survival (OS; secondary end point).
`
`Methods
`Study design and treatment
`In this study of
`the Dutch-Belgian Hemato-Oncology Co-
`operative Group (HOVON97), patients who had entered CR or
`CRi after at least 2 cycles of remission-induction chemotherapy
`were randomly assigned to 12 cycles of azacitidine (50 mg/m2
`subcutaneously for 5 days every 4 weeks) or to observation (no
`further treatment). Randomizations were balanced by minimi-
`zation with the factors hospital, platelet count (,100 3 109/L
`vs $100 3 109/L) at randomization, and cytogenetic risk at
`diagnosis (favorable/intermediate vs unfavorable). Between
`30 June 2009 and 1 December 2016 a total of 118 patients were
`registered in the study. Two patients were considered ineligible
`(1 was registered twice; the second patient had no CR/CRi), so
`that a total of 116 eligible patients were randomized and in-
`cluded in the analyses. Azacitidine was provided free of charge
`by Celgene. The study was approved by the ethics committees
`of the participating institutions, and was conducted in accordance
`with the Declaration of Helsinki. The HOVON97 study is regis-
`tered with The Netherlands Trial Registry (NTR1810) and EudraCT
`(2008-001290-15). The database was locked on July 12, 2018.
`
`Eligibility
`Patients with an initial cytopathologically confirmed diagnosis of
`AML (M0-M2 and M4-M7) and a minimum of 20% blast infiltrate
`in the bone marrow, who were 60 years of age or older, were
`eligible, provided they had a World Health Organization (WHO)
`performance status of 2 or less and had given their written in-
`formed consent and had less than 5% bone marrow blasts after
`2 cycles of induction chemotherapy. Eligibility also included an
`initial subtype of the MDS (ie, refractory anemia with excess of
`blasts) with an International Prognostic Scoring System score of
`1.5 or higher and less than 5% bone marrow blasts after 2 cycles
`of induction chemotherapy. Patients with extramedullary disease,
`AML after previous polycythemia rubra vera or primary myelofi-
`brosis, blast crisis of CML or AML-FAB-M3, or AML with cytoge-
`netic abnormality t15,17, and patients with a concurrent severe
`
`and/or uncontrolled medical condition or cardiac dysfunction were
`considered not eligible. For randomization, postremission patients
`were required to be in CR/CRi after at least 2 cycles of intensive
`chemotherapy, and to have an absolute neutrophil count greater
`than 0.5 3 109/L and a platelet count greater than 50 3 109/L.
`
`Patient characteristics and classification
`On the basis of karyotype at diagnosis, patients were classified
`into distinct prognostic categories. Patients with core binding
`factor abnormalities [t8,21(q22;q22), inv16(p13.1q22), or t16,
`16(p13.1;q22)] were classified as favorable risk. Patients without
`cytogenetic abnormalities or with loss of X or Y as the only
`abnormality were classified as normal cytogenetics. Patients with
`complex karyotypes [$3 abnormalities; 25(q), 27(q), abn (3q)]
`were classified as unfavorable risk. The remaining patients with
`AML were classified as intermediate risk.
`
`Statistical analysis, criteria of response, and
`evaluation of outcome
`The primary objective of this study in postremission patients was
`to compare the value, in relation to DFS, of azacitidine therapy
`(intervention group) and no further therapy (observation group).
`DFS was measured from the date of randomization to relapse
`or death from any cause, whichever came first. Cox regression
`analysis with adjustment for the stratification factors (except
`center) was the primary analysis for this comparison. According
`to the protocol, bone marrow aspirate had to be performed after
`24 weeks (observation group) or after 6 cycles (azacitidine group),
`and in case of suspicion of relapse (in both groups). The com-
`pliance to these bone marrow evaluations was fairly reasonable,
`with 7 patients (observation) vs 8 patients (azacitidine) of whom no
`bone marrow aspirate was performed at approximately 6 months.
`
`Secondary objectives were to evaluate the effects of azacitidine
`after remission in relation to OS measured from the date of
`randomization, probability of relapse and death after inclusion
`from date of randomization (calculated as competing risks), and
`number and duration of hospitalizations, transfusion require-
`ments (red cell and platelet transfusion), and adverse events. CR
`was defined as a cellular marrow with less than 5% blasts, no
`Auer rods, no evidence of extramedullary leukemia, and pe-
`ripheral granulocyte and platelet counts of at least 1.0 3 109/L
`and 100 3 109/L, respectively. CRi was defined as CR except
`for residual neutropenia (,1.0 3 109/L) or thrombocytopenia
`(,100 3 109/L). Relapse was defined as recurrence of leukemia
`after CR or CRi. OS was measured from the date of registration
`until death from any cause. Patients known to be still alive at the
`date of last contact were then censored.
`
`Based on our experience with the previous HOVON43 study, in
`the present study, we estimated that 40% of patients in the ob-
`servation group would have a DFS of 12 months.2 We hypoth-
`esized that 60% of patients in the azacitidine maintenance group
`would have a DFS of 12 months. A target number of 126 patients,
`with 97 events required, would give a power of 80% to detect this
`difference with a 2-sided test at 5% significance level, an accrual
`period of 3 years, and an additional follow-up of 1 year.
`
`All analyses were performed according to intention to treat,
`irrespective of protocol compliance. The log-rank test and Cox
`regression analysis were used to analyze the differences between
`
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`Table 1. Patient characteristics
`
`Sex, male/female
`
`Age, median/range
`
`WHO performance
`WHO 0
`WHO 1
`WHO 2
`Unknown
`
`Unfavorable risk cytogenetic abnormalities at
`diagnosis*
`
`CR(i) obtained after
`Induction cycle 1
`Induction cycle 2
`
`Platelet count $100 3 109/L
`
`Neutrophils, 3109/L
`Median
`Range
`
`CR
`
`MDS-refractory anemia with excess of blasts
`
`Observation group (N 5 60)
`
`Azacitidine group (N 5 56)
`
`33/27 (55%/45%)
`
`69/60-79
`
`23 (38%)
`34 (57%)
`—
`3 (5%)
`
`14 (23%)
`
`45 (75%)
`15 (25%)
`
`45 (75%)
`
`4.1
`1.5-38
`
`45 (75%)
`
`6 (10%)
`
`35/21 (63%/37%)
`
`69/64-81
`
`29 (52%)
`17 (30%)
`5 (9%)
`5 (9%)
`
`9 (16%)
`
`35 (63%)
`21 (37%)
`
`38 (68%)
`
`3.3
`0.6-13.7
`
`37 (66%)
`
`6 (11%)
`
`All characteristics were obtained from randomization except unfavorable risk cytogenetic abnormalities, which were obtained at diagnosis.
`*27, 27q, 25, 25q, abn 3q, complex $3 abnormalities.
`
`both groups with respect to OS and DFS. These analyses were
`performed without and with adjustment for platelet count
`(,100 vs $100) at randomization and cytogenetic risk classi-
`fication at diagnosis. All P values reported are 2-sided.
`
`Possible heterogeneity of the treatment effects between sub-
`groups (poor-risk cytogenetic abnormalities at diagnosis [yes vs
`no], platelet count [$100 vs ,100 3 109/L] at randomization,
`age [younger vs older than median age 69 years], cycles to
`CR/CRi [1 vs 2], and performance status [0 vs $1]) were explored.
`For each of the variables, a multivariate Cox regression with
`treatment group, variable, and treatment group 3 variable
`
`interaction term was performed. Only if the hazard ratio (HR) for
`the interaction term was statistically significant different from
`1 (P , .05) were subgroup analyses performed. Otherwise,
`subgroup analyses were not warranted, and the estimate of
`the overall treatment effect also was considered the best
`estimate for the treatment effect within a specific subgroup.
`
`Results
`Patient cohort
`The study was terminated before the accrual of the planned
`126 patients. Because of declining accrual of new patients, it was
`
`Patients with
`AML (except FAB M3 or t(15;17)) or MDS
`RAEB with IPSS ≥1.5 who are sixty years or older
`and have <5% bone
`marrow blasts after 2 cycles
`of (intensive) chemotherapy
`
`R
`
`Arm A
`
`Arm B
`
`Figure 1. Trial design. IPSS, International Prognostic
`Scoring System.
`
`No maintenance
`
`Azacitidine
`maintenance
`50 mg/m2, day 1-5 q 4 wks
`until relapse for a
`maximum of 12 cycles
`
`AZACITIDINE MAINTENANCE IN AML
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`not eligible n=2
` double reg. n=1
`(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:3)(cid:33)5% blast n=1
`
`Randomized
`n=118
`
`Randomized &
`eligible
`n=116
`
`Arm A
`
`Arm B
`
`off protocol n=21 35%
`relapse n=17
`death n=1
`major prot.viol. n=1
`other n=2
`
`off protocol n=10 17%
`relapse n=10
`
`Observation 1-4
`n=60 100%
`month 1 n=60
`month 2 n=57
`month 3 n=53
`month 4 n=47
`
`Observation 5-8
`n=39 65%
`month 5 n=39
`month 6 n=36
`month 7 n=32
`month 8 n=30
`
`Observation 9-12
`n=29 48%
`month 9 n=29
`month 10 n=26
`month 11 n=23
`month 12 n=23
`
`cycles 1-4
`n=55 100%
`1 cycle n=55
`2 cycles n=51
`3 cycles n=47
`4 cycles n=46
`
`cycles 5-8
`n=44 80%
`5 cycles n=44
`6 cycles n=43
`7 cycles n=40
`8 cycles n=38
`
`cycles 9-12
`n=37 67%
` 9 cycles n=37
`10 cycles n=37
`11 cycles n=37
`12 cycles n=35
`
`off protocol n=1
` relapse n=1
`
`off protocol n=11 20%
` n=5
`relapse
`no compliance n=2
`hypoplastic BM abnorm n=2
`excessive extramedullary
`drug toxicity
` n=1
`other
`
` n=1
`
`off protocol n=7 13%
`relapse
`n=6
`other
`n=1
`
`off protocol n=29 48%
`n=5
`relapse
`
`n=1
`death
`
`normal completion n=23
`
`off protocol n=37 67%
`n=1
`relapse
`
`normal completion n=35
`other
`
`n=1
`
`Figure 2. CONSORT study diagram. Arm A, observation; Arm B, azacitidine maintenance. The main reason for failure to complete protocol was intercurrent relapse.
`
`estimated that the number of events, as defined in the original
`statistical plan, could not be reached within a reasonable time.
`The median follow-up time of the 116 evaluable and eligible
`patients still alive at the date of the last contact since the date of
`randomization was 41.4 months. Table 1 presents the charac-
`teristics of the patients enrolled in the observation and azacitidine
`maintenance groups.
`
`protocol (6 relapse, 1 other reason), and finally, after 12 cycles,
`37 patients went off protocol (1 relapse, 1 other reason, 35 protocol
`completion). This is illustrated in the CONSORT flow diagram
`(Figure 2). Interestingly, in the azacitidine group, 35 (63%) of
`56 patients completed protocol treatment, whereas in the
`observation group, this was feasible (ie, alive without relapse
`on protocol) in 23 (38%) of 60 patients.
`
`Feasibility of azacitidine maintenance treatment
`After randomization, 60 patients were assigned to the obser-
`vation group and 56 patients to the azacitidine maintenance
`group (Figure 1). Because 1 patient had a relapse between
`randomization and start of azacitidine postremission treatment,
`55 patients started azacitidine cycles 1 to 4. Subsequently,
`44 patients started cycles 5 to 8 of azacitidine treatment, and
`37 patients started cycles 9 to 12. After 4 cycles, 11 patients went
`off protocol (5 relapse, 2 no compliance, 2 hypoplastic bone
`marrow, 1 excessive extra-medullary toxicity, and 1 other rea-
`son); after 4 additional cycles, another 7 patients went off
`
`The adherence to treatment according to the protocol was high.
`On average, 90% of the azacitidine cycles were given full dose
`according to schedule (mean, 90%; range, 81%-97%). The time
`intervals between 2 consecutive cycles was were 30 days for, on
`average, 86% of the cycles (mean, 86%; range, 76%-90%) and
`between 30 and 40 days for, on average, 10% of the cycles
`(median, 10%; range, 7%-14%).
`
`Azacitidine maintenance was associated with a low transfusion
`dependence, a limited number of nights in the hospital, and
`a limited number of adverse events (AEs) and serious AEs (SAEs)
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`Table 2. Feasibility and safety
`
`Transfusion requirements
`RBC (median/mean), units
`No. of patients receiving no RBC
`Platelets, median/mean
`Patients receiving no platelets, n
`
`Nights in hospital
`Median/mean
`Patients without nights in hospital, n
`
`AEs
`Median
`AE $2 grade (total), n
`
`Patients with SAEs
`0 SAE
`1 SAE
`2 SAE
`3 SAE
`
`RBC, red blood cells.
`
`Observation group (N 5 60)
`
`Azacitidine group (N 5 56)
`
`0/1
`55 (92%)
`0/1
`56 (93%)
`
`0/1
`55 (92%)
`
`1
`449
`
`56 (93%)
`4 (7%)
`
`0/1
`48 (86%)
`0/1
`48 (86%)
`
`0/2
`48 (86%)
`
`2
`510
`
`42 (75%)
`11 (20%)
`2 (3%)
`1 (2%)
`
`(Table 2; supplemental Table 1, available on the Blood Web site).
`Red blood cell transfusions were not given to 92% of control
`patients and 86% of patients in the azacitidine group, whereas
`93% and 86%, respectively, did not require any platelet trans-
`fusions. Furthermore, 92% of patients in the observation group
`and 86% in the azacitidine treatment group did not require
`clinical hospital admission. The number of AEs and SAEs were
`also comparable between both groups: 93% of patients in the
`observation group and 75% of those in the azacitidine treatment
`group did not experience any SAEs (ie, 4 patients in observation
`group and 14 patients in the azacitidine group experienced
`SAEs).
`
`a platelet count ,100 3 109/L) had a significant better DFS after
`azacitidine maintenance (supplemental Figure 2). In line with
`this, a significant interaction between treatment group and CR
`(and not CRi) was observed (supplemental Figure 3).
`
`This significant improvement in DFS did not translate to a sig-
`nificant improvement in OS (84% vs 70% at 12 months; logrank;
`P 5 .69) (Figure 4). Cox regression analysis confirmed the lack
`of improvement in OS after azacitidine maintenance (Cox re-
`gression; HR, 0.91; 95% confidence interval, 0.58-1.44; P 5 .69).
`At the same time, we noted an imbalance in the use of salvage
`therapy after relapse between the study groups. Thirty-two
`
`armB
`
`armA
`
`30
`
`71
`
`7
`
`Disease free survival from CR/CRi
`
`F
`49
`0
`armA
`56
`44
`armB
`Cox LR P =0.04
`
`N6
`
`6
`
`35
`46
`
`12
`
`25
`36
`
`Time
`
`18
`
`13
`23
`
`24
`
`10
`23
`
`100
`
`75
`
`50
`
`25
`
`Cumulative percentage
`
`0
`
`0
`
`At risk:
`armA
`armB
`
`60
`56
`
`Figure 3. Kaplan-Meier estimates for DFS. armA, observation group; armB,
`azacitidine maintenance group. Azacitidine maintenance treatment increased
`the median DFS by 5.6 months (armA, 10.3 months; armB, 15.9 months).
`
`Treatment outcome according to
`postremission randomization
`DFS was significantly improved after azacitidine maintenance
`treatment (64% vs 42% at 12 months; logrank; P 5 .04; Figure 3).
`DFS at 24 and 36 months was estimated at 44% and 32% for the
`azacitidine group and 20% and 16% for the control group, re-
`spectively. Cox regression analysis, with adjustment for poor-risk
`cytogenetic abnormalities at diagnosis and platelet count of
`at least 100 3 109/L (according to protocol), confirmed the
`significant improvement in DFS after azacitidine maintenance
`(Cox regression; HR, 0.62; 95% confidence interval, 0.41-0.95;
`P 5 .026).
`
`Multivariate Cox regression analysis was performed to in-
`vestigate possible heterogeneity of the treatment effects (DFS)
`between subgroups (poor-risk cytogenetic abnormalities at di-
`agnosis [yes vs no], platelet count [$100 vs ,100 3 109/L], age
`[younger vs older than median age 69 years], response CR[i]
`reached after induction cycle 1 vs induction cycle 2, cycles to
`CR/CRi [1 vs 2], performance status [0 vs $ 1]). Only a statistically
`significant interaction between treatment group and platelet
`count was found, which revealed that patients with a platelet
`count of at least 100 3 109/L at inclusion (and not those with
`
`AZACITIDINE MAINTENANCE IN AML
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`Overall survival
`
`armB
`armA
`
`F
`N
`39
`armA 60
`36
`armB
`56
`Cox LR P =0.69
`
`6
`
`54
`49
`
`Months
`
`12
`
`41
`46
`
`18
`
`30
`34
`
`24
`
`27
`25
`
`30
`
`18
`20
`
`A
`
`100
`
`75
`
`50
`
`25
`
`Cumulative percentage
`
`0
`
`0
`
`At risk:
`armA
`armB
`
`60
`56
`
`Overall survival (censored at date transplant)
`
`B
`
`100
`
`75
`
`50
`
`25
`
`Cumulative percentage
`
`armB
`
`armA
`
`F
`N
`44
`armA 60
`40
`armB
`56
`Cox LR P =0.21
`
`6
`
`50
`48
`
`12
`Months
`
`37
`45
`
`18
`
`25
`33
`
`24
`
`20
`24
`
`30
`
`13
`18
`
`0
`
`0
`
`At risk:
`armA
`armB
`
`60
`56
`
`Figure 4. Kaplan-Meier estimates of OS. (A) OS of all randomized patients
`(N 5 116); (B) OS after censoring of 15 patients at allo-HCT (11 in arm A and
`4 in arm B). arm A, observation group; arm B, azacitidine maintenance group.
`
`patients in CR who are not candidates for allo-HCT. Furthermore,
`the use of azacitidine, with its hypomethylating mechanism of
`action, after conventional chemotherapy, may result in antileukemic
`effects that are additive to the effects of chemotherapy. In-
`creasing knowledge about the clonal hierarchy and the fact
`that preleukemic HSCs have been identified in remission samples,
`which may survive after exposure to chemotherapy, supports
`the concept of using azacitidine during maintenance.30,31 In-
`deed, our study shows that azacitidine both delays relapse and
`prolongs DFS in patients in CR/CRi after 2 cycles of intensive
`chemotherapy. These data may support the use of azacitidine
`in the clinical management of older pa-tients with AML.
`
`A question that remains is why the improvement in DFS did not
`translate into a significant benefit in OS. First, the trial was not
`powered to assess differences in OS between treatment groups.
`Second, the markedly greater frequency of the use of salvage
`treatment at first relapse in the observation group may have
`
`patients in the control group (7 azacitidine, 19 other chemo-
`therapy, 6 other treatment) and 9 patients in the azacitidine
`maintenance group (5 other chemotherapy, 4 other treatment)
`received rescue treatment after relapse while on protocol. In
`total, 87 patients relapsed until database lock (including relapses
`that occurred off protocol). The OS, as expected, was signifi-
`cantly better in those 86 relapsed patients (1 patient was lost
`to follow-up) who received rescue treatment (P , .001). When
`considering patients in each group separately, the effect of rescue
`treatment was observed in the relapsed patients in both the
`control group (P 5 .005) and the azacitidine maintenance group
`(P 5 .03; supplemental Figure 1). Apparently, maintenance with
`azacitidine did not result in resistance for rescue treatment.
`
`Allo-HCT was used after relapse in 11 patients in the observation
`group and in 4 patients in the azacitidine maintenance group.
`After censoring patients for allo-HCT, no significant difference in
`OS was apparent between the groups (82% vs 63% at 12 months;
`logrank; HR, 0.76; 95% confidence interval, 0.49-1.17; P 5 .209)
`(Figure 4).
`
`Discussion
`The results of this study represent the first evidence from
`a randomized trial indicating that maintenance treatment with
`azacitidine significantly improves DFS for older patients with
`AML in CR/CRi after intensive remission-induction chemother-
`apy. Safety benchmarks such as protocol adherence, transfusion
`requirements, nights in hospital, and SAEs confirm the feasibility
`and efficacy of applying azacitidine maintenance treatment at
`a dose of 50 mg/m2 subcutaneously for 5 days every 28 days.
`
`In general, CRs obtained after remission-induction chemother-
`apy in patients aged 60 years and older are short lived, and these
`CRs result in an OS of approximately 10% at 5 years from di-
`agnosis. In recent years, various efforts have been undertaken to
`prevent relapse after CR, with limited success. Also, high-dose
`Ara-C consolidation schedules have failed to produce better
`outcomes in patients aged at least 60 years.25 Low-dose Ara-C
`(10 mg/m2 subcutaneously, twice daily, for 12 days) maintenance
`treatment has been shown to result in a modest (but significant)
`improvement of DFS but not OS.15 A study with rIL-2/histamine
`dihydrochloride showed a statistically significant benefit in DFS
`without a difference in OS.12 A recent study reported that main-
`tenance therapy with norethandrolone significantly improves sur-
`vival in elderly patients with AML without increasing toxicity.26
`Studies evaluating gemtuzumab ozogamicin and rIL2 provided
`no indication for a survival advantage.12-14,16,17 Recent studies in
`patients aged 60 years or younger suggest benefits from main-
`tenance therapy with the tyrosine kinase inhibitors midostaurin
`and sorafenib in FLT3-mutated AML.27,28 The effect of sorafenib
`maintenance treatment in older patients with AML has not been
`elucidated, as only 8 patients in the sorafenib group completed
`maintenance in a placebo-controlled randomized trial involving
`older patients with AML.29
`
`Several previous studies have shown that azacitidine is well
`tolerated and has single-agent activity in AML and MDS, which
`was the basis for the present study on the value of maintenance
`treatment with azacitidine. Therefore, we considered mainte-
`nance treatment with azacitidine after intensive induction che-
`motherapy to be a potentially interesting option, especially for
`
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`blood® 28 MARCH 2019 | VOLUME 133, NUMBER 13
`
`HULS et al
`
`

`

`confounded the analysis of OS. In total, 32 patients in the control
`group and 9 patients in the azacitidine group received therapy
`after relapse while on study. It is unclear why salvage treatments
`were considered less often in the azacitidine group. One possible
`explanation is that continued treatment is less commonly con-
`sidered in older patients with relapse after two different lines of
`treatment.
`
`limitations, the most important being
`This study has several
`the slow accrual and early termination: 7.5 years were needed
`to include 118 older patients with AML in CR(i), instead of the
`126 patients in the original statistical plan. Other phase 3 studies
`on maintenance treatment in older patients with AML also re-
`ported relatively low randomization rates.12-17 Apparently, older
`patients are less likely to enter treatment protocols of prolonged
`duration. In the current study, for instance, the burden of hospital
`visits needed for azacitidine injections, after extensive hospi-
`talization for intensive chemotherapy, could have been a rea-
`son for older patients with AML to refrain from participating in
`the study. Therefore, the results on the safety and efficacy of
`maintenance with oral azacitidine, which is currently being ex-
`plored in a randomized clinical trial in older patients with AML
`(NCT01757535), are eagerly awaited. Oral azacitidine may en-
`sure better protocol compliance. Furthermore, the results of our
`study, with regard to DFS, might have been even better if the
`duration of azacitidine was not limited to 1 year, and azacitidine
`maintenance had been given until progression, in accordance
`with the previous studies on azacitidine treatment.19,20 Another
`limitation is the lack of detailed information on the molecular
`characterization of the AML blasts and minimal residual disease
`(flow and molecular). Although this is now standard practice in
`all HOVON AML studies, this was not common practice at the
`time when the HOVON97 study was planned. We were therefore
`unable to evaluate the effect of azacitidine maintenance within
`certain molecular subgroups or on reduction or elimination of
`minimal residual disease.
`
`In summary, this study provides the first prospective evidence
`for the feasibility and effectiveness of azacitidine maintenance
`in newly diagnosed, intensely treated older patients with AML.
`It demonstrates that this therapeutic approach significantly
`improves DFS.
`
`Acknowledgments
`The authors thank the HOVON data center, especially Ren ´e Hollestein,
`and the Data Safety Monitoring Board (N. J. G. M. Veeger, T. de Witte,
`and J. A. Gietema) for their enduring support for this trial. Thanks to the
`Dutch-Belgian Hemato-Oncology Cooperative Group for its participa-
`tion in this study.
`
`This investigator-sponsored trial was financially supported by Celgene,
`and they provided the azacitidine used in the trial free of charge. This
`study has been supported by a grant for the Dutch Cancer Foundation
`(KUN 2008-4291).
`
`Authorship
`Contribution: The study was designed by the Leukemia Working Group
`of the HOVON; the HOVON Data Center was responsible for the central
`data management; D.A.C. performed the analysis of the data; G.H and
`subsequently D.A.C., E.V., and B.L. produced the first version of the
`manuscript, which was circulated for comments to the other authors; and
`the decision to publish was made by the cooperative group.
`
`Conflict of interest disclosure: G.H. has received research funding from
`Celgene; G.H. and B.L. have been involved in advisory boards for Celgene.
`The remaining authors declare no competing financial interests.
`
`A complete list of the members of the Dutch-Belgian Hemato-Oncology
`Cooperative Group (HOVON) appears in “Appendix.”
`
`Correspondence: Gerwin Huls, Department of Hematology, University
`Medical Center Groningen, University of Groningen, PO Box 30.001,
`9700 RB Groningen, The Netherlands; e-mail: g.huls@umcg.nl.
`
`Footnotes
`Submitted 11 October 2018; accepted 21 December 2018. Prepublished
`online as Blood First Edition paper, 10 January 2019; DOI 10.1182/
`blood-2018-10-879866.
`
`Prefinal analyses presented at the 59th annual meeting of the American
`Society of Hematology, Atlanta, GA, 9-12 December 2017.
`
`The online version of this article contains a data supplement.
`
`There is a Blood Commentary on this article in this issue.
`
`The publication costs of this article were defrayed in part by page
`charge payment. Therefore, and solely to indicate this fact, this article
`is hereby marked “advertisement” in accordance with 18 USC section
`1734.
`
`Appendix: study group members
`The members of the Dutch-Belgian Hemato-Oncology Cooperative
`Group (HOVON) who participated in this study are: D. A. Breems,
`Ziekenhuis Netwerk Antwerpen, Antwerp, Belgium; V. Havelange and
`M.-C. Vekemans, Saint-Luc University Hospital, Brussels, Belgium;
`G. Verhoef, University Hospital Gasthuisberg, Leuven, Belgium; B. Hodossy,
`Citadelle, Li `ege, Belgium; D. Deeren, AZ Delta, Roeselare, Belgium;
`C. Schuermans, GasthuisZusters Antwerpen, Wilrijk, Belgium; C. Graux,
`CHU UCL Namur (Godinne), Yvoir, Belgium; S. K. Klein, Meander MC,
`Amersfoort, The Netherlands; B. J. Biemond, Academic Medical
`Center, Amsterdam, The Netherlands; J. Terpstra, OLVG, Amsterdam,
`The Netherlands; G. J. Ossenkoppele and A. van de Loosdrecht, VU
`University Medical Cente