Decitabine in Combination with Idarubicin Within a Modified Busulfan/cyclophosphamide Conditioning Regimen for Patients with Advanced Myelodysplastic Syndrome: A Prospective Multicenter Clinical Cohort Study.

To the Editor: Allogeneic hemopoietic stem cell transplantation (allo-HSCT) represents the only long-term survival treatment choice for patients with myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasm (MPN). Unfortunately, post-hemopoietic stem cell transplantation (HSCT) relapse remains a cause of treatment failure and the results of salvage treatments are poor. Developing better conditioning regimens is urgently needed. Previous studies have shown synergistic antileukemic effects between decitabine (DEC) and idarubicin (IDA).[1] In an attempt to design a conditioning strategy with very low toxicity but considerable myelosuppressive activity and potential immune-enhancing effects for patients with high-risk MDS and MDS/MPN, we combined DEC and IDA with busulfan, cyclophosphamide, and fludarabine for a modified myeloablative regimen in this prospective, multicenter cohort study (hereafter referred to as the "DEC/IDA study"). The trial was registered with http://www.chictr.org.cn/ as ChiCTR-ONC-17012640. The protocol was reviewed and approved by the Ethic Committee of Blood Diseases Hospital, Institute of Hematology, Chinese Academy of Medical Sciences (No. IHBDH-IIT2017003). This clinical trial was conducted in accordance with the Declaration of Helsinki. All patients provided their written informed consent before participating in the study. Patients aged between 15 years and 65 years, Eastern Cooperative Oncology Group performance status ≤2, with intermediate risk MDS or worse (according to the revised international scoring system for evaluating prognosis [IPSS-R]), chronic myelomonocytic leukemia (CMML), and secondary acute myeloid leukemia (sAML) after MDS or MDS/MPN from 10 medical centers in China were eligible for enrollment. With a sample size of 120 patients, the study had a power of more than 80%, using a 5% level of significance to show significance determined by a binomial distribution calculation with the expected and threshold 2-year relapse rates (RRs) of 10% and 20%, respectively. Eligible patients in the DEC/IDA study received the myeloablative conditioning regimen consisting of 20 mg·m–2·day–1 DEC (days –9 to –5), 3.2 mg·kg–1∙day–1 busulfan (Bu, days –9 to –7), 30 mg·m–2·day–1 fludarabine (Flu, days –6 to –4), 12 mg·m–2·day–1 IDA (days –6 to –4), and 40 mg·kg–1·day–1 cyclophosphamide (Cy, days –3 to –2), followed by allo-HSCT. All patients with unrelated or mismatched-related donors received antithymocyte globulin (rabbit) at 2.5 mg·kg–1·day–1 (days –4 to –1). For graft-versus-host disease (GVHD) prophylaxis, tacrolimus at 0.03 mg/kg from day –5 and methotrexate at 15 mg/m2 on day 1, 10 mg/m2 on days 3, 6, and 11 were used. The endpoints definitions and statistical analysis method were described in Supplementary File, https://links.lww.com/CM9/B938. From January 2017 to February 2021, a total of 121 patients with MDS (≥IPSS-R intermediate risk), CMML, and sAML after MDS or MDS/MPN from 10 Chinese hospitals were registered in the DEC/IDA study, of which 120 entered the study and were included in the analysis. The study flow diagram is shown in Supplementary Figure 1, https://links.lww.com/CM9/B938. The median follow-up time after HSCT was 986 days (range, 8–2026 days; interquartile range [IQR] 461–1423 days). The demoimagedata and clinical characteristics of the patients are shown in Supplementary Table 1, https://links.lww.com/CM9/B938. The median age was 44.5 years (range, 16–64 years) at the time of allo-HSCT. Overall, 100 (83.3%) patients had MDS, 7 (5.8%) patients had CMML, and 13 (10.8%) patients had sAML. Thirty-eight (31.7%) patients were diagnosed with intermediate-risk MDS and 62 (51.7%) were diagnosed with high- or very high-risk MDS according to IPSS-R. Nighty-one (75.8%) patients had active disease before HSCT, including 24 (20.0%) patients who did not respond to chemotherapy and 67 (55.8%) patients who did not receive chemotherapy. All patients in the DEC/IDA study received peripheral blood-derived donor stem cells. Successful neutrophil repopulation was achieved in 119 (99.2%) patients with a median time of 13 (range, 6–23) days. Successful platelet repopulation was achieved in 116 (96.7%) patients with a median time of 16 (range, 9–314) days and 104 of 116 (89.7%) were within 28 days. From the conditioning regimen to hematopoietic reconstitution, a median of 7 (range, 1–62) packages of platelets and 8 (range, 0–36) units of peripheral red blood cells were transfused. All 85 evaluable patients achieved full donor chimerism within a median time of 15 (range, 12–58) days post-transplant. The DEC/IDA conditioning regimen was well tolerated. The most common non-hematologic adverse event was oral mucositis and no patient experienced grade 4 oral mucositis or died before transplantation. Overall, 30.8%, 25.0%, and 21.2% of patients developed grades 1, 2, and 3 oral mucositis, respectively. Fifty-eight (48.3%) patients experienced aGVHD within 100 days after transplantation, and cGVHD occurred in 35 (29.2%) patients (including 12 cases of extensive cGVHD). The cumulative incidences of grades 1–4 and 3–4 aGVHD at 100 days were 48.3% (95% confidence interval [CI], 39.3%–57.3%) and 20.0% (95% CI, 12.8%–27.2%), respectively. The 3-year OS rate, RFS rate, relapse incidence, and NRM incidence were 70.5% (95% CI, 62.7%–79.2%), 67.5% (95% CI, 59.6%–76.4%), 10.0% (95% CI, 5.4%–16.2%), and 22.5% (95% CI, 15.5%–30.4%), respectively Supplementary Figure 2A–C, https://links.lww.com/CM9/B938. Importantly, we observed that only 13 patients relapsed within 3 years after HSCT, and the RFS rate (67.5%) was relatively higher than that reported previously, which arranges from 30% to 50%.[2–4] Thirteen patients, including two MDS with excess blasts (MDS-EB) I, eight MDS-EB II, and three sAML, experienced a relapse in a median time of 186 (range, 59–1401) days after HSCT. Ten of 13 (76.9%) patients received at least one cycle of chemotherapy followed by donor lymphocyte infusion after relapse, while 3 of 13 (23.1%) patients only received supportive care according to the willingness of the patients. Five of 13 (38.5%) patients achieved complete remission and survived at the last follow-up. Among the 35 patient deaths, 8 (22.9%) were due to relapse, and the deaths of 27 patients were due to treatment-related complications. Two patients died from persistent neutropenia and subsequent bloodstream infection early on day 8 and 20. The causes of NRM were aGVHD (n = 15, 42.9%), followed by infectious complications (n = 9, 25.7%) and cerebral hemorrhage (n = 3, 8.6%) Supplementary Figure 2D, https://links.lww.com/CM9/B938. The median time from allo‑HSCT to death was 165 days (range, 8–789). It has been reported that with an increase in the number of oncogenic mutations, patient outcomes progressively worsen.[2] In our study, the number of mutations has no effect on RFS and OS. The OS and RFS of the patients with ≥3 mutations were 70.8% and 66.6%, respectively, superior to that reported in the previous studies (approximately 40%).[2,5] These results indicated that conditioning that consisted of DEC and IDA followed by transplantation may overcome obstacles of adverse mutations in MDS. Univariate analysis for OS and RFS of the DEC/IDA study was conducted [Supplementary Table 2, https://links.lww.com/CM9/B938]. Patient age ≥50 years and TP53 mutation were the factors significantly associated with both poor OS and poor RFS. It is noteworthy that RFS was significantly higher in high/very high-risk MDS compared to intermediate-risk MDS when patient age and TP53 mutation were included as covariates in the multivariate analysis (hazard ratio [HR], 0.47; 95% CI, 0.22–1.00; P = 0.049; Supplementary Table 3, https://links.lww.com/CM9/B938). The 3-year OS was similar between patients receiving a matched sibling donor and alternative donor HSCT (74.1% [95% CI, 61.3%–89.4%] vs. 68.7% [95% CI, 59.3%–79.7%], P = 0.410). To identify patients with more favorable outcomes from the DEC/IDA study, we compared outcomes with those of a historical cohort who received myeloablative conditioning regimen without DEC or IDA between January 2013 and January 2017, including Bu/Cy/Flu/cytarabine (Ara-c), Bu/Cy/Flu and Bu/Flu/Ara-c (dosage: Bu, 3.2 mg·kg–1·day–1, days –9 to –7; Cy, 40 mg·kg–1·day–1, days –3 to –2; Flu, 30 mg·m–2·day–1, days –6 to –4; Ara-c, 2 g·m–2·day–1, –4 to –2 days). The historical control cohort satisfied the same enrollment criteria. Ninety-five patients were included as historical controls. Patient and transplantation characteristics are shown in Supplementary Table 4, https://links.lww.com/CM9/B938. The proportion of patients with MDS-EB or sAML was higher in the DEC/IDA study than in the historical controls (78.3% vs. 60.0%, P = 0.006). Patients in the historical control cohort received transplants more from matched sibling donors than in the DEC/IDA study (76.8% vs. 33.3%, P <0.001). Although there were no significant differences in OS or RFS between the DEC/IDA study and the historical control cohort, a subgroup analysis showed that patients with MDS-EB or sAML tended to benefit from DEC/IDA treatment, which was associated with a lower risk of death (HR, 0.60; 95% CI, 0.35–1.02; P = 0.057; Supplementary Figure 3, https://links.lww.com/CM9/B938). In patients with MDS-EB or sAML, the DEC/IDA study and historical control cohort achieved a 3-year OS of 70.9% (95% CI, 62.2%–80.8%) and 53.6% (95% CI, 42.0%–68.4%), respectively (P = 0.054) and a 3-year RFS of 67.0% (95% CI, 58.1%–77.2%) and 51.9% (95% CI, 40.35%–66.8%), respectively (P = 0.130) [Supplementary Figure 4, https://links.lww.com/CM9/B938]. The subgroup survival analysis in patients with MDS-EB or sAML was performed for patients in the DEC/IDA study and the historical control cohort. The results indicated that compared to the historical control, the DEC/IDA group had a lower risk of death in alternative donor transplants (HR, 0.43; 95% CI, 0.20–0.91; P = 0.028; Supplementary Figure 5, https://links.lww.com/CM9/B938). Donor type, the percentage of blasts in the bone marrow before transplant, as well as the conditioning regimen were included as covariates in the multivariate analysis. The analysis showed that DEC/IDC was a favorable factor associated with better OS, compared to the historical control cohort in patients with MDS-EB or sAML (HR, 0.51; 95% CI, 0.29–0.92; P = 0.024; Supplementary Table 5, https://links.lww.com/CM9/B938). To enhance the credibility and generalizability of the study findings, the transition from single-arm trials to randomized controlled trials is crucial, as it allows for better control over biases, leading to more robust conclusions. In conclusion, the addition of DEC and IDA to the myeloablative conditioning regimen was feasible and effective, with acceptable toxicity. This study provides an optimized strategy to improve the outcomes of patients with MDS and MDS/MPN, especially in patients with MDS-EB or sAML. Funding This work was supported by grants from the Tianjin Health Science and Technology Project (No. TJWJ2022MS001), Clinical research project of Tianjin Society of Hematology and Regenerative Medicine (No. 2022 TSHRM08004), Key Project of Tianjin Natural Science Foundation (No. 20JCZDJC00410), CAMS Innovation Fund for Medical Sciences (No. 2021-I2M-1-073), Haihe Laboratory of Cell Ecosystem Innovation Fund (No. 22HHXBSS00034), and National Natural Science Foundation of China (Nos. 82070192, 8230012348 and 82170217). Conflicts of interest None.