ORIGINAL ARTICLE
`Oncology & Hematology
`
`http://dx.doi.org/10.3346/jkms.2015.30.10.1416 (cid:1495) J Korean Med Sci 2015; 30: 1416-1422
`
`Oral Maintenance Chemotherapy with 6-Mercaptopurine and
`Methotrexate in Patients with Acute Myeloid Leukemia Ineligible
`for Transplantation
`
`Yong Won Choi, Seong Hyun Jeong,
`Mi Sun Ahn, Hyun Woo Lee,
`Seok Yun Kang, Jin-Hyuk Choi,
`and Joon Seong Park
`
`Department of Hematology-Oncology, Ajou
`University School of Medicine, Suwon, Korea
`
`Received: 5 March 2015
`Accepted: 7 July 2015
`
`Address for Correspondence:
`Joon Seong Park, MD
`Department of Hematology-Oncology, Ajou University Hospital,
`164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea
`Tel: +82.31-219-5989, Fax: +82.31-219-5983
`E-mail: jspark65@ajou.ac.kr
`
`For decades, maintenance chemotherapy has failed to improve the cure rate or prolong the
`survival of patients with acute myeloid leukemia (AML), other than those with acute
`promyelocytic leukemia. Immediately after the first complete remission following
`consolidation therapy was obtained, oral maintenance chemotherapy (daily
`6-mercaptopurine and weekly methotrexate) was given and continued for two years in
`transplant-ineligible AML patients. Leukemia-free survival (LFS) and overall survival (OS)
`were studied and compared between these patients and the historical control group who
`did not receive maintenance therapy. Consecutive 52 transplant-ineligible AML patients
`were analyzed. Among these patients, 27 received oral maintenance chemotherapy. No
`significant difference was found in the patients’ characteristics between the maintenance
`and the control groups. The median OS was 43 (95% CI, 19-67) and 19 (95% CI, 8-30)
`months in the maintenance and the control groups, respectively (P = 0.202). In the
`multivariate analysis, the presence of maintenance therapy was an independent prognostic
`factor for better OS (P = 0.021) and LFS (P = 0.024). Clinical benefit from maintenance
`chemotherapy was remarkable in older patients (≥ 60 yr) (P = 0.035), those with
`intermediate or unfavorable cytogenetics (P = 0.006), those with initial low blast count in
`peripheral blood (P = 0.044), and those receiving less than two cycles of consolidation
`therapy (P = 0.017). Maintenance oral chemotherapy as a post-remission therapy can
`prolong the survival of patients with AML who are not eligible for transplantation,
`particularly older patients, those with intermediate or unfavorable cytogenetics, those
`with initial low blast count, and those receiving less than two cycles of consolidation
`therapy.
`
`Keywords: Maintenance; Leukemia; Myeloid; Acute
`
`INTRODUCTION
`
`Acute myeloid leukemia (AML) is the most common type of
`leukemia, and it has the lowest survival rate of all leukemia types
`in adults (1). Although attaining complete remission (CR) is the
`important goal of initial therapy in AML, the median disease
`free survival of patients who received the induction therapy only
`without post-remission therapy is four to eight months (2, 3). In
`the past two decades, little has changed in induction chemo-
`therapy (4). However, improved understanding of the AML bi-
`ology with modern cytogenetics and molecular testing has led
`to the customization of post-remission therapy based on relapse
`risk-stratification (5, 6). Hematopoietic stem cell transplanta-
`tion (HSCT) has been considered a potentially curative therapy
`for AML with intermediate and adverse cytogenetics (7). How-
`ever, several factors, such as old age, absence of a matched do-
`nor, and comorbidities, enable only about one-third of patients
`
`to be eligible for HSCT (8). The remaining patients who cannot
`receive HSCT should be followed up until disease progression
`after two to four courses of high-dose cytarabine-based chemo-
`therapy and more than half of these patients eventually relapse
`(9). For decades, although several trials with different strategies
`of maintenance therapy have been conducted to reduce the re-
`lapse of disease in patients, these trials have failed to show the
`improvement of outcomes (10-13). Consequentially, mainte-
`nance chemotherapy is not a standard therapy for AML except
`for acute promyelocytic leukemia (APL).
`Nonetheless, reducing the relapse rate and the prolongation
`of the relapse free interval by minimizing the residual disease
`and preventing the regrowth of dormant leukemic stem cells
`through the prolonged exposure to maintenance chemothera-
`py remain attractive (14). The maintenance therapy with low
`dose cytotoxic agents 6-mercaptopurine (6MP) and methotrex-
`ate (MTX) has been clinically proven beneficial to ALL (15) and
`
`© 2015 The Korean Academy of Medical Sciences.
`pISSN 1011-8934
`This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0)
`eISSN 1598-6357
`which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
`CELGENE 2072
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`Choi YW, et al. (cid:1495) Maintenance Therapy for Acute Myeloid Leukemia Patients
`
`APL (16). However, no study has been conducted yet to prove
`the clinical benefit of this therapy in AML. In this study, we ret-
`rospectively analyzed the clinical outcomes of AML patients who
`received oral maintenance therapy with 6MP and MTX after re-
`mission induction and consolidation therapy.
`
`MATERIALS AND METHODS
`
`Patients
`From a single institute, 52 AML patients including those who
`were ineligible for HSCT (Age ≥ 65, absence of a matched do-
`nor and significant comorbidities) received at least one cycle of
`consolidation therapy in the first complete remission (CR1) were
`analyzed. Among these patients, 27 received maintenance che-
`motherapy and 25 did not.
`
`Treatment
`Patients received 6MP (50 mg/day, p.o.) and MTX (10 mg/week,
`p.o.) for two years or until disease progression. The historical
`control group had completed remission induction and at least
`one cycle of consolidation therapy. Then, the group received no
`specific anti-leukemic treatment.
`
`structural abnormalities; unfavorable, 11q23 rearrangement,
`-5, del(5q), -7, del(7q), inv(3)/t(3;3)/ins(3;3). Leukemia-free sur-
`vival (LFS) was calculated from the date of diagnosis to the last
`follow-up or first event (failure to achieve remission, demon-
`stration of resistant leukemia, or relapse). Overall survival (OS)
`was defined as the time from diagnosis to death from any cause.
`The characteristics of the two groups were compared by the chi-
`square test or Fischer’s exact test for categorical data and the
`Mann-Whitney U-test for continuous variables. LFS and OS were
`estimated by the Kaplan-Meier method and compared by the
`Log Rank and Breslow method. The Cox proportional hazard
`model was used in the multivariate analysis of prognostic fac-
`tors. P values lower than 0.05 were considered statistically sig-
`nificant. Statistical analysis was performed using SPSS version
`13.0 (IBM, Armonk, NY, USA).
`
`Ethics statement
`The study (AJIRB-MED-MDB-14-258) was approved by the Ajou
`University Hospital institutional review board. The board waived
`written informed consent.
`
`RESULTS
`
`Definitions and statistical analysis
`Initial diagnosis and leukemia subtypes were recorded using
`the French-American-British (FAB) classification system (17).
`Cytogenetics were classified into 3 risk groups: favorable, t(8;21),
`inv(16); intermediate, normal karyotype or other numerical or
`
`Patient and disease characteristics
`The patient and disease characteristics are given in Table 1. No
`significant difference was found in the baseline patient and dis-
`ease characteristics between the maintenance and the histori-
`cal control groups.
`
`Table 1. Patients characteristics
`
`Parameters
`
`Number of patients, N (%)
`Median age, yr (range)
`Age ≥ 60, N, (%)
`Gender (male/female), N (%)
`ECOG PS < 2, N (%)
`FAB subtype, N (%)
` M0-M2
` M4-M5
` M6-M7
`MDS/therapy related AML, N (%)
`Cytogenetic risk group, N (%)
` Favorable
` Intermediate
` Unfavorable
`LDH (U/L), median (range)
`Baseline CBC
` Hb, median (range)
` Plt, median (range)
` WBC, median (range)
`Initial median
` PB Blasts (%, range)
`Initial median
` BM Blasts (%, range)
`
`Total
`
`52 (100)
`53 (18-74)
`17 (32.7)
`24:28 (46.2:53.8)
`50 (96.2)
`
`30 (57.7)
`20 (38.5)
`2 (3.8)
`8 (15.4)
`
`17 (32.7)
`33 (63.5)
`2 (3.8)
`426 (123-4027)
`
`7.4 (2.3-10.7)
`48.5 (6-353)
`13.4 (0.7-358)
`
`35.5 (0-89)
`
`65.2 (20-98)
`
`Maintenance
`
`27 (51.9)
`55 (21-69)
`11 (40.7)
`13:14 (48.1:51.9)
`25 (92.6)
`
`14 (51.9)
`13 (48.1)
`0 (0.0)
`4 (14.8)
`
`7 (25.9)
`20 (74.1)
`0 (0.0)
`436 (156-2014)
`
`7.5 (3.0-10.7)
`57 (11-316)
`14.1 (0.7-97.5)
`
`31 (0-84)
`
`64.8 (20-98)
`
`Control
`
`25 (48.1)
`48 (18-74)
`6 (24.0)
`11:14 (46.4:53.6)
`25 (100)
`
`16 (64.0)
` 7 (28.0)
` 2 (8.0)
`4 (16)
`
`10 (40.0)
`13 (52.0)
`2 (8.0)
`419 (123-4027)
`
`6.9 (2.3-10.7)
`40.0 (6-353)
`10.4 (1.9-358)
`
` 45.0 (0-89)
`
`65.5 (21.1-95)
`
`P value
`
`0.126
`0.199
`0.788
`0.360
`0.145
`
`0.906
`0.139
`
`0.653
`0.978
`0.327
`0.742
`
`0.527
`
`0.756
`
`ECOG PS, Eastern Cooperative Oncology Group (ECOG) performance status; FAB, French-American-British; MDS, myelodysplastic syndrome; LDH, lactate dehydrogenase; CBC,
`complete blood count; Hb, hemoglobin; Plt, platelet; WBC, white blood cell; PB, peripheral blood; BM, bone marrow.
`
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`Choi YW, et al. (cid:1495) Maintenance Therapy for Acute Myeloid Leukemia Patients
`
`Rank [P = 0.202], Breslow [P = 0.044], Fig. 1A). The median LFS
`was 31 months and 12 months in the maintenance group and
`historical control group, respectively (Log Rank [P = 0.261], Bre-
`slow [P = 0.090], Fig. 1B). In the multivariate analysis (Table 3),
`older age was an independent poor prognostic factor for OS
`(P = 0.020) and LFS (P = 0.028). Maintenance therapy was in-
`dependently associated with favorable OS (P = 0.021) and LFS
`(P = 0.024). Higher baseline WBC count was associated with
`shorter LFS (P = 0.033).
`
`Subgroup analysis
`Subgroup analysis was performed using a univariate Cox pro-
`portional hazard model to evaluate the effects of maintenance
`treatment on OS and LFS (Table 4). All hazard ratios were made
`for patients who received maintenance treatment in compari-
`son with those who did not. The OS (50 months vs. 16 months,
`P = 0.004, Fig. 2A) and LFS (not reached vs. 10 months, P = 0.011)
`were significantly prolonged with oral maintenance therapy
`when the cytogenetic study showed intermediate or unfavor-
`able risk. Furthermore, clinical benefit from maintenance che-
`motherapy (OS and LFS) was documented for patients aged
`≥ 60 yr (total: 17 patients, maintenance group: 11 patients, con-
`trol group: 6 patients), (P = 0.035, Fig. 2B and P = 0.019), those
`with low peripheral blood (PB) blast count at diagnosis (P = 0.044,
`Fig. 2C and P = 0.022), and those who received less than two
`cycles of consolidation chemotherapy (P = 0.017, Fig. 2D and
`P = 0.016).
`
`Treatment results
`The treatment characteristics for induction, number of consoli-
`dation therapy, and cause of death are presented in Table 2. Al-
`most all patients (96.4%) received remission induction chemo-
`therapy with idarubicin and cytarabine. More than one-half of
`the patients received more than two cycles of consolidation che-
`motherapy. Relapse was observed in 27 patients (51.9%) who
`achieved CR after induction treatment. Median LFS and OS were
`28 months (95% confidence interval [CI], 1-44 months) and 29
`months (95% CI, 10-48 months), respectively. Disease progres-
`sion (54.5%) was the main cause of death, followed by infection
`(34.5%). The rate of achieving CR and the number of consolida-
`tion were not statistically different between the two groups.
`
`OS, LFS, and prognostic factors
`The median OS was 43 months and 19 months in the mainte-
`nance group and the historical control group, respectively (Log
`
`Table 2. Characteristics in treatment and results for induction and consolidation che-
`motherapy
`
`P value
`0.491
`
`0.920
`
`0.213
`
`Parameters
`
`Remission induction chemotherapy
` Idarubicin/Ara-C
` Daunorubicin/Ara-C
`CR after 1st remission induction
` chemotherapy
`Number of consolidation therapy
` 1
` 2
` 3
`Cause of death
` Disease progression
` Infection
` Hemorrhage
` Others
`
`Total
`
`Maintenance
`
`Control
`
`52
`51 (98.1)
`1 (1.9%)
`46 (88.5)
`
`27
`27 (100.0)
`0 (0.0)
`24 (88.9)
`
`25
`24 (96.0)
`1 (4.0)
`22 (88.0)
`
`13 (25.0)
`28 (53.8)
`11 (21.2)
`
`7 (25.9)
`17 (63.0)
`3 (11.1)
`
`6 (24.0)
`11 (44.0)
`8 (32.0)
`
`21 (72.4)
`3 (10.3)
`2 (6.9)
`3 (10.3)
`
`12 (75.0)
`2 (12.5)
`1 (6.3)
`1 (6.3)
`
`9 (69.2)
`1 (7.7)
`1 (7.7)
`2 (15.4)
`
`Ara-C, cytosine arabinoside; CR, complete remission.
`
`0.851
`
`DISCUSSION
`
`Despite intensive consolidation after achieving CR in patients
`with AML, less than one-third of the patients were cured, main-
`ly because of the high incidence of relapse (18). Although sev-
`
`Maintenance
`Non-maintenance
`
`Log rank (P = 0.261)
`Breslow (P = 0.090)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Probability of EFS
`
`Maintenance
`Non-maintenance
`
`Log rank (P = 0.202)
`Breslow (P = 0.044)
`
`2
`
`4
`6
`Years after diagnosis
`
`8
`
`10
`
`0
`
`2
`
`A
`
`4
`6
`Years after diagnosis
`
`8
`
`10
`
`B
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`Probability of OS
`
`Fig. 1. Survival by the presence or absence of maintenance therapy. (A) Overall survival (OS). (B) Leukemia-free survival (LFS).
`
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`

`Choi YW, et al. (cid:1495) Maintenance Therapy for Acute Myeloid Leukemia Patients
`
`Table 3. Multivariate analysis of OS and LFS
`
`Variables
`
`Age (10-yr increase)
`Gender (Male vs. female)
`ECOG PS (0/1 vs. 2/3/4)
`Chromosome (Favorable vs. Intermediate/unfavorable)
`De novo AML vs. Secondary AML
`FAB (M1/M2 v M0, M4, M5, M6)
`WBC, × 109/L (10-fold value)
`Hemoglobin (g/L)
`Platelet, × 109/L
`PB blast count (%)
`BM blast count (%)
`LDH, U/L (10-fold value)
`N of consolidation Tx. (0,1 vs. 2,3)
`Non-maintenance vs. Maintenance
`
`HR
`
`1.50
`0.80
`0.35
`0.94
`1.417
`0.56
`2.09
`1.00
`1.27
`1.00
`1.01
`0.99
`0.65
`0.33
`
`OS
`
`95% CI
`
`1.07-2.10
`0.31-2.07
`0.04-2.87
`0.32-2.77
`0.46-4.35
`0.23-1.35
`0.99-4.40
`0.79-1.27
`0.51-3.14
`0.98-1.02
`0.99-1.03
`0.30-3.29
`0.26-1.59
`0.13-0.84
`
`P value
`0.020
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`0.021
`
`HR
`
`1.49
`
`0.30
`1.01
`0.70
`0.64
`2.33
`0.90
`1.41
`1.01
`1.01
`1.25
`0.43
`0.33
`
`LFS
`
`95% CI
`
`1.04-2.12
`
`0.04-2.42
`0.31-3.35
`0.20-2.45
`0.27-1.52
`1.07-5.09
`0.71-1.16
`0.53-3.75
`0.99-1.03
`0.99-1.03
`0.39-4.02
`0.17-1.07
`0.13-0.87
`
`P value
`0.028
`
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`0.024
`
`OS, overall survival; LFS, leukemia free survival; HR, Hazard ratio; CI, confidence interval; NS, not significant; ECOG PS, Eastern Cooperative Oncology Group (ECOG) perfor-
`mance status; AML, acute myeloid leukemia; FAB, French-American-British; LDH, lactate dehydrogenase All candidate prognostic factors were included in the Cox regression
`model without selection of variables.
`
`Table 4. Subgroup analysis of OS and LFS
`
`Parameters
`
`Age < 60
`Age ≥ 60
`Favorable cytogenetics
`Intermediate/Unfavorable cytogenetics
`WBC < 50,000/mm2
`WBC ≥ 50,000/mm2
`PB blast % ≤ median
`PB blast % > median
`BM blast % ≤ median
`BM blast % > median
`De novo AML
`Secondary AML
`LDH (U/L) ≤ 700
`LDH (U/L) > 700
`N of consolidation Tx. = 1
`N of consolidation Tx. > 1
`
`HR
`
`0.86
`0.23
`2.49
`0.27
`0.99
`0.21
`0.30
`1.12
`0.78
`0.53
`0.85
`0.01
`0.62
`0.63
`0.14
`0.87
`
`OS
`
`95% CI
`
`0.34-2.22
`0.06-0.90
`0.62-10.07
`0.11-0.69
`0.41-2.37
`0.00-14.72
`0.09-0.97
`0.43-3.22
`0.27-2.26
`0.19-1.52
`0.36-1.98
`0.00-40.75
`0.25-1.56
`0.17-2.40
`0.03-0.70
`0.43-2.73
`
`P value
`NS
`0.035
`NS
`0.006
`NS
`NS
`0.044
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`0.017
`NS
`
`HR
`
`0.97
`0.17
`2.48
`0.31
`0.91
`0.01
`0.24
`1.61
`0.67
`0.62
`0.79
`0.01
`0.56
`0.91
`0.14
`1.11
`
`LFS
`
`95% CI
`
`0.38-2.56
`0.04-0.74
`0.59-10.39
`0.12-0.81
`0.38-2.17
`0.00-36.30
`0.07-0.81
`0.55-4.71
`0.23-1.93
`0.20-1.90
`0.34-1.84
`0.00-246.87
`0.22-1.41
`0.23-3.67
`0.03-0.69
`0.43-2.88
`
`P value
`NS
`0.019
`NS
`0.016
`NS
`NS
`0.022
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`0.016
`NS
`
`OS, overall survival; LFS, leukemia free survival; HR, Hazard ratio; CI, confidence interval; NS, not significant; WBC, white blood cell; PB, peripheral blood; BM, bone marrow;
`AML, acute myeloid leukemia; LDH, lactate dehydrogenase; Tx., therapy.
`
`eral previous studies demonstrated the clinical benefit of cyta-
`rabine-based maintenance therapy (12, 19, 20), these results
`were inconsistent (21-23). However, our data indicated that oral
`maintenance therapy with 6MP and MTX prolonged the OS and
`LFS in AML patients. Moreover, the benefit was more prominent
`during and early after maintenance therapy.
`
` Not all patients have experienced clinical benefit from main-
`tenance therapy, even those with APL (24-26). In one AML study,
`clinical benefit from maintenance therapy with tipifarnib, farne-
`syltransferase inhibitor was observed only in patients with sec-
`ondary AML or AML with adverse cytogenetics (27). In the pres-
`ent study, patients with intermediate risk cytogenetics achieved
`more prominent OS and LFS benefits from maintenance thera-
`
`py, whereas patients with favorable cytogenetics received no
`additional benefits from maintenance therapy. Older patients
`(Age ≥ 60), patients with low PB blast count, and patients who
`received insufficient consolidation therapy (≤ 1 cycle) obtained
`prominent clinical benefits from maintenance therapy. There-
`fore, risk-adapted maintenance therapy in AML patients may
`be a more appropriate approach, consistent with previous stud-
`ies (26, 27).
`
` As results from previous trials with conventional chemother-
`apy-based therapy have been regarded as negative in support-
`ing maintenance therapy, many ongoing clinical trials have been
`designed with immunotherapy, demethylating therapy, or tar-
`geted therapy (14). However, it is notable that among studies
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`Choi YW, et al. (cid:1495) Maintenance Therapy for Acute Myeloid Leukemia Patients
`
`OS
`(Age ≥ 60)
`
`Maintenance
`Non-maintenance
`
`P = 0.023
`
`2
`
`4
`6
`Years after diagnosis
`
`8
`
`B
`
`OS
`(N of consolidation Tx. ≤1)
`
`Maintenance
`Non-maintenance
`
`P = 0.004
`
`2
`
`4
`6
`Years after diagnosis
`
`8
`
`D
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`Probability of OS
`
`Probability of OS
`
`OS
`(Intermediate/Unfavorable risk group)
`
`Maintenance
`Non-maintenance
`
`P = 0.004
`
`2
`
`4
`6
`Years after diagnosis
`
`8
`
`A
`
`OS
`(PB blast % ≤ median)
`
`Maintenance
`Non-maintenance
`
`P = 0.034
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Probability of OS
`
`Probability of OS
`
`0
`
`0
`
`2
`
`4
`6
`Years after diagnosis
`
`8
`
`10
`
`C
`
`Fig. 2. Overall survival (OS) of patients with risks by the presence or absence of maintenance therapy. (A) OS of those with intermediate or unfavorable cytogenetics, (B) older
`patients, (C) those with initial low blast count in peripheral blood, (D) those receiving less than two cycles of consolidation therapy.
`
`using maintenance chemotherapy, those using identical con-
`solidation regimens followed by a randomization to mainte-
`nance or no maintenance chemotherapy are rare (28). As the
`pharmacodynamic and pharmacokinetic features and toxicity
`profile of conventional agents are well known and cost effec-
`tive, chemotherapeutic agents such as 6MP and MTX are good
`candidates for further studies about the validation of clinical ef-
`ficacy as maintenance chemotherapy.
` The duration of maintenance therapy is another issue. In the
`present study, the OS of the maintenance and non-maintenance
`groups was 66.5% and 45.2%, respectively, within two years, which
`was the period of maintenance therapy. However, five-year OS
`was similar between the two groups. Further studies are need-
`ed to prove that prolonged exposure to maintenance therapy is
`more effective and safe. Exposure to anti-cancer drugs during
`
`the two years did not evoke secondary malignancy in our result.
` To our knowledge, this study is the first report about the clini-
`cal outcome of oral maintenance chemotherapy with 6MP and
`MTX in AML patients. However, the present study has several
`limitations. First, although patients were well balanced for age,
`cytogenetics, and prevalence of secondary AML, this study is a
`retrospective non-randomized study from a single institution.
`Second, although AML with normal karyotype is a heterogene-
`ous group according to molecular alteration (5), AML with nor-
`mal karyotype was simply classified and analyzed as an interme-
`diate risk group, as measuring such molecular abnormalities
`was not routine practice throughout the duration of the study.
`
`In conclusion, oral maintenance therapy prolonged the me-
`dian OS (43 months vs. 19 months) in AML patients. Given that
`most AML patients in CR after several cycles of consolidation
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`Choi YW, et al. (cid:1495) Maintenance Therapy for Acute Myeloid Leukemia Patients
`
`therapy experience relapse, the clinical efficacy of maintenance
`therapy to reduce the relapse from dormant leukemic cells needs
`to be reconsidered and verified by prospective randomized tri-
`als. Nonetheless, the present study suggests that AML patients,
`especially older patients (≥ 60 yr), those with intermediate or
`unfavorable cytogenetic results, those with initially low PB blast
`count (%, ≤ median), and those receiving less than two cycles
`of consolidation therapy, could benefit from maintenance ther-
`apy with 6MP and MTX without incurring clinically or biologi-
`cally significant adverse events.
`
`DISCLOSURE
`
`The authors declare that they have no conflicts of interest.
`
`AUTHOR CONTRIBUTION
`
`Study design and literature review: Park JS, Jeong SH, Choi YW,
`Ahn MS, Lee HW, Kang SY, Choi JH. Data management and anal-
`yses: Choi YW, Jeong SH, Park JS. Interpretation of findings and
`writing manuscript: Choi YW, Jeong SH , Park JS
`
`ORCID
`
`Yong Won Choi http://orcid.org/0000-0002-3659-8126
`Seong Hyun Jeong http://orcid.org/0000-0003-4098-1184
`Mi Sun Ahn http://orcid.org/0000-0002-7081-9826
`Hyun Woo Lee http://orcid.org/0000-0002-6879-9686
`Seok Yun Kang http://orcid.org/0000-0002-4995-9912
`Jin-Hyuk Choi http://orcid.org/0000-0003-2387-204X
`Joon Seong Park http://orcid.org/0000-0001-7999-0577
`
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