Long‐Term Survival After Allogeneic Hematopoietic Stem Cell Transplantation for <i>BCR::ABL1</i>‐Negative Atypical Chronic Myeloid Leukemia: A Nationwide Retrospective Study by Adult <scp>CML</scp>/<scp>MPN</scp> and <scp>MDS</scp> Working Groups of the Japanese Society for Transplantation and Cellular Therapy
Authors: Hidehiro Itonaga, Yasushi Miyazaki, Takeshi Kondo, Yutaka Shimazu, Jun Aoki, Shuhei Kurosawa, Takashi Ikeda, Tetsuya Eto, Naoyuki Uchida, Hideyuki Nakazawa, Koji Kawamura, Junya Kanda, Yoshiko Atsuta, Takayoshi Tachibana
Journal: American Journal of Hematology (2025)

Atypical chronic myeloid leukemia (aCML), BCR::ABL1-negative (also known as myelodysplastic/myeloproliferative neoplasm [MDS/MPN] with neutrophilia) is a rare hematological disorder with increased numbers of neutrophils in the bone marrow and peripheral blood [1]. aCML typically has a very poor prognosis, with median survival of approximately 2 years [2]. Cytoreductive therapy and novel molecular agents are therapeutic options for aCML, and the main aim of these treatments is to improve symptoms and control the proliferation of leukemic cells. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a promising approach for curative outcomes in aCML patients [3, 4]. Due to recent advances in transplant modalities, the reduced-intensity conditioning (RIC) regimen and alternative donors (e.g., unrelated cord blood [U-CB] and human leukocyte antigen [HLA]-haploidentical related donor [haplo-RD]) is being increasingly used in MDS/MPN patients [5, 6]. However, the impact of the conditioning intensity and alternative donors on the post-transplant outcomes of aCML patients remains unclear. To investigate the post-transplant outcomes of aCML patients treated with current modalities, we herein conducted a nationwide retrospective study. The original data set consisted of 74 adults (i) who were 16 years or older, (ii) were diagnosed with BCR::ABL1-negative aCML, and (iii) underwent initial allo-HSCT between January 1, 2003 and December 31, 2021. The intensity of conditioning regimens was classified as low, intermediate, and high according to total conditioning intensity (TCI) score. The patient characteristics and the conditioning regimens are shown in Tables S1 and S2. The median age at transplantation was 54 years (range, 18–72 years). The median time from the diagnosis to HSCT was 206 days (range, 10–1945 days). As for transplant procedures, 51 (68.9%) had received a high TCI regimen; and 11 (14.9%), 35 (47.3%), 19 (25.7%), and 9 (12.2%) patients used HLA-matched related donors (MRD), unrelated bone marrow/peripheral blood stem cell donors (URD), U-CB, and haplo-RD, respectively. In transplantation from haplo-RD, 7 out of 9 patients used post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis. The median follow-up was 3.01 years (interquartile range, 1.60–6.15 years) (reverse Kaplan–Meier method). The 3-year unadjusted probabilities of overall survival (OS), chronic GVHD- and relapse-free survival (CRFS), and GVHD- and relapse-free survival (GRFS) were 44.2% (31.7%–55.9%), 22.7% (13.1%–33.9%), and 17.9% (9.5%–28.6%), respectively (Figure S1). The 3-year unadjusted cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 40.4% (28.5%–51.9%) and 25.5% (16.0%–36.1%), respectively (Figure S1). The unadjusted incidence of neutrophil engraftment on day 100 was 90.5% (81.2%–95.4%), and the unadjusted incidence of platelet recovery on day 150 was 61.0% (48.9%–71.1%). The unadjusted incidence of total acute GVHD on day 100 was 43.2% (31.8%–54.1%), and the unadjusted incidence of total chronic GVHD at 3 years was 37.2% (23.5%–50.8%). As for the causes of death, the most frequent cause of non-relapse death was idiopathic pulmonary syndrome (n = 5, 11.9%), followed by GVHD (n = 4, 9.5%) (Table S3). Regarding the post-transplant therapy, no patient received the maintenance therapy to prevent the relapse of aCML. In 29 patients who experienced the post-transplant relapse, 3 patients received donor lymphocyte infusion-based therapy but none showed any response of aCML. The multivariate analysis for OS, CIR, and NRM revealed the following five factors (Table S4): (i) patient age (≥ 60 years) was associated with worse OS (hazard ratio [HR], 3.18; 95% confidence intervals [CI], 1.03–9.84; p = 0.045), (ii) the presence of the monosomy 7/del(7q) cytogenetic abnormality was associated with higher CIR (HR, 2.39; 95% CI, 1.27–4.51; p = 0.007), (iii) HSCT from a female donor to a male recipient correlated with worse OS (HR, 2.94; 95% CI, 1.44–6.00; p = 0.003), CRFS (HR, 2.18; 95% CI, 1.23–3.87; p = 0.008), and NRM (HR, 3.09; 95% CI, 1.18–8.05; p = 0.021), (iv) tacrolimus-based prophylaxis was associated with worse OS (HR, 2.61; 95% CI, 1.07–6.37; p = 0.034), and (v) HSCT between 2013 and 2021 correlated with better NRM (HR, 0.28; 95% CI, 0.10–0.82; p = 0.020). No significant impact of TCI or the donor source was observed. Two factors correlated with a lower incidence of neutrophil engraftment: the use of U-CB (HR, 0.26; 95% CI, 0.10–0.64; p = 0.003) and HSCT from a female donor to a male recipient (HR, 0.56; 95% CI, 0.34–0.92; p = 0.023) (Table S5). Three factors correlated with a lower incidence of platelet recovery: patient age (40–59 years) (HR, 0.39; 95% CI, 0.17–0.87; p = 0.021), the use of U-CB (HR, 0.18; 95% CI, 0.07–0.46; p < 0.001), and the use of the low/intermediate TCI regimen (HR, 0.45; 95% CI, 0.21–0.98; p = 0.045). No factors correlated with the incidence of acute or chronic GVHD. We next estimate the outcomes by conditioning intensity. In the high and low/intermediate TCI regimens, the 3-year adjusted probabilities of OS were 37.3% (23.2%–59.9%) and 57.1% (37.1%–88.0%) (Figure 1A); the 3-year adjusted probabilities of CRFS were 27.2% (15.9%–46.5%) and 14.5% (4.4%–48.1%) (Figure 1B); the 3-year adjusted probabilities of GRFS were 26.6% (15.9%–44.5%) and 3.9% (0.4%–41.2%) (Figure S2A); the 3-year adjusted CIR were 45.8% (31.3%–63.3%) and 33.9% (17.3%–59.4%) (Figure 1C); the 3-year adjusted NRM were 17.3% (9.0%–31.9%), and 26.7% (12.1%–52.6%), respectively (Figure 1D). In the high and low/intermediate TCI regimens, the adjusted incidences of neutrophil engraftment were 88.7% (77.7%–95.8%) and 93.9% (78.0%–99.4%), and the adjusted incidence of platelet recovery were 68.7% (55.0%–81.6%) and 41.2% (24.3%–63.6%), respectively (Figure 1E,F). The adjusted cumulative incidences of GVHD are shown in Figure S2B,C. To understand the role of donor source, we estimated the outcomes by donor source. In MRD, URD, U-CB, and haplo-RD, the 3-year adjusted probabilities of OS were 60.8% (32.4%–100.0%), 68.3% (44.5%–100.0%), 37.5% (13.9%–100.0%), and 76.7% (50.7%–100.0%) (Figure 1G); the 3-year adjusted probabilities of CRFS were 29.2% (10.4%–82.4%), 34.3% (19.9%–59.2%), 31.5% (14.6%–67.8%), and 27.1% (7.3%–100.0%) (Figure 1H); the 3-year adjusted probabilities of GRFS were 42.8% (18.2%–100.0%), 40.0% (18.9%–84.6%), 40.2% (17.8%–90.8%), and 49.0% (20.2%–100.0%) (Figure S2D); the 3-year adjusted CIR were 41.9% (19.9%–73.7%), 42.0% (25.0%–64.4%), 37.9% (20.4%–63.0%), and 38.5% (14.1%–78.6%) (Figure 1I); the 3-year adjusted NRM were 12.0% (20.2%–55.1%), 26.2% (9.1%–61.7%), 27.4% (9.5%–64.3%), and 0.0%, respectively (Figure 1J). In MRD, URD, U-CB, and haplo-RD, the adjusted incidences of neutrophil engraftment were 96.3% (77.5%–99.9%), 95.7% (85.4%–99.4%), 84.4% (60.9%–97.5%), and 98.9% (80.4%–100.0%), and the adjusted incidences of platelet recovery were 93.2% (68.7%–99.8%), 90.6% (69.2%–99.1%), 61.7% (33.3%–89.7%), and 96.5% (69.1%–100.0%), respectively (Figure 1K,L). The adjusted cumulative incidences of GVHD are shown in Figure S2E,F. One of the most important results was that no significant differences were observed in OS, CIR, or NRM between the high and low/intermediate TCI regimens. Similar findings were reported by EBMT with the RIC regimen, although the number of patients was small (n = 10) [4]. These results indicate the potential of the low/intermediate TCI regimen for the treatment of aCML. Due to the high percentage of elderly patients (≥ 60 years) in the aCML cohort [2], the low/intermediate TCI regimen may increase the opportunity to utilize allo-HSCT for these patients. However, the low/intermediate TCI regimen had a significantly lower incidence of platelet recovery, raising concerns about delayed hematopoietic recovery. To identify specific subgroups at risk of delayed hematopoietic recovery (e.g., the presence of splenomegaly and BM fibrosis) with the preferential utilization of the conditioning intensity, a large-scale study is needed in the future. The present study reported the outcomes of U-CB transplantation in 19 patients with aCML. Although no significant differences were observed in OS between U-CB and MRD, adjusted survival curves showed that OS was slightly worse with U-CB, which appeared to be due to higher NRM. Because U-CB transplantation and the use of the low/intermediate TCI regimen were identified as significant risk factors for delayed hematopoietic recovery in our study, the high TCI regimen would be preferred in the setting of U-CB transplantation for aCML. Another significant point was that transplantation using haplo-RD also appeared to be feasible for aCML in our study, which was consistent with previous findings on outcomes of haplo-RD for MDS/MPN [6]. Based on the small number of aCML patients in our study (n = 9) and the study by the EBMT (n = 5), it is difficult to draw a definitive conclusion about allo-HSCT using haplo-RD for aCML. However, recent advances, such as post-transplant cyclophosphamide and conditioning regimens containing antithymocyte globulin, may increase indications for allo-HSCT using haplo-RD in aCML patients. With the regard to search for alternative donor, intervals from transplant initiation to allografts are usually shorter in allo-HSCT using U-CB and haplo-RD than URD. Because optimal bridging therapy has not yet been established for aCML patients, physicians need to select these alternative donors in aCML patients with high risk of disease progression (e.g., leukocytosis, marrow blast percentage, splenomegaly, hypercellular marrow before HSCT, transfusion dependency, and gene mutation profile). In the terms of the lower incidence of hematopoietic recovery in U-CB transplantation, haplo-RD would have an advantage over U-CB when allo-HSCT is needed at an early timing from transplant initiation. In conclusion, current low/intermediate TCI conditioning regimens have potential as therapeutic options for aCML, and alternative donors would be used to achieve curative outcomes. These results suggest that the development of transplant modalities will increase opportunities for allo-HSCT and enable us to personalize the management of aCML patients. To maximize the benefit of allo-HSCT, further clinical research is required to monitor the minimal residual disease and initiate the post-transplant therapy. H.I. and Y.M. designed the research, organized the project, analyzed the data, and wrote the manuscript. H.I., Y.M., and T.T. collected data from the Transplant Registry Unified Management Program (TRUMP) database. H.I., Y.M., T.K., Y.S., J.A., S.K., T.I., T.E., N.U., H.N., K.K., J.K., Y.A., and T.T. interpreted data and reviewed and approved the final manuscript. This work was supported in part by the Takeda Science Foundation, Nagasaki-ken Medical Association, SGH Foundation, and a Grant-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (22K08480 [Nagasaki; H.I.]). The authors would like to thank all the physicians and data managers at the various institutes who contributed valuable data on transplantation to the Japanese Society for Transplantation and Cellular Therapy (JSTCT), all the members of the data management committees of JSTCT, and all the members of "Adult Myelodysplastic Syndromes (MDS) Working Group and Adult Chronic Myeloid Leukemia/Myeloproliferative Neoplasms (CML/MPN) of the JSTCT". The present study was approved by the TRUMP Committee (approval no. 6–10) and by the Ethics Committee of Nagasaki University Hospital (approval no. 23082117) at which this study was organized in accordance with the principles of the Declaration of Helsinki. The authors declare no conflicts of interest. All data are available within the article or Supporting Information or upon reasonable request from the corresponding author H.I. ([email protected]). Data S1. Supporting Information. 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