Patients with TP53-mutated myelodysplastic syndromes (MDS) generally have poor prognoses and face significant treatment challenges. To improve the survival outcomes of these patients, Professor Jimin Shi's team at The First Affiliated Hospital, Zhejiang University School of Medicine conducted an in-depth investigation into the treatment options for TP53-mutated MDS patients before transplantation. At the recent 29th European Hematology Association (EHA) Annual Meeting, they presented the results of their study (P1367), which compared cytoreductive and non-cytoreductive therapies. To provide a comprehensive understanding of the findings and their implications, "Oncology Frontier - Hematology Frontier" invited Professor Jimin Shi to share insights from this research.

Study Overview

Background Patients with TP53-mutated myelodysplastic syndromes (MDS) have poor prognoses. There is ongoing debate about whether these patients should receive cytoreductive therapy before hematopoietic stem cell transplantation (HSCT).

Objective To investigate the impact of cytoreductive therapy before HSCT on the prognosis of TP53-mutated MDS patients.

Methods A retrospective analysis was conducted on a multicenter cohort of 42 TP53-mutated MDS patients who underwent allogeneic HSCT from January 2017 to October 2022. Among them, 30 patients received cytoreductive therapy before transplantation, while 12 received best supportive care (BSC) only.

Results The 2-year overall survival (OS) rate was 30.5% (95% CI: 17.1%-54.3%) in the cytoreductive therapy group, significantly lower than the 70.7% (95% CI: 47.2%-100.0%) in the BSC group (P=0.016). No benefits were found in relapse-free survival (RFS), graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS), cumulative incidence of relapse (CIR), or non-relapse mortality (NRM) in the cytoreductive therapy group. When patients were subdivided into the chemotherapy subgroup, hypomethylating agent (HMA) subgroup, and BSC subgroup, there were no statistical differences in prognosis between the groups (all P>0.05). Patients who did not achieve complete remission (CR) before HSCT had a 2-year OS rate of 17.1% (95% CI: 5.0%-58.8%), lower than the 40.0% (95% CI: 20.7%-77.2%) in the cytoreductive CR group and the 70.7% in the BSC group (P=0.021). Multivariable analysis identified pre-HSCT cytoreductive therapy as an independent risk factor for OS (HR=9.437, 95% CI: 2.182-40.816, P=0.003), but it was not associated with other prognostic indicators.

Conclusion Cytoreductive therapy before HSCT did not improve treatment outcomes for TP53-mutated MDS patients, whether chemotherapy or HMA was used. Even patients who achieved CR after cytoreductive therapy did not have a survival advantage over those who received BSC only.

Expert Interview

Oncology Frontier – Hematology Frontier: TP53-mutated MDS patients face poor prognoses, and hematopoietic stem cell transplantation (HSCT) is considered one potential treatment option. Could you first discuss the current status and challenges of HSCT for TP53-mutated MDS patients?

Professor Jimin Shi: Existing studies have shown that TP53 mutations are significantly associated with high levels of blasts and chromosomal karyotype abnormalities, which have a major impact on the poor survival outcomes of MDS patients and are related to a high risk of relapse after HSCT. Our team retrospectively analyzed TP53-mutated patients among more than 300 MDS patients who underwent allo-HSCT at 11 bone marrow transplant centers in Zhejiang Province from January 2017 to October 2022. The results indicated that the efficacy in the TP53-positive group was significantly lower than in patients without TP53 mutations, suggesting that the prognosis for TP53-positive patients undergoing immediate transplantation is still not ideal. This is currently the biggest challenge for TP53-positive patients undergoing HSCT. Additionally, the choice of pre-transplant treatment for these patients also poses a significant challenge. Thirdly, there is still no optimal recommendation for preventing post-transplant relapse in this patient population.

Oncology Frontier – Hematology Frontier: At this year’s EHA conference, your team presented the study “Better Pre-Transplant Treatment Options for TP53-Mutated MDS Patients: Cytoreductive or Non-Cytoreductive Therapy” (P1367). Could you briefly introduce this study and its key findings?

Professor Jimin Shi: We conducted a retrospective analysis of 42 TP53-mutated patients who underwent HSCT from January 2017 to October 2022. The results showed that the 2-year OS for patients who received chemotherapy before transplantation was only 30.5%, significantly lower than the 70.7% in the supportive care group. There were no statistical differences in RFS, GRFS, CIR, or NRM between the groups. When we further subdivided the chemotherapy group into those receiving hypomethylating treatment and those receiving supportive care, there was still no statistical difference in transplantation efficacy between the two groups. However, we found that among patients who received chemotherapy before transplantation, those who achieved remission had a significantly higher 2-year OS of 40%, compared to only 17% in non-remission patients, though still lower than the 70.7% in the supportive care group. This is a result worth considering—why pre-transplant chemotherapy did not bring the expected benefits and even resulted in worse prognoses for some patients.

Oncology Frontier – Hematology Frontier: The study shows that cytoreductive therapy before HSCT did not improve OS rates for TP53-mutated MDS patients. What specific impact do you think this important finding will have on treatment strategies for TP53-mutated MDS patients? How might this change our treatment approach for these patients?

Professor Jimin Shi: There is controversy over whether TP53-mutated MDS patients should receive chemotherapy before transplantation, with some studies suggesting that pre-transplant chemotherapy does not affect prognosis. Our results showed that patients who received chemotherapy before transplantation had worse outcomes, especially those who did not achieve remission after chemotherapy. We believe that chemotherapy may not be able to suppress disease progression in these patients and might lead to persistent cytopenias, poor general condition, increased infections, and complications, thereby increasing the risk of transplant-related complications. Therefore, for these patients, it might be more beneficial to proceed with hematopoietic stem cell transplantation as soon as possible while in good general condition.

Oncology Frontier – Hematology Frontier: Based on your team’s research findings, how should future research directions or new treatment methods be adjusted to improve the prognosis of TP53-mutated MDS patients?

Professor Jimin Shi: Our study had a small sample size and was retrospective, so further case accumulation and prospective studies are needed to verify our findings. In 2022, our center applied for and registered a multicenter clinical study on hematopoietic stem cell transplantation for TP53-positive myeloid malignancies. The trial is progressing well, and we hope to share more research results with everyone in the future.