Improved myeloablative conditioning regimen for allogeneic stem cell transplantation in adult patients with chronic myelomonocytic leukaemia

Chronic myelomonocytic leukaemia (CMML) is a clonal haematopoietic stem cell disorder associated with overlapping characteristics of myelodysplastic syndrome and myeloproliferative neoplasm (MDS/MPN).1 In a recent study of this disease, 15%–20% of CMML cases transformed into secondary acute myeloid leukaemia (sAML) over 3–5 years. The estimated three-year disease-free survival (DFS) and overall survival (OS) were only 36% and 41% in patients with sAML evolving from CMML.2 Despite the particular responsiveness of malignant clones to epigenetic therapy with DNA-hypomethylating agents (HMAs), they are not eradicated by them.3 Therefore, we aimed to update knowledge of Chinese practice and outcomes in CMML patients receiving improved myeloablative conditioning, particularly in the era of novel diagnostics and therapeutics. The clinical data of 43 patients enrolled between January 2009 and December 2021 were obtained from the Haematopoietic Stem Cell Transplantation Center of the Chinese Academy of Blood Diseases Hospital (Tianjin, China). All diagnostic materials were re-categorized and met the 2016 WHO classification of myeloid neoplasms and acute leukaemia.1 The inclusion criteria were as follows: age 14 years or older, first allogeneic haematopoietic stem cell transplantation (allo-HSCT), and availability of follow-up data. Candidates were excluded if their outcome data were incomplete or missing. All patients were followed-up until 30 June 2022. Informed consent was obtained from the patients or their guardians. This study was approved by the ethics committee of the Chinese Academy of Blood Diseases Hospital. The schedules of different myeloablative conditioning regimens are presented in the Supporting information. The baseline characteristics of the 43 enrolled patients are presented in Table 1. In the mutational analyses of 114 genes, nine (22.5%) of 40 patients were found to harbour one mutation and 11 (27.5%) harboured two or more. We divided the cohort into two groups based on the age of 40 years and observed that gene mutation was more common in the older group (59.3% vs 30.8%, p = 0.022). Meanwhile, the proportion of genetic mutations involved in the activated signalling pathways was as high as 70.4% in the older group, much higher than the 23.1% in the group of age less than 40 (Figure 1). At a mean follow-up of 37.7 months (range: 3–161 months), the estimated three-year OS and DFS were 69.8% and 53.5% respectively (Figure 2). The univariate and multivariate analyses of the prognostic factors are outlined in Table 2. In multivariate analysis, complete remission (CR) before allo-HSCT was the only significant predictor of survival. In terms of recurrence-free survival (RFS), CR before allo-HSCT remained the only independent factor affecting relapse (Table S1). Seven patients underwent supportive care and 36 patients underwent chemotherapy before allo-HSCT. The three-year OS in the supportive-care group, CR after chemotherapy, and non-CR after chemotherapy were 85.7%, 76.9% and 40.0% (p = 0.015, Figure S1A) respectively. Meanwhile, the three-year DFS between the three subgroups was 71.4%, 61.5% and 20.0% (p = 0.007, Figure S1B), respectively. In particular, among the 23 patients undergoing HMA treatment followed by decitabine (Dec)-containing conditioning, the three-year OS between first complete remission (CR1), second complete remission (CR2) or partial remission (PR), and non-remission (NR) was 91.7%, 80.0% and 50.0% (p = 0.072, Figure S2A) respectively, while the three-year DFS was 83.3%, 60.0% and 16.7% (p = 0.006, Figure S2B) respectively. Dec-based myeloablative regimen Bu/Cy/Flu/Ara-c Notably, we demonstrated favourable long-term outcomes with a three-year OS and DFS of 69.8% and 53.5% respectively. The reason for the pronounced survival advantage was that up to 72.1% of patients attained CR before allo-HSCT. Additionally, Dec-based conditioning was administered to 29 patients. Given that the intermediate-2 and high-risk patients accounted for 72.1% of this cohort, where this was much higher than the 27.3%–37.8% in other studies,4, 5 the relapse rate increased and the DFS advantages were somewhat offset. This also reflected that salvage therapies after relapse improved significantly, which benefited the prolonged OS of the patients. In this study, we emphasized the feasibility of early initiation of allo-HSCT in patients with low or intermediate-1 risk. Seven patients that received supportive care prior to allo-HSCT demonstrated a clear post-HSCT survival advantage. Moreover, a recent study also suggested that allo-HSCT offered the best survival advantage among patients in the chronic phase of CMML compared with non-transplant patients or patients undergoing blast transformation. The median OS between the three groups was 70, 27 and 32 months, respectively (p = 0.0014).6 Accordingly, for intermediate-2 or high-risk patients, chemotherapy was the necessary approach before allo-HSCT to attain CR and reduce the relapse rate. In this study, pre-transplant CR was the only independent prognostic factor. Similarly, the Chronic Malignancies Working Party analysed the outcomes in 513 patients with CMML and emphasized that patients in CR who underwent transplantation had a lower probability of non-relapse mortality (NRM) (p = 0.002) and longer DFS and OS (p = 0.001 and p = 0.005 respectively).7 During the past decade, a Dec-based conditioning regimen has shown promising results in patients with high-risk MDS.8 Considering that HMAs have been the cornerstone of therapy for CMML and were administered to most patients prior to allo-HSCT,9, 10 we wondered whether we should perform a Dec-based conditioning regimen depending on the pre-transplant sensitivity for HMAs. Among the 23 patients undergoing therapy with HMAs followed by Dec-containing conditioning, patients with CR1 derived the most survival benefits after the administration of HMAs. Thus, it may be tempting to consider Dec-based conditioning in patients who attained CR1 during chemotherapy with HMAs. We conclude that allo-HSCT remains the curative treatment strategy for patients with adult CMML. The early initiation of allo-HSCT could be encouraging, especially in patients with low and intermediate-1 risk. Furthermore, patients achieving CR prior to allo-HSCT are associated with superior outcomes, and patients in CR1 undergoing HMA treatment before allo-HSCT derive the most benefits from Dec-based conditioning. Tingting Zhang performed research and analysed the data; Xin Liu, Hairong Fei, and Lining Zhang evaluated and collected the clinic data; Yuyan Shen and Tingting Zhang contributed to the writing of the paper; Aiming Pang and Runzhi Ma supervised the statistical analysis; Donglin Yang, Xin Chen, Rongli Zhang, Jialin Wei, Yi He, Erlie Jiang and Mingzhe Han checked the clinic data; Sizhou Feng and Yuyan Shen designed the research. This research was supported by Tianjin Municipal Science and Technology Commission Grant (21JCZDJC01170), Tianjin Foundational Research (JingJinJi) program (grant number 19JCZDJC64100), Haihe Laboratory of Cell Ecosystem Innovation Fund (grant number HH22KYZX0036), Innovation Fund for Medical Sciences (CIFMS) (grant numbers 2021-I2M-1-017 and 2021-I2M-C&T-B-080), and the Youth Program of National Natural Science Foundation of China (No. 81900182). The authors declare that the research was conducted in the absence of any commercial relationships. 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