A Multi-Center Clinical Trial of Allogeneic Hematopoietic Stem Cell Transplants in Transfusion Dependent Thalassemia

Liu, Rongrong

Oral and Poster Abstracts
Oral
721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Optimizing Outcomes in Pediatric, Adolescent and Young Adult Patients

Thalassemia, Hemoglobinopathies, Diseases

Rongrong Liu¹^*, Hongwen Xiao, MD¹^*, Chunjie Qin²^*, Jiong Hu, MD³, Jianming Luo⁴^*, Hong Chen²^*, Xi Zhang, PhD⁵, Xiaolin Yin⁶^*, Guanye Nai⁷^*, Guyun Wan⁸^*, Zan Li⁹^*, Wei Tang¹⁰^*, Hua Zhang¹¹^*, Xiaotao Wang¹²^*, Mei Lan, MD¹³^*, Chuande Liao¹⁴^*, Tonghua Yang¹⁵^*, Sanbin Wang¹⁶^*, Jinxiong Huang¹⁷^*, Yunyan He⁴^*, Li Wang¹⁸^*, Zhongming Zhang¹^*, Lianjin Liu¹^*, Zhenbin Wei¹^*, Lingling Shi, MD¹^*, Meiqing Wu¹^*, Qi Zhou¹⁹^*, Borje S. Andersson, MD, PhD^20,21,22, Xiao Jun Huang^23,24 and Yongrong Lai, MD¹^*

¹Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
²Department of Hematology, Liuzhou Worker’s Hospital, Liuzhou, China
³Shanghai Institute of Hematology, RuiJin Hospital Medical School, Shanghai JiaoT, Shanghai, China
⁴Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
⁵Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China
⁶Department of Hematology, 923rd Hospital of the People's Liberation Army, Nanning, China
⁷Department of Hematology ,The Affiliated Hospital of Youjiang Medical College, Baise, China
⁸Department of Hematology , Hainan Provincial People's Hospital, Haikou, China
⁹Department of Hematology, Maoming People's Hospital, Maoming, China
¹⁰Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
¹¹Department of Hematology , Yulin Red Cross Hospital, Yulin, China
¹²Department of Hematology, The Affiliated Hospital of Guilin Medical College, Guilin, China
¹³The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
¹⁴Department of Pediatrics, Wuzhou People's Hospital, Wuzhou, China
¹⁵Department of Hematology , The First People's Hospital of Yunnan Province, Kunming,, China
¹⁶Department of hematology, 920th Hospital of Joint Logistics Support Force of People's Liberation Army of China, Kunming, Yunnan, China
¹⁷Department of Hematology, Liuzhou People’s Hospital, Liuzhou, China
¹⁸Department of Pediatrics, 923rd Hospital of the People's Liberation Army, Nanning, China
¹⁹Gobroad Research Center, Shanghai, China
²⁰M.D. Anderson Cancer Center, Houston, TX
²¹Department of Stem Cell Transplantation & Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston
²²Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
²³Peking University People's Hospital, Beijing, China
²⁴Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China

Background: Graft failure (GF) and graft-versus-host disease (GVHD) remain major barriers to successful outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with transfusion dependent thalassemia (TDT). We had reported an encouraging outcome of allo-HSCT in a single center study, which the 3-year event-free survival (EFS) was 97% in patients with TDT transplanted with HLA-matched sibling donors. We aimed to confirm this result and to assess the outcomes of allo-HSCT for TDT patients transplanted with alternative donor.

Methods: A prospective, multicenter, clinical trial was conducted at eighteen hospitals in China from July 2019 to July 2023. Patients with TDT underwent allo-HSCT with matched sibling donors (MSDs), matched unrelated donors (MUDs) and haploidentical related donors (HIDs) using the protocol of GX-07-TM. The conditioning regimen consisted of busulfan (Bu, 16mg/kg), cyclophosphamide (Cy, 200 mg/kg), fludarabine (Flu, 150 mg/m2), and anti-thymocyte (ATG, Thymoglobulin, 10mg/kg). The GVHD prophylaxis was cyclosporine A (CsA), methotrexate (MTX), mycophenolate mofetil (MMF) for patients with matched sibling donors and tacrolimus (Tac), MTX, MMF for patients with matched unrelated donors or haploidentical related donors. The primary end point was the 2-year overall survival (OS) and EFS after allo-HSCT. The study was registered at www.clinicaltrials.gov as NCT04009525.

Results: A total of 823 patients with TDT underwent allo-HSCT were enrolled, including 331 patients with MSDs, 352 patients with MUDs and 140 patients with HIDs. The median age was 8 years (IQR 5-11) and the median follow-up was 23 months (IQR 13–36). The 2-year OS and EFS of all patients were both of 95%. The 2-year TRM was 4.4% and the rate of GF was 0.5%. The 2-year OS and EFS was both 97% for MSDs, both 93% for MUDs and both 95% for HIDs. The 2-year EFS of patients with alternative donors were inferior to patients with MSDs (93% [ 95%CI: 91, 96] vs 97% [95, 99], HR 2.39, 95% CI 1.14–5.01; p=0.022). The 2-year TRM of patients with alternative donors was higher than patients with MSDs (5.8% [3.7, 7.9] vs 2.5% [0.8, 4.2], HR 2.34, 95% CI 1.06–5.14; p=0.035). Grades 2-4 and 3-4 acute GvHD in patients with MSDs were 7.5% [4.9, 11] and 1.9% [0.8, 3.9], which was lower than for patients with MUDs (28% [23, 33] and 15% [11, 19], both p<0.0001) and patients with HIDs (32%[24, 41] and 15%[8.9, 22], both p<0.0001). Total and moderate-severe cGvHD in patients with MSDs were 8.5% [5.7, 12] and 5.0% [2.9, 7.9], which was lower than for patients with MUDs (19% [15, 24] and 11% [7.9, 15], both p<0.001) and patients with HIDs (23% [15, 31] and 15% [8.9, 23], both p<0.05). Patients from HIDs showed higher incidences of pneumonia (49%), CMV (52%) and EBV (33%) reactivation compared to those from MSDs and MUDs. Moreover, rates of bacterial and fungal infections, septicemia, hepatic veno-occlusive disease, and posterior reversible encephalopathy syndrome was similar between groups. In multi-variate analyses，OS and EFS were associated with recipient age > 15 years (HR 3.07, 95%CI 1.06-8.88; and 2.88,1.01-8.23); grade 2-4 acute GvHD (5.24, 2.70-10.20 and 4.56, 2.40-8.69) and previous splenectomy (3.36,1.49-7.54 and 3.15, 1.41-7.02).

Conclusion: We report excellent 2-year OS and EFS after allo-HSCT in children and adolescents with transfusion dependent thalassemia using matched sibling donors or alternative donors. The outcomes were similar between patients with matched unrelated donors and haploidentical related donors. Allo-HSCT with alternative donors can be considered as a frontline option for TDT patients lacking matched sibling donors. Patients receiving alternative donors will also benefit from an improved GvHD-prophylaxis strategy.

Disclosures: No relevant conflicts of interest to declare.

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378 A Multi-Center Clinical Trial of Allogeneic Hematopoietic Stem Cell Transplants in Transfusion Dependent Thalassemia