Allogeneic hematopoietic stem cell transplantation (allo-HSCT) stands as a pivotal treatment for malignant hematological diseases. The preconditioning phase plays a crucial role in the overall transplantation process, influencing the eradication of residual tumor cells, enhancing transplant success rates, and reducing post-transplant complications and relapse rates. At the 65th Annual Meeting of the American Society of Hematology (ASH) in 2023, Professor Jiang Erlie’s team from the Hematology Hospital of the Chinese Academy of Medical Sciences presented two studies focusing on optimizing and exploring preconditioning regimens for allo-HSCT in relapsed/refractory acute myeloid leukemia (R/R AML) and elderly myeloid tumor patients. This article shares the key findings and clinical significance of these two studies.
- The Improved MCBC conditioning regimen improved relapse-free survival after allo-HSCT in R/R AML
Background:
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potentially curative treatment for patients with refractory/relapsed (R/R) acute myeloid leukemia (AML). However, the long-term survival results are suboptimal. Optimization of the conditioning regimen is needed to eradicate leukemia blasts and reduce early relapse. In this study, we made refinements in the double alkylators based conditioning regimen, namely MCBC (the combination of melphalan, cladribine, busulfan, and cyclophosphamide). We aim to investigate the efficacy and safety of MCBC conditioning regimen for allo-HSCT in R/R AML patients.
Methods:
This prospective multi-center clinical trial was conducted in 13 tertiary hospitals in China, and enrolled R/R AML patients who underwent allo-HSCT from July 2020 to October 2022 (ChiCTR Registration ID: ChiCTR2000029936). The protocol was approved by institutional review boards at participating centers. All patients enrolled received MCBC preconditioning regimen (MCBC group): melphalan 60mg/m2/d, day -9~-8, cladribine 5mg/m2/d, day -7~-5, busulfan 3.2mg/kg/d, day -5~-3, cyclophosphamide 30mg/kg/d, day -2~-1. Rabbit ATG was added in haploid-identical and unrelated-matched donor transplantation. FK506/CsA +short course MTX±MMF was mostly used to prevent graft-versus-host disease (GVHD). We also retrospectively collected data from R/R AML patients who proceeded to allo-HSCT using the classical Bu/Cy2 based conditioning regimen, including Bu/Cy/Flu/Ara-C, Bu/Cy/Flu/IDA, et al, between Nov 2017 to Feb 2022 as history control (Bu/Cy2 group). Probabilities of OS, RFS were calculated by Kaplan-Meier method. A landmark survival analysis was performed.
Results and Discussion:
This multicenter MCBC trial prospectively enrolled 89 R/R AML patients, with median age 36 (ranged 11–59 years). Only 39.33% (35/89) patients achieved hematology remission at HSCT. Haplo-identical-donor HSCT (HID-HSCT) was the predominance HSCT type (n=62, 69.67%). Mucositis was the main reported regimen-related toxicity, mostly were mild and well tolerated. No graft failure was documented. All patients achieved hematology complete remission (CR) (100%) and 85.39% achieved MRD clearance on reconstitution day, indicating profound anti-leukemia capacity of MCBC regimen. The incidence of II to IV acute GVHD was 50.56%, with severe aGVHD (III to IV) only 8.99%. In comparison to the history control group, MCBC and Bu/Cy2 group were similar for age, gender, disease status, HSCT type. Notably, the incidence rate of mucositis (65.17% vs 63.48%, p=0.43) and diarrhea (87.64% vs 82.6%, p=0.57) were comparable in both groups. The median follow-up post HSCT was 431.29 days (95%CI 437.34~570.65) in MCBC group, and 1236 days (95%CI 1169.32~1302.68) in Bu/Cy2 group, respectively. The estimated one-year overall survival (OS), relapse-free survival (RFS) in MCBC and Bu/Cy2 group patients were 71.4±5.19% vs 65.2±4.45% (p=0.13), and 67.5±5.29% vs 56.2±4.62% (p=0.06, respectively. Notably, the survival advantages in MCBC group were expanded in the estimated two-year data. The estimated two-year overall survival (OS), relapse-free survival (RFS) in MCBC and Bu/Cy2 group patients were 66.9±5.87% vs 52.4±4.47%, and 62.1±6.11% vs 45.6±4.69%. We furtherly performed landmark survival analysis, and the result demonstrated the relapse-free survival superiority in MCBC group within 500 days post-HSCT, compared to Bu/Cy2 group (p=0.05).
Conclusion:
Our study confirms the excellent anti-leukemic capacity and good acceptable toxicity of MCBC conditioning regimen in R/R AML.
2. Efficacy of Venetoclax Combined with Decitabine Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk and Elderly Patients with Myeloid Neoplasms
Background:
High-risk and elderly patients with myeloid neoplasms are a special group because it’s challenging to find the right balance between safety and efficacy during the peri-transplant period. Traditional transplant protocols have unsatisfactory treatment outcomes for patients with a high risk of recurrence, while the elderly couldn’t tolerate the toxicity of high-dose chemotherapy drugs. Thus, new regimens are needed to improve treatment outcomes for high-risk and elderly patients.
Through BCL-2 binding, venetoclax could induce leukemia cell apoptosis, increase chemosensitivity, and perform a synergistic role with HMAs. And its combination with HMAs or other cytotoxic drugs showed a promising effect on R/R AML. This prospective clinical study reported the efficacy and safety of adding venetoclax and decitabine to myeloablative conditioning regimens in high-risk and elderly patients receiving allogeneic hematopoietic stem cell transplantation.
Methods:
We performed an investigator-initiated, prospective, one-arm, single-center, open-label trial. In total, 19 patients were enrolled in the trial between December 2021 and February 2023. Eligible patients met the following inclusion criteria: (1) undergoing allo-HSCT over the age of 50 years (i.e., ≥50 years), (2) having an Eastern Cooperative Oncology Group performance status of 0–2, and (3) having AML, MDS, and CMML with a high risk of recurrence: (a) For patients with MDS, (i) a diagnosis of MDS with excess blasts 2 (EB-2), (ii) a poor karyotype, (iii) a very high-risk disease according to the International Prognostic Scoring System-Revised, and (iv) a TP53 mutation; (b) For patients with AML, (i) relapsed/refractory AML, (ii) detected MRD test before transplantation, (iii) with adverse risk according to the European Leukemia Net (ELN) Guidelines 2017, and (iv) AML transformed from MDS or CMML.
Venetoclax was administered at 400 mg per day orally from day -14 to day -1 in the initial regimen and from day -14 to day -5 in the modified regimen. Decitabine was administered at 20mg/m2/d orally from day -7 to day -3. Detailed dosage of the Bu/Flu/Cy comprised of fludarabine 30 mg/m2/d IV Qd, day -4 to -2, busulfan 3.2 mg/kg/d IV Q6h, day -7 to -5, and cyclophosphamide 40mg/kg/d IV Qd, day -3 to day -2. Either rabbit ATG or porcine ATG was administered at 2.5mg/kg/d IV Qd, day -4 to -1, or 20mg/kg/d IV Qd, day -3 to -1 for GVHD prophylaxis.
Results:
19 patients were enrolled in the trial with a median follow-up time of 258 (range, 35-544) days. Grade 3/4 adverse events included hematological events, hypertension, infections, allergy, and increased amylase. The 30-day cumulative incidence of neutrophil and platelet engraftment was 100% and 68% (Figure 1A).
Acute GVHD occurred in 9 of 19 patients (grade I, n=2; grade II, n=1; grade III, n =4; grade IV, n =2). The cumulative incidence of grade II to IV acute GVHD events at 100 days was 31% (95% confidence interval (CI], 12-53) among all patients, and 45% (95% CI, 15-72), and 13% (95% CI, 0-45) for the initial regimen group and the modified regimen group, respectively (p=0.28, Figure 1B, C). While 1 patient in the modified regimen group occurred diarrhea and was clinically diagnosed with grade III acute GVHD (late-onset) at 132 days post-HSCT. The cumulative incidence of chronic GVHD at 1 year was 37% (95% CI, 16-58).
For the entire cohort, OS and RFS at 6 months was 63% (95% CI, 45-89) and 63% (95% CI, 45-89), and the NRM and CIR at 6 months was 37% (95% CI, 16-58) and 0, respectively (Figure 1D, E). All 8 deaths were attributed to transplant-related complications, including 4 patients from aGVHD, 2 patients from infection, 1 from transplant-associated thrombotic microangiopathy (TA-TMA) and 1 from bloody pleural effusion. Here it should be pointed out that the patient with bloody pleural effusion couldn’t exclude the probability of tumor invasion because he had previous esophageal carcinoma.
Conclusion:
In conclusion, although the hematological and molecular recurrence rate of the venetoclax combined with the decitabine conditioning regimen is significantly decreased, the high incidence of severe aGVHD and NRM limits its clinical application. It still needs further exploration to optimize the conditioning regimen for high-risk and elderly patients with myeloid neoplasms.
Researcher’s Perspective:
While the venetoclax combined with decitabine preconditioning regimen significantly reduces hematologic and molecular relapse rates, its clinical application is hindered by an increased occurrence of severe aGVHD and NRM rates. Therefore, further research is necessary to refine treatment strategies for high-risk elderly patients with myeloid malignancies.
Medical Doctor, Chief Physician, Doctoral Supervisor
Director of Stem Cell Transplantation Center, Hematology Hospital, Chinese Academy of Medical Sciences (Hematology Research Institute, Chinese Academy of Medical Sciences)
Deputy Leader of Hematopoietic Stem Cell Application Group, Hematology Branch, Chinese Medical Association
Standing Committee Member of Hematologic Oncology Professional Committee, Chinese Anti-Cancer Association
Deputy Leader of Hematopoietic Stem Cell Transplantation and Cell Therapy Group, Hematology Branch, Chinese Society of Clinical Oncology
Deputy Leader of Autologous Hematopoietic Stem Cell Transplantation Working Group, Chinese Society of Clinical Oncology
Executive Director, Tianjin Anti-Cancer Association
Vice Chairman, Tianjin Society of Hematology and Regenerative Medicine
Editorial Board Member of Chinese Journal of Hematology, Chinese Journal of Comprehensive Clinical, Leukemia & Lymphoma, among others.
