The 29th Annual Meeting of the European Hematology Association (EHA) was held from June 13 to 16, 2024, in Madrid, Spain. As the largest international conference in the field of hematology in Europe, it attracts experts and scholars from around the world to share and discuss innovative ideas and the latest scientific and clinical research findings in hematology. At this year's conference, Professor Zhihui Li from Beijing GoBroad Boren Hospital presented research on the "Safety and Efficacy of Luspatercept in Allogeneic Transplantation for Malignant Hematologic Diseases." This study provides valuable insights for clinical practice. Oncology Frontier - Hematology Frontier had the opportunity to interview Dr. Zhihui Li at the conference to delve into the study's findings and their clinical implications.Study Overview
Background
Luspatercept is an Fc fusion protein and the first-in-class erythroid maturation agent that primarily promotes the maturation of late-stage red blood cells, influencing the bone marrow microenvironment and improving hematopoiesis. However, there have been no studies exploring the efficacy and safety of luspatercept after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hematologic malignancies.
Objective
This study retrospectively analyzed whether luspatercept can promote erythroid engraftment in patients with hematologic malignancies post-allo-HSCT and its safety.
Methods
We retrospectively analyzed data from 74 patients with hematologic malignancies who underwent allo-HSCT at our hospital between March 2023 and December 2023. Diagnoses included acute myeloid leukemia (AML) (31 cases, 41.89%), acute B-lymphoblastic leukemia (B-ALL) (18 cases, 24.32%), T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) (15 cases, 20.27%), and non-Hodgkin lymphoma (NHL) (10 cases, 13.51%). Twenty-nine patients (39.18%) received a second transplant. The median age was 29 years (range: 2-67 years). Disease status before transplantation included complete remission (CR) (52 cases, 70.27%), non-remission (NR) (15 cases, 20.27%), and partial remission (PR) (7 cases, 9.45%). Donor types included sibling (2 cases, 2.70%), unrelated (23 cases, 31.08%), and haploidentical (49 cases, 66.22%). The conditioning regimens were based on total body irradiation/fludarabine (47 cases, 63.51%) or busulfan/fludarabine (27 cases, 36.48%). Thirty-five patients (47.29%) started luspatercept on day 6 post-HSCT (luspatercept group), while the remaining 39 patients (52.70%) did not receive luspatercept (control group). Clinical characteristics were similar between the two groups. Luspatercept was administered subcutaneously every three weeks, starting at 1.0 mg/kg body weight, with potential increases to 1.33 mg/kg and a maximum dose of 1.75 mg/kg. Patients received an average of 1.1 treatments (range: 1-2).
Results
The 6-month overall survival (OS) rate was 81.39% (95% CI: 67.07%-89.93%), and the 6-month progression-free survival (PFS) rate was 72.57% (95% CI: 56.48%-83.53%). Before luspatercept administration, the median hemoglobin level was 68.92 g/L. One week after luspatercept administration, hemoglobin levels increased by an average of 10% compared to baseline, significantly higher than the control group (P=0.049). Neutrophil counts were also significantly higher than the control group (P<0.001). There was no significant difference in platelet counts between the two groups (P=0.68).
Luspatercept significantly reduced levels of pro-inflammatory cytokines such as IL-1, IL-6, IFN-γ, and TNF-α post-transplantation. The luspatercept group showed a reduced incidence of acute graft-versus-host disease (GVHD), but there was no significant difference between the groups (P=0.87). The most common adverse reactions during luspatercept treatment were fatigue, nausea, dyspnea, and hypertension, all of which were grade 1 or 2. No grade 3 or higher adverse effects were observed. There were no observed cases of organ toxicity or drug-related deaths.
Conclusion
This study demonstrates that luspatercept is safe and effective for use in patients with hematologic malignancies post-allo-HSCT. It can improve hemoglobin and neutrophil levels, reduce cytokine levels, and lower the incidence of acute GVHD without increasing the incidence of viral infections. Future studies with larger sample sizes and prospective, randomized controlled trials are needed.
Expert Interview
Oncology Frontier – Hematology Frontier: At this conference, your study on the safety and efficacy of luspatercept in allogeneic transplantation for malignant hematologic diseases was selected for poster presentation. Could you share the background and main findings of this study?
Dr. Zhihui Li: Allo-HSCT is an effective curative method for hematologic diseases like leukemia. However, some patients experience suboptimal hemoglobin levels post-transplant, affecting prognosis. Luspatercept (luspatercept) is an activin receptor type IIB (ACVR2B)-Fc fusion protein that promotes the maturation of late-stage red blood cells by binding specific TGF-β superfamily ligands, reducing abnormally enhanced Smad 2/3 signaling, and restoring late-stage erythroid maturation. Preclinical studies have shown that luspatercept can reshape the SDF-1-mediated hematopoietic support through mesenchymal stem cells (MSCs). In MDS patients treated with luspatercept, MSCs maintained the potential for normal stem/progenitor cell colony formation. Based on these preclinical findings, we hypothesized that luspatercept could promote erythroid engraftment post-allo-HSCT through multiple mechanisms. This study aimed to evaluate the efficacy and safety of luspatercept in promoting erythroid engraftment in patients with hematologic malignancies post-allo-HSCT.
The results showed that one week after luspatercept administration, the percentage increase in hemoglobin levels was significantly higher in the luspatercept group compared to the control group (P=0.049). Neutrophil counts were also significantly higher in the luspatercept group (P<0.001). Additionally, luspatercept significantly reduced levels of pro-inflammatory cytokines such as IL-1, IL-6, IFN-γ, and TNF-α post-transplantation. This preliminary evidence suggests that luspatercept is safe and effective for use in patients with hematologic malignancies post-allo-HSCT, improving hemoglobin and neutrophil levels, reducing cytokine levels, and lowering the incidence of acute GVHD without increasing the incidence of viral infections.
Oncology Frontier – Hematology Frontier: Your study found that luspatercept significantly improved hemoglobin and neutrophil levels in patients. Can you share how these improvements impact patient recovery and quality of life?
Dr. Zhihui Li: In post-transplant patients, we focus on changes in hemoglobin and neutrophil levels because these indicators reflect the success of hematopoietic reconstruction and significantly impact patient quality of life. For hemoglobin, the COMMANDS study presented at this year’s EHA confirmed that increasing hemoglobin levels is clinically associated with improved quality of life (QoL). Hemoglobin levels ≥10 g/dL are more likely to meaningfully improve anemia-related fatigue and dyspnea symptoms and QoL as measured by QLQ-C30. Therefore, enabling post-transplant patients to achieve higher hemoglobin levels earlier and become transfusion-independent is highly significant.
Oncology Frontier – Hematology Frontier: Your study also validated the safety of luspatercept. How do you view the future prospects of luspatercept in allogeneic transplantation for malignant hematologic diseases? What areas need further exploration?
Dr. Zhihui Li: The mechanism of action of luspatercept is not fully understood. Current clinical research shows that it not only acts at the late stage of red blood cell maturation but also plays a role in the early stages of erythropoiesis. In studies on MDS, luspatercept improved anemia and increased neutrophil and platelet levels in most patients, suggesting that luspatercept may have broad applications post-allo-HSCT. Future research should explore the optimal timing, beneficiary characteristics, and whether luspatercept can reduce the risk of graft dysfunction in post-transplant patients.
Oncology Frontier – Hematology Frontier: At this conference, what other significant studies on stem cell transplantation and its complications caught your attention? Specifically, are there any notable advances in CAR-T bridging transplantation?
Dr. Zhihui Li: At EHA, a real-world study compared the prognosis of Chinese chronic myelomonocytic leukemia (CMML) patients treated with HSCT and non-HSCT therapies, analyzing the impact of different prognostic subtypes on treatment choices. The study concluded that low-risk CPSS patients had better long-term survival in the HSCT group than the non-HSCT group, suggesting that even low-risk patients could benefit from timely transplantation to improve long-term outcomes.
CAR-T bridging transplantation is a crucial focus of our center. At the 2023 American Society of Hematology (ASH) meeting, we reported on the survival of T-cell malignancy patients treated with CD7 CAR-T bridging transplantation, comparing outcomes with patients receiving traditional chemotherapy-bridging transplantation and non-remission transplantation. The study found that survival rates were comparable between CAR-T and chemotherapy-bridging transplantation groups and significantly higher than non-remission patients, indicating that CAR-T bridging transplantation can significantly improve survival rates, particularly for T-cell malignancy patients.
A notable characteristic of CAR-T therapy for T-cell and myeloid malignancies is the associated immunodeficiency, which cannot be mitigated by immunoglobulin replacement therapy, necessitating bridging transplantation. Our research showed that bridging transplantation in patients with CD7 CAR-T and myeloid CAR-T remission significantly improved prognosis, increasing OS and DFS rates, providing new hope for patients with relapsed/refractory malignancies. Our goal is not only to enable patients with relapsed/refractory hematologic malignancies to survive but also to improve their quality of life.
