Annals of Hematology https://doi.org/10.1007/s00277-018-3419-1
ORIGINAL ARTICLE
Allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia with 11q23 abnormality: a retrospective study of the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) Takaaki Konuma 1 & Shohei Mizuno 2 & Tadakazu Kondo 3 & Hiroki Yamaguchi 4 & Takahiro Fukuda 5 & Naoyuki Uchida 6 & Yuho Najima 7 & Heiwa Kanamori 8 & Shuichi Ota 9 & Hirohisa Nakamae 10 & Mika Nakamae 10 & Ishikazu Mizuno 11 & Junichi Sugita 12 & Yasushi Onishi 13 & Akira Yokota 14 & Satoshi Takahashi 15 & Yoshinobu Kanda 16 & Tatsuo Ichinohe 17 & Yoshiko Atsuta 18,19 & Shingo Yano 20 & Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation Received: 9 May 2018 / Accepted: 25 June 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract An 11q23 abnormality presents in approximately 5% of adults with acute myeloid leukemia (AML) and is associated with adverse outcomes even after allogeneic hematopoietic cell transplantation (allo-HCT). To evaluate the outcomes and prognostic factors following allo-HCT for adult AML with 11q23 abnormality, we retrospectively analyzed the Japanese registration data of 322 adult AML patients with 11q23 abnormality who had received allo-HCT between 1990 and 2014. In total, the disease status at HCT was first complete remission (CR1) in 159 (49%) patients. The probability of overall survival and the cumulative incidence of relapse at 3 years were 44 and 44%, respectively. In the multivariate analysis, disease status beyond CR1 at the time of HCT was significantly associated with a higher overall mortality and relapse. The 11q23 fusion partner did not have a significant impact on survival. We also evaluated the prognostic value of minimal residual disease (MRD) status at HCT on transplant outcomes among hematological CR patients. MRD status at HCT was the significant prognostic indicator for hematological relapse and survival. These data suggested that allo-HCT offered a curative option for adult AML with 11q23 abnormality. Pretransplant MRD status was the significant prognostic indicator for relapse and survival in CR patients. Keywords 11q23 abnormality . Mixed lineage leukemia . Lysine-specific methyltransferase 2A . Acute myeloid leukemia . Allogeneic hematopoietic cell transplantation . Minimal residual disease . Adult
Introduction Chromosomal abnormality at the time of diagnosis is one of the most powerful prognostic indicators both for treatment responses and the prognosis of chemotherapy [1–4] and allogeneic hematopoietic cell transplantation (allo-HCT) [5–8] in
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00277-018-3419-1) contains supplementary material, which is available to authorized users. * Takaaki Konuma
[email protected] Extended author information available on the last page of the article
adult patients with acute myeloid leukemia (AML). The 11q23 chromosomal abnormalities involving a lysine[K]-specific methyltransferase 2A (KMT2A) (previously called mixed lineage leukemia (MLL)) gene rearrangements have been observed in acute lymphoblastic leukemia (ALL), de novo and therapy-related AML, and myelodysplastic syndrome (MDS). Although 11q23 abnormality is one of the most common chromosomal abnormalities seen in patients with infant or pediatric ALL, it also presents in approximately 5% of adults with AML [3, 4]. Several studies have shown that 11q23 abnormality is associated with adverse outcomes because of higher rates of relapse when conventional chemotherapy is used alone [2, 3]. However, the prognosis of adult AML with 11q23 abnormality is heterogeneous and dependent on the 11q23 fusion partner [2, 3, 9, 10]. Several studies have shown
Ann Hematol
Patients and methods
≥ 7.2 mg/kg, or melphalan doses of ≥ 140 mg/m2, whereas other regimens were classified as reduced-intensity conditioning (RIC) [21]. The 11q23 abnormalities or KMT2A/MLL rearrangements were classified into six groups: t(6;11)(q27;q23) or MLL-AF6; t(9;11)(p22;q23) or MLL-AF9; t(11;17)/ t(11;19)(q23;p13) or MLL-ELL/MLL-ENL; t(11;v)(q23;v) comprised of other balanced 11q23 translocations; and unbalanced 11q23 abnormalities including add(11q23) and del(11q23). Minimal residual disease (MRD) status at HCT was measured at each institution by qualitative or quantitative PCR of KMT2A/MLL fusion transcripts.
Study design and data collection
Statistical analysis
The clinical data were provided by the Transplant Registry Unified Management Program (TRUMP) of the Japan Society of Hematopoietic Cell Transplantation (JSHCT) [18–20]. The inclusion criteria in this retrospective analysis consisted of patients aged ≥ 16 years with AML, including 11q23 abnormalities on a karyotypic analysis or KMT2A (MLL) rearrangements on fluorescence in situ hybridization, or reverse transcriptase polymerase chain reaction (PCR), who received the first allo-HCT between 1990 and 2014 in Japan. We excluded the patients with acute promyelocytic leukemia or t(11;17)(q23;q12), which consisted of the ZBTB16 (also known as PLZF)-RARα fusion gene. Finally, 322 patients were eligible for this study. In almost all patients in this study, AML with 11q23 abnormality was diagnosed by the presence of 11q23 abnormalities on a standard karyotypic analysis alone, except that no or only an insufficient number of metaphases were obtained. The institutional review board of the Institute of Medical Science, University of Tokyo, where this study was carried out, approved this retrospective study.
The probabilities for OS and DFS were estimated according to the Kaplan–Meier method, and the groups were compared using a log-rank test. The probability of relapse and TRM were estimated using a cumulative incidence method to accommodate competing risks, and the groups were compared using Gray’s test. A multivariate analysis was performed with a Cox proportional hazard model for overall mortality and treatment failure of DFS or a Fine and Gray proportional hazards model for relapse and TRM using all of these variables: age (16–39 vs. ≥ 40 years), sex (male vs. female), French– American–British (FAB) classification [M4/M5 vs. other than M4/M5], white blood cell (WBC) count at diagnosis (< 20,000 vs. ≥ 20,000/μL), extramedullary manifestation at diagnosis (absent vs. present), cytogenetics [t(6;11) or t(9;11) vs. others], disease status at HCT [CR1 vs. beyond CR1], the interval time from diagnosis to HCT (< 6 vs. ≥ 6 months), donor source [bone marrow transplantation/peripheral blood stem cell transplantation from a related donor (RBMT/ PBSCT) vs. BMT from an unrelated donor (UBMT) vs. cord blood transplantation from an unrelated donor (UCBT)], conditioning regimen (MAC vs. RIC), and year of HCT (1990– 2007 vs. 2008–2014). All P values were two-sided, and all statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [22], a graphical user interface for the R 3.0.2 software program (R Foundation for Statistical Computing, Vienna, Austria).
a beneficial effect of allo-HCT during first complete remission (CR1) in adult AML with 11q23 abnormality [10–17]. Nevertheless, large-scale data regarding the outcomes and prognostic factors following allo-HCT for adult AML with 11q23 abnormality are limited [16, 17]. To clarify the outcomes and prognostic factors in adult AML with 11q23 abnormality treated with allo-HCT, we performed a retrospective analysis using a nationwide Japanese database.
Endpoints and definitions The study endpoints consisted of overall survival (OS), disease-free survival (DFS), relapse, and transplant-related mortality (TRM). The OS (inverse of overall mortality) was defined as the time from the date of HCT to the date of death or last contact. The DFS (inverse of treatment failure) was defined as the time from the date of HCT to the date of relapse, death in complete remission (CR), or last contact. CR was defined as less than 5% bone marrow blasts. Relapse was defined as hematological evidence of disease. Patients who never achieved CR following HCT were considered to have had a relapse on day 1. TRM was defined as death during CR. The myeloablative conditioning (MAC) regimen was defined according to the criteria of the Center for International Blood and Marrow Transplant Research (CIBMTR), which included a regimen containing either total body irradiation (TBI) single doses of ≥ 5 Gy or fractionated doses totaling ≥ 8 Gy, oral busulfan doses of ≥ 9 mg/kg, intravenous busulfan doses of
Results Patient characteristics The characteristics of the patients, disease status, and transplant procedures are listed in Table 1. The median age at HCT was 39 years (range: 16–75 years). Among 274 evaluable patients, 249 (77%) patients had de novo AML, and 25 (8%) patients had secondary AML. The most common of the FAB classification was M4/M5, which is monocytic leukemia
Ann Hematol Table 1 Characteristics of patients, disease status, and transplant procedures Characteristic
Value
Number of patients
322
Age, years, median (range)
39 (16–75)
Age, number (%) 16–39 years
165 (51)
≥ 40 years
157 (49)
Sex, number (%) Male Female Etiology
173 (54) 149 (46)
De novo AML
249 (77)
Secondary AML
25 (8)
Missing data FAB classification, number (%) M4/M5 Other than M4/M5 Missing data WBC count at diagnosis, /μL, median (range) WBC count at diagnosis, number (%)
48 (15)
Cytogenetics, number (%) t(6;11) t(9;11) t(11;17) t(11;19)
97 (30) 14 (4) 13,300 (500–761,000)
221 (69) 36 (11) 65 (20) 72 (22) 83 (26) 19 (6) 83 (26)
t(11;v)** 37 (11) Unbalanced 11q23 28 (9) Additional chromosomal abnormality, number (%) Absent 242 (75) Present 80 (25) Disease status at HCT*, number (%) Complete remission 195 (60) Complete remission 1 159 (49) Complete remission 2 36 (11) Primary induction failure 78 (24) Refractory relapse 40 (12) Untreated Missing data Time from diagnosis to HCT, months, median (range) Time from diagnosis to HCT, number (%) < 6 months ≥ 6 months
Characteristic
Value
Donor source, number (%) RBMT/PBSCT
127 (39)
UBMT UCBT Conditioning regimen, number (%) MAC RIC GVHD prophylaxis, number (%)
124 (39) 71 (22) 237 (74) 85 (26)
Cyclosporine-based Tacrolimus-based
153 (48) 167 (52)
Others/missing data
2 (< 1)
Year of HCT 1990–2007
139 (43)
2008–2014
183 (57)
211 (66)
< 20,000/μL 168 (52) ≥ 20,000/μL 142 (44) Missing data 12 (4) Extramedullary involvement at diagnosis, number (%) Absent Present Missing data
Table 1 (continued)
6 (2) 3 (< 1) 7 (0–244)
AML acute myeloid leukemia, FAB French–American–British, WBC white blood cell, HCT hematopoietic cell transplantation, RBMT/ PBSCT bone marrow transplantation/peripheral blood stem cell transplantation from a related donor, UBMT bone marrow transplantation from an unrelated donor, UCBT cord blood transplantation from an unrelated donor, MAC myeloablative conditioning, RIC reduced-intensity conditioning, GVHD graft-versus-host disease *Primary induction failure was defined as failure to achieve complete remission with induction chemotherapy. Refractory relapse was defined as failure to achieve complete remission with salvage chemotherapy after first or subsequent relapse. Untreated was defined as no induction chemotherapy before the conditioning regimen **v denotes various chromosomes other than t(6;11), t(9;11), t(11;17), and t(11;19)
(69%). The median WBC count at diagnosis among 310 evaluable patients was 13,300/μL (range 500–761,000/μL), and the extramedullary involvement at diagnosis was observed in 36 (11%) of 257 evaluable patients. The common cytogenetic 11q23 abnormalities were t(6;11) in 72 (22%) patients, t(9;11) in 83 (26%) patients, and t(11;19) in 83 (26%) patients. The disease status at HCT was CR1 in 159 (49%) patients. A total of 127 patients (39%) received RBMT/ PBSCT, 124 (39%) received UBMT, and 71 (22%) received UCBT. The MAC regimen (74%) and tacrolimus-based GVHD prophylaxis (52%) were more commonly performed in this study group. The median time from diagnosis to HCT was 7 months (range 0–244 months), and the median period of follow-up for survivors after HCT was 42.5 months (range 1– 219 months).
Survival, relapse, and TRM in the entire cohort 137 (43) 185 (57)
In the entire cohort, the probability of OS and DFS at 3 years was 44% [95% confidence interval (CI) 38–49%] and 38%
Ann Hematol Fig. 1 The probability of overall survival and disease-free survival (a) and the cumulative incidences of relapse and transplant-related mortality (b) following allogeneic hematopoietic cell transplantation for acute myeloid leukemia with 11q23 abnormality
[95% CI 33–44%], respectively (Fig. 1a). In a univariate analysis by the log-rank test, extramedullary involvement at diagnosis, KMT2A/MLL fusion partner, disease status at HCT, and the donor source were significantly associated with OS (Fig. 2, Supplementary Table 1). In a univariate analysis by the log-rank test, extramedullary involvement at diagnosis and the disease status at HCT were significantly associated with DFS. In the multivariate analysis, beyond CR1 disease status
at HCT alone was significantly associated with higher overall mortality and treatment failure (Table 2). The cumulative incidence of relapse and TRM at 3 years was 44% (95% CI 38–50%) and 18% (95% CI 14–22%) in the entire cohort, respectively (Fig. 1b). In a univariate analysis performed using Gray’s test, extramedullary involvement at diagnosis, KMT2A/MLL fusion partner, and disease status at HCT were significantly associated with
Fig. 2 The probabilities of overall survival (OS) after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia with 11q23 abnormality according to white blood cell (WBC) count at
diagnosis (a), extramedullary manifestation at diagnosis (b), cytogenetics (c), disease status at HCT (d), the interval time from diagnosis to HCT (e), and donor source (f)
Ann Hematol Table 2
Multivariate analysis of transplant outcomes Number
Overall mortality HR (95% CI)
P
Treatment failure HR (95% CI)
0.43
1.00 (0.71–1.41)
P
Relapse HR (95% CI)
P
TRM HR (95% CI)
P
Age 16–39 years ≥ 40 years Sex Male Female FAB classification M4/M5 Other than M4/M5
165
1.00
157
1.15 (0.80–1.63)
1.00
1.00
173
1.00
149
1.13 (0.79–1.61)
0.50
1.18 (0.83–1.68)
0.33
1.13 (0.73–1.75)
0.58
0.99 (0.54–1.82)
1.00
211 97
1.00 1.08 (0.72–1.62)
0.69
1.00 1.01 (0.68–1.49)
0.93
1.00 1.06 (0.67–1.68)
0.78
1.00 0.91 (0.44–1.89)
0.81
1.00 1.21 (0.85–1.72)
0.28
1.00 1.21 (0.85–1.71)
0.27
1.00 1.05 (0.68–1.60)
0.82
1.00 1.45 (0.78–2.71)
0.24
0.97
1.00
0.83 (0.54–1.28)
1.00 0.40
1.00
1.28 (0.71–2.30)
0.40
1.00
WBC count at diagnosis < 20,000/μL ≥ 20,000/μL
168 142
Extramedullary involvement at diagnosis Present 36 1.00 Absent Cytogenetics t(6;11) or t(9;11)
221 155
0.74 (0.45–1.20)
1.00
1.00
0.22
0.88 (0.55–1.42)
1.00
0.62
1.00
0.74 (0.45–1.20)
1.00 0.22
1.00
1.18 (0.47–2.95)
0.71
1.00
Other than t(6;11) 167 and t(9;11) Disease status at HCT
0.78 (0.53–1.13)
0.19
0.88 (0.62–1.26)
0.50
0.77 (0.44–1.37)
0.39
1.15 (0.58–2.27)
0.69
CR1 159 Beyond CR1 160 Time from diagnosis to HCT < 6 months 137 185 ≥ 6 months Donor source
1.00 2.47(1.65–3.70)
< 0.001
1.00 2.51 (1.71–3.68)
< 0.001
1.00 2.28 (1.43–3.65)
< 0.001
1.00 1.48 (0.76–2.90)
0.25
1.00 1.20 (0.79–1.80)
0.37
1.00 1.11 (0.75–1.62)
0.58
1.00 1.18 (0.75–1.86)
0.45
1.00 0.75 (0.38–1.47)
0.41
0.92 0.22
1.00 1.06 (0.70–1.62) 1.30 (0.84–2.02)
0.75 0.22
1.00 1.14 (0.69–1.85) 1.17 (0.70–1.96)
0.60 0.53
1.00 1.06 (0.51–2.17) 1.26 (0.57–2.80)
0.87 0.56
0.36
1.28 (0.82–2.00)
0.88
0.93 (0.62–1.38)
RBMT/PBSCT UBMT UCBT Conditioning regimen MAC
127 124 71
1.00 1.02 (0.66–1.59) 1.32 (0.84–2.08)
237
1.00
RIC Year of HCT 1990–2007
85
1.23 (0.77–1.96)
139
1.00
183
0.97 (0.64–1.47)
2008–2014
1.00
1.00 0.27
1.00
1.02 (0.53–1.96)
1.00 0.93
1.00 0.73
1.37 (0.84–2.24)
1.36 (0.65–2.80)
0.40
1.00 0.20
0.44 (0.22–0.87)
0.01
The P values in italic are statistically significant TRM transplant-related mortality, FAB French–American–British, WBC white blood cell, HCT hematopoietic cell transplantation, CR1 first complete remission, RBMT/PBSCT bone marrow transplantation/peripheral blood stem cell transplantation from a related donor, UBMT bone marrow transplantation from an unrelated donor, UCBT cord blood transplantation from an unrelated donor, MAC myeloablative conditioning, RIC reduced-intensity conditioning, HR hazard ratio, CI confidence interval
relapse (Supplementary Fig. 1). In the multivariate analysis, beyond CR1 disease status at HCT alone was significantly associated with higher relapse (Table 2). Recent year of HCT alone was significantly associated with lower TRM in the multivariate analysis (Table 2). In the multivariate analysis, age, sex, FAB classification, WBC count at diagnosis, extramedullary involvement at
diagnosis, time from diagnosis to HCT, intensity of conditioning regimen, and donor source were not significant prognostic indicator for relapse and survival. Among the entire 322 patients, 188 patients had died at the last follow-up. The causes of death are summarized in Supplementary Table 2. The most frequent cause of death was relapse. Compared with patients with CR1,
Ann Hematol
relapse was more common cause of death in patients with beyond CR1.
Survival, relapse, and TRM according to 11q23 fusion partner The prognosis of AML with 11q23 abnormality after chemotherapy depends on the 11q23 fusion partner [2, 3, 9, 10]. Therefore, we examined the prognostic impact of six 11q23 fusion partner groups on transplant outcomes. In a univariate analysis, 11q23 fusion partner was not significantly associated with OS, DFS, relapse, and TRM for the entire group (Table 3, Fig. 3). Using Bonferroni’s multiple comparison procedure, there were no significant differences in OS, DFS, relapse, and TRM among each group of 11q23 fusion partner. To determine whether disease status at HCT influences the outcomes according to the 11q23 fusion partner, we also analyzed a subgroup of patients with CR1 or beyond CR1 at HCT. However, 11q23 fusion partner was not significantly associated with transplant outcomes both in patients with CR1 and those with beyond CR1 (Table 3). Compared with patients with t(11;17), who had the lowest relapse, the hazard ratio of relapse was significantly higher in patients with t(6;11) (P =
Table 3
0.04), and a trend toward a higher incidence of relapse was observed in patients with t(9;11), but this was not significant (P = 0.05) (Supplementary Table 3). We also examined the impact of an additional chromosomal abnormality on the transplant outcomes. In a univariate analysis, the presence of additional chromosomal abnormality in AML patients with 11q23 abnormality was not associated with OS and relapse (Supplementary Fig. 2).
Impact of molecular status on transplant outcomes among patients with CR MRD status has prognostic significance in AML with t(9;11) [23]. However, the impact of MRD status at HCT on the transplant outcomes for adult AML with 11q23 abnormality has yet to be clarified. Therefore, we evaluated whether the MRD status at HCT were associated with survival and hematological relapse among 109 evaluable hematological CR patients. In a univariate analysis, the probability of OS at 3 years was 64% (95% CI 48–76%) in MRD (−) at HCT and 39% (95% CI 24–53%) in MRD (+) at HCT (P = 0.02; Fig. 4a). In the multivariate analysis, extramedullary involvement at
Univariate analysis of overall survival, disease-free survival, relapse, and transplant-related mortality at 3 years according to the 11q23 fusion partner Number
OS % (95% CI)
P
DFS % (95% CI)
Relapse % (95% CI)
0.44
P
TRM % (95% CI)
Entire cohort t(6;11) t(9;11) t(11;17)
72 83 19
29 (18–41) 40 (28–51) 58 (33–76)
29 (18–41) 34 (24–45) 53 (29–72)
53 (40–64) 48 (37–59) 21 (6–42)
19 (10–29) 18 (10–27) 26 (9–48)
t(11;19) t(11;v)*
83 37
55 (43–65) 47 (29–63)
46 (35–57) 41 (24–57)
39 (28–50) 42 (25–59)
15 (8–24) 17 (7–31)
Unbalanced 11q23
28
42 (23–59)
CR1 t(6;11) t(9;11) t(11;17) t(11;19) t(11;v) * Unbalanced 11q23 Beyond CR1 t(6;11) t(9;11) t(11;17) t(11;19) t(11;v) * Unbalanced 11q23
0.32
P
34 (18–52) 0.32
35 41 10 42 19 12
47 (28–64) 58 (37–71) 80 (41–95) 71 (53–83) 59 (32–78) 65 (31–85)
36 40 9 41 18 16
12 (3–27) 26 (13–41) 33 (8–62) 38 (24–53) 35 (14–57) 25 (8–47)
0.18
44 (24–61) 0.27
46 (18–41) 49 (24–45) 80 (29–72) 64 (35–57) 53 (24–57) 56 (18–52) 0.84
0.82
22 (9–39) 0.14
37 (21–54) 38 (23–53) 0 23 (11–38) 36 (14–58) 26 (6–54) 0.93
13 (4–28) 22 (10–51) 22 (16–43) 29 (16–43) 29 (10–52) 19 (5–40)
0.85 17 (6–33) 13 (5–26) 20 (3–49) 13 (5–26) 11 (2–31) 18 (3–45)
0.84 12 (3–27) 26 (13–41) 33 (8–62) 38 (24–53) 35 (14–57) 25 (8–47)
0.95 20 (9–36) 22 (10–36) 33 (6–65) 17 (8–30) 23 (7–46) 25 (7–49)
OS overall survival, DFS disease-free survival, TRM transplant-related mortality, CR1 first complete remission, CI confidence interval *v denotes various chromosomes other than t(6;11), t(9;11), t(11;17), and t(11;19)
P
Ann Hematol Fig. 3 The probabilities of overall survival (a) and the cumulative incidences of relapse (b) following allogeneic hematopoietic cell transplantation according to the 11q23 fusion partner
diagnosis, MRD (+) at HCT, and UCBT were significantly associated with higher overall mortality (Supplementary Table 4). In a univariate analysis, the cumulative incidence of hematological relapse at 3 years was 26% (95% CI 15–38%) in MRD (−) at HCT and 46% (95% CI 31–59%) in MRD (+) at HCT (P = 0.02; Fig. 4b). In the multivariate analysis, extramedullary involvement at diagnosis, MRD (+) at HCT, and UBMT were significantly associated with higher hematological relapse (Supplementary Table 4).
Discussion The purpose of this retrospective study was to evaluate the outcomes after allo-HCT and determine the prognostic factors
Fig. 4 The probabilities of overall survival (a) and the cumulative incidences of hematological relapse (b) following allogeneic hematopoietic cell transplantation according to the minimal residual disease (MRD) status at HCT
regarding the transplant outcomes in adult AML with 11q23 abnormality. Our data demonstrated that beyond CR1 at HCT alone was significantly associated with higher overall mortality, treatment failure, and relapse in the multivariate analysis. In contrast, age, time from diagnosis to HCT, intensity of conditioning regimen, and donor source were not significantly associated with overall mortality, treatment failure, and relapse. Relapse was significantly higher in patients with t(6;11), and a trend toward a higher incidence of relapse was observed in patients with t(9;11) compared with those with t(11;17), who had the lowest relapse incidence. Moreover, MRD status at HCT significantly affected the overall survival and relapse incidence among patients with hematological CR at HCT. Several studies have shown that allo-HCT does not improve survival in childhood ALL or AML with 11q23
Ann Hematol
abnormality [24–26]. Therefore, the role of allo-HCT in infant or pediatric ALL with 11q23 abnormality in CR1 is controversial. In contrast, the potential benefits of allo-HCT over post-remission consolidation chemotherapy in adult AML with 11q23 abnormality have been demonstrated in several retrospective studies [10, 13]. Wang et al. reported on a multicenter cohort study of 85 patients with MLL-rearranged acute leukemia and found that allo-HCT in CR1 significantly decreased the relapse rate compared with those beyond CR1 [14], indicating that allo-HCT in CR1 should be recommended for all AML patients with 11q23 abnormality. In our study, 159 (49%) patients received allo-HCT in CR1. Among the patients with beyond CR1 at HCT, survival was very poor due to the higher rates of relapse, which was consistent with a previous study [27]. On the other hand, donor source did not affect the transplant outcome in our study. In fact, several studies have demonstrated highly similar survival results between UCBT and UBMT in adult AML [28–30]. Our previous study showed that UCBT was an effective treatment for adult AML patients with 11q23 abnormality, if HLA-compatible related and unrelated donors were not available [31]. Therefore, allo-HCT from an alternative donor also should be considered in adult AML with 11q23 abnormality when HLA-compatible related donors are not available. The prognosis of AML with 11q23 abnormality is partly dependent on the 11q23 fusion partner. Although 135 different partner genes in 11q23 abnormalities have been identified so far, the most common partner genes in adult AML are AF9 in t(9;11), AF6 in t(6;11), and ELL in t(11;19) [32]. Several studies have shown that t(9;11) was associated with better survival compared to other 11q23 abnormalities in adult AML [2, 3, 9, 10]. In contrast, the Cancer and Leukemia Group B (CALGB) 8461 study suggested that patients with t(6;11) AML have a short CR duration and poor survival [2, 11]. Therefore, t(9;11) was categorized as an intermediate cytogenetic group, whereas other 11q23 abnormalities except for t(9;11) were categorized as an adverse cytogenetic group by the National Comprehensive Cancer Network (NCCN) Guidelines [33], or European LeukemiaNet (ELN) criteria [4] in adult patients with AML who had primarily received chemotherapy. Among adult patients with AML who had received allo-HCT, Chen et al. reported that t(9;11) was similar to the intermediate prognostic for survival, whereas other 11q23 abnormalities, including t(6;11), t(11,19), and unbalanced 11q23 abnormalities were similar to the poor prognostic for survival [16]. Pigneux et al. reported that t(9;11) and t(11;19) had better survival compared with t(6;11) and t(10;11) in adult AML [17]. Thus, these results are consistent with previous studies on adult patients with AML who primarily received chemotherapy [2, 3, 9, 10]. In contrast, we found no significant difference in the survival according to the 11q23 fusion partner, which was consistent with other studies [13, 34]. However, in more detail, our study clearly demonstrated that t(9;11) and
t(6;11) had a higher relapse incidence compared with t(11;17), which had the lowest relapse incidence following allo-HCT. Apart from 11q23 fusion partner, several studies have reported that AML patients with 11q23 abnormality often had overexpression of MECOM (also known as Evi1), and higher expression of MECOM was the sole independent adverse prognostic factor for survival in adult AML with 11q23 abnormality [35–37]. Interestingly, MECOM overexpression was observed in t(6;11), which is the worst prognostic translocation among AML with 11q23 abnormality [37]. Thus, further studies are required to clarify the impact of MECOM overexpression on the outcomes after allo-HCT for adult AML with 11q23 abnormality. Monitoring of MRD status is useful for the detection of relapse in AML patients with t(9;11) who had primarily received chemotherapy [23]. Liu et al. used quantitative PCR of MLL expression to detect the impact of MRD on outcomes after allo-HCT in acute leukemia with MLL rearrangements and found that MRD-positive status at HCT was associated with higher relapse and mortality [38]. In fact, our study also confirmed that MRD-positive status at HCT was a significant prognostic factor for relapse and mortality in adult AML with 11q23 abnormality during CR. However, because MRD measurement was not standardized in this study, and we were unable to monitor MRD status after allo-HCT due to insufficient data in the TRUMP, further studies are required to clarify the impact of MRD at HCT and after HCT on the outcomes for AML with 11q23 abnormality. Our study had several limitations. First, because of insufficient data in the TRUMP, we were unable to evaluate the somatic mutation profiles, such as MECOM, FLT3-ITD, FLT3-TKD, and NPM1, which were observed in AML with 11q23 abnormality [37]. These somatic mutations may also affect the transplant outcomes. Second, MLL partial tandem duplications (MLL-PTD) were not evaluated in our study. However, MLL-PTD was predominantly observed in elderly AML with a normal karyotype or trisomy 11, and chromosomal abnormalities involving 11q23 are not coexistent with MLL-PTD [39]. Therefore, MLL-PTD is considered as a distinct entity of AML. Third, because MRD status was measured at each institution, the same method and threshold were not used to detect MRD at HCT in our study. Therefore, further studies with the standardization of MRD detection are warranted to confirm the impact of MRD status on the outcomes after HCT for AML with 11q23 abnormality. In conclusion, this registry-based study confirmed that the 11q23 fusion partner did not have a significant impact on survival in adult AML with 11q23 abnormality following alloHCT. Disease status at HCT rather than age, time from diagnosis to HCT, intensity of conditioning regimen, and donor source was the only significant prognostic indicator for relapse and
Ann Hematol
survival, indicating that adult AML with 11q23 abnormality seems to benefit from allo-HCT in CR1. MRD status at HCT was the significant prognostic indicator for relapse and survival in CR patients. Although allo-HCT offered a curative option for adult AML with 11q23 abnormality, novel transplant approaches or effective targeted therapies, such as Dot1L Inhibitors, are also warranted for AML with 11q23 abnormality. Acknowledgements We thank all of the physicians and staff at the centers who provided the clinical data to the Transplant Registry Unified Management Program (TRUMP) of the Japan Society of Hematopoietic Cell Transplantation (JSHCT).
6.
7.
8.
Author contributions T Konuma designed the research, analyzed the data, performed the statistical analysis, and wrote the first draft of the manuscript. SM, T Kondo, HY, and SY contributed to the critical review of the manuscript. All the other authors contributed to data collection. All authors approved the final version.
Compliance with ethical standards Conflicts of interest The authors declare that they have no conflict of interest.
References 1.
2.
3.
4.
5.
Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR (2000) Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96:4075–4083 Byrd JC, Mrózek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, Pettenati MJ, Patil SR, Rao KW, Watson MS, Koduru PR, Moore JO, Stone RM, Mayer RJ, Feldman EJ, Davey FR, Schiffer CA, Larson RA, Bloomfield CD, Cancer and Leukemia Group B (CALGB 8461) (2002) Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 100:4325–4336 Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, Wheatley K, Harrison CJ, Burnett AK, on behalf of the National Cancer Research Institute Adult Leukaemia Working Group (2010) Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116:354–365 Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Löwenberg B, Bloomfield CD (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129:424–447 Burnett AK, Wheatley K, Goldstone AH, Stevens RF, Hann IM, Rees JH et al (2002) The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol 118: 385–400
9.
10.
11.
12.
13.
14.
15.
Tallman MS, Dewald GW, Gandham S, Logan BR, Keating A, Lazarus HM, Litzow MR, Mehta J, Pedersen T, Perez WS, Rowe JM, Wetzler M, Weisdorf DJ (2007) Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first or second complete remission. Blood 110:409–417 Armand P, Kim HT, DeAngelo DJ, Ho VT, Cutler CS, Stone RM et al (2007) Impact of cytogenetics on outcome of de novo and therapy-related AML and MDS after allogeneic transplantation. Biol Blood Marrow Transplant 13:655–664 Armand P, Kim HT, Zhang MJ, Perez WS, Dal Cin PS, Klumpp TR, Waller EK, Litzow MR, Liesveld JL, Lazarus HM, Artz AS, Gupta V, Savani BN, McCarthy PL, Cahn JY, Schouten HC, Finke J, Ball ED, Aljurf MD, Cutler CS, Rowe JM, Antin JH, Isola LM, di Bartolomeo P, Camitta BM, Miller AM, Cairo MS, StockerlGoldstein K, Sierra J, Savoie ML, Halter J, Stiff PJ, Nabhan C, Jakubowski AA, Bunjes DW, Petersdorf EW, Devine SM, Maziarz RT, Bornhauser M, Lewis VA, Marks DI, Bredeson CN, Soiffer RJ, Weisdorf DJ (2012) Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transplant 18:280–288 Mrózek K, Heinonen K, Lawrence D, Carroll AJ, Koduru PR, Rao KW et al (1997) Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study. Blood 90:4532–4538 Krauter J, Wagner K, Schäfer I, Marschalek R, Meyer C, Heil G, Schaich M, Ehninger G, Niederwieser D, Krahl R, Büchner T, Sauerland C, Schlegelberger B, Döhner K, Döhner H, Schlenk RF, Ganser A (2009) Prognostic factors in adult patients up to 60 years old with acute myeloid leukemia and translocations of chromosome band 11q23: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol 27:3000–3006 Blum W, Mrózek K, Ruppert AS, Carroll AJ, Rao KW, Pettenati MJ, Anastasi J, Larson RA, Bloomfield CD (2004) Adult de novo acute myeloid leukemia with t(6;11)(q27;q23): results from Cancer and Leukemia Group B Study 8461 and review of the literature. Cancer 101:1420–1427 Tamai H, Yamaguchi H, Takahashi S, Tojo A, Hamaguchi H, Kobayashi T, Akiyama H, Sakamaki H, Okumura H, Nakao S, Arai A, Miura O, Tajika K, Inokuchi K, Dan K (2008) Treatment of adult AML with t(6;11)(q27;q23) by allogeneic hematopoietic SCT in the first CR. Bone Marrow Transplant 42:553–554 Tamai H, Yamaguchi H, Hamaguchi H, Yagasaki F, Bessho M, Kobayashi T, Akiyama H, Sakamaki H, Takahashi S, Tojo A, Ohmine K, Ozawa K, Okumura H, Nakao S, Arai A, Miura O, Toyota S, Gomi S, Murai Y, Usui N, Miyazawa K, Ohyashiki K, Takahashi N, Sawada K, Kato A, Oshimi K, Inokuchi K, Dan K (2008) Clinical features of adult acute leukemia with 11q23 abnormalities in Japan: a co-operative multicenter study. Int J Hematol 87:195–202 Wang Y, Liu QF, Qin YZ, Liu DH, Xu LP, Jiang B, Jiang Q, Dai M, Yu SJ, Jiang XM, Liu YR, Huang XJ (2014) Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of patients with mixed-lineage-leukemia-rearranged acute leukemia: results from a prospective, multi-center study. Am J Hematol 89:130–136 Muto T, Takeuchi M, Yamazaki A, Sugita Y, Tsukamoto S, Sakai S, Takeda Y, Mimura N, Ohwada C, Sakaida E, Aotsuka N, Iseki T, Nakaseko C (2015) Efficacy of myeloablative allogeneic hematopoietic stem cell transplantation in adult patients with MLL-ELLpositive acute myeloid leukemia. Int J Hematol 102:86–92
Ann Hematol 16.
Chen Y, Kantarjian H, Pierce S, Faderl S, O’Brien S, Qiao W, Abruzzo L, de Lima M, Kebriaei P, Jabbour E, Daver N, Kadia T, Estrov Z, Garcia-Manero G, Cortes J, Ravandi F (2013) Prognostic significance of 11q23 aberrations in adult acute myeloid leukemia and the role of allogeneic stem cell transplantation. Leukemia 27: 836–842 17. Pigneux A, Labopin M, Maertens J, Cordonnier C, Volin L, Socié G et al (2015) Outcome of allogeneic hematopoietic stem-cell transplantation for adult patients with AML and 11q23/MLL rearrangement (MLL-r AML). Leukemia 29:2375–2381 18. Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A, Kato K, Tabuchi K, Tsuchida M, Morishima Y, Mitamura M, Kawa K, Kato S, Nagamura T, Takanashi M, Kodera Y (2007) Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol 86:269–274 19. Atsuta Y (2016) Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol 103:3–10 20. Kanda J (2016) Scripts for TRUMP data analyses. Part II (HLArelated data): statistical analyses specific for hematopoietic stem cell transplantation. Int J Hematol 103:11–19 21. Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, Sandmaier B (2009) Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 15:367–369 22. Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’for medical statistics. Bone Marrow Transplant 48: 452–458 23. Scholl C, Schlenk RF, Eiwen K, Döhner H, Fröhling S, Döhner K, AML Study Group (2005) The prognostic value of MLL-AF9 detection in patients with t(9;11)(p22;q23)-positive acute myeloid leukemia. Haematologica 90:1626–1634 24. Pui CH, Gaynon PS, Boyett JM, Chessells JM, Baruchel A, Kamps W, Silverman LB, Biondi A, Harms DO, Vilmer E, Schrappe M, Camitta B (2002) Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 359:1909–1915 25. Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M et al (2007) A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 370:240–250 26. Balgobind BV, Raimondi SC, Harbott J, Zimmermann M, Alonzo TA, Auvrignon A, Beverloo HB, Chang M, Creutzig U, Dworzak MN, Forestier E, Gibson B, Hasle H, Harrison CJ, Heerema NA, Kaspers GJL, Leszl A, Litvinko N, Nigro LL, Morimoto A, Perot C, Pieters R, Reinhardt D, Rubnitz JE, Smith FO, Stary J, Stasevich I, Strehl S, Taga T, Tomizawa D, Webb D, Zemanova Z, Zwaan CM, van den Heuvel-Eibrink MM (2009) Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood 114: 2489–2496 27. Garrido SM, Bryant E, Appelbaum FR (2000) Allogeneic stem cell transplantation for relapsed and refractory acute myeloid leukemia patients with 11q23 abnormalities. Leuk Res 24:481–486 28. Milano F, Gooley T, Wood B, Woolfrey A, Flowers ME, Doney K, Witherspoon R, Mielcarek M, Deeg JH, Sorror M, Dahlberg A, Sandmaier BM, Salit R, Petersdorf E, Appelbaum FR, Delaney C (2016) Cord-blood transplantation in patients with minimal residual disease. N Engl J Med 375:944–953
29.
Terakura S, Atsuta Y, Tsukada N, Kobayashi T, Tanaka M, Kanda J, Najima Y, Fukuda T, Uchida N, Takahashi S, Nagamura-Inoue T, Morishima Y, Miyamura K, Japan Society for Hematopoietic Cell Transplantation (2016) Comparison of outcomes of 8/8 and 7/8 allele-matched unrelated bone marrow transplantation and singleunit cord blood transplantation in adults with acute leukemia. Biol Blood Marrow Transplant 22:330–338 30. Eapen M, Rocha V, Sanz G, Scaradavou A, Zhang MJ, Arcese W, Sirvent A, Champlin RE, Chao N, Gee AP, Isola L, Laughlin MJ, Marks DI, Nabhan S, Ruggeri A, Soiffer R, Horowitz MM, Gluckman E, Wagner JE, Center for International Blood and Marrow Transplant Research, Acute Leukemia Working Party Eurocord (the European Group for Blood Marrow Transplantation), National Cord Blood Program of the New York Blood Center (2010) Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol 11:653–660 31. Konuma T, Ooi J, Takahashi S, Tomonari A, Tsukada N, Kato S, Kasahara S, Uchimaru K, Iseki T, Tojo A, Asano S (2008) Myeloablative unrelated cord blood transplantation for adult acute myeloid leukemia patients with 11q23 abnormalities. Eur J Haematol 80:545–548 32. Meyer C, Burmeister T, Gröger D, Tsaur G, Fechina L, Renneville A et al (2018) The MLL recombinome of acute leukemias in 2017. Leukemia 32:273–284 33. O’Donnell MR, Tallman MS, Abboud CN, et al (2016) National comprehensive cancer network. NCCN clinical practice guidelines in oncology. Acute Myeloid Leukemia Version 1. [cited 2016 Feb 16] Available from: http://www.nccn.org/professionals/physician_ gls/f_guidelines.asp 34. Schoch C, Schnittger S, Klaus M, Kern W, Hiddemann W, Haferlach T (2003) AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 102:2395–2402 35. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel-van de Luytgaarde S, Hack R et al (2003) High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood 101: 837–845 36. Gröschel S, Lugthart S, Schlenk RF, Valk PJ, Eiwen K, Goudswaard C et al (2010) High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities. J Clin Oncol 28:2101–2107 37. Gröschel S, Schlenk RF, Engelmann J, Rockova V, Teleanu V, Kühn MW et al (2013) Deregulated expression of EVI1 defines a poor prognostic subset of MLL-rearranged acute myeloid leukemias: a study of the German-Austrian Acute Myeloid Leukemia Study Group and the Dutch-Belgian-Swiss HOVON/SAKK Cooperative Group. J Clin Oncol 31:95–103 38. Liu J, Wang Y, Xu LP, Liu DH, Qin YZ, Chang YJ, Liu KY, Huang XJ (2014) Monitoring mixed lineage leukemia expression may help identify patients with mixed lineage leukemia—rearranged acute leukemia who are at high risk of relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 20: 929–936 39. Basecke J, Whelan JT, Griesinger F, Bertrand FE (2006) The MLL partial tandem duplication in acute myeloid leukaemia. Br J Haematol 135:438–449
Ann Hematol
Affiliations Takaaki Konuma 1 & Shohei Mizuno 2 & Tadakazu Kondo 3 & Hiroki Yamaguchi 4 & Takahiro Fukuda 5 & Naoyuki Uchida 6 & Yuho Najima 7 & Heiwa Kanamori 8 & Shuichi Ota 9 & Hirohisa Nakamae 10 & Mika Nakamae 10 & Ishikazu Mizuno 11 & Junichi Sugita 12 & Yasushi Onishi 13 & Akira Yokota 14 & Satoshi Takahashi 15 & Yoshinobu Kanda 16 & Tatsuo Ichinohe 17 & Yoshiko Atsuta 18,19 & Shingo Yano 20 1
2
3
12
Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
13
Division of Hematology, Department of Internal Medicine, School of Medicine, Aichi Medical University, Nagakute, Japan
Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan
14
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Department of Hematology, Chiba Aoba Municipal Hospital, Chiba, Japan
15
Division of Molecular Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
16
Division of Hematology, Jichi Medical University, Saitama Medical Center, Saitama, Japan
17
Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
18
Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan
19
Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
20
Division of Clinical Oncology and Hematology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
4
Department of Hematology, Nippon Medical School, Tokyo, Japan
5
Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
6
7
8
9
Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo, Japan Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan Department of Hematology, Kanagawa Cancer Center, Kanagawa, Japan Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan
10
Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan
11
Department of Hematology, Hyogo Cancer Center, Akashi, Japan
