Maintenance therapy after allo-HSCT in patients with MDS

Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only curative treatment for patients with myelodysplastic syndromes (MDS). Over 10% of all allo-HSCTs are undertaken in patients with MDS, with the rate increasing year on year. When compared with conventional therapies, such as hypomethylating agents (HMAs), allo-HSCT is associated with significant survival benefit, even in elderly patients who make up a growing proportion of transplant candidates. Despite this, posttransplant mortality and relapse remain major challenges, and investigations are underway to develop strategies to overcome these complications.

During the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Francesco Onida reviewed the current evidence surrounding the role of maintenance therapy in relapse prevention after allo-HSCT in patients with MDS.¹ A summary of his presentation is captured here.

Benefit–risk profile when considering allo-HSCT

Given the high incidence of relapse and mortality after allo-HSCT in MDS patients, it is important to maximize the benefit–risk ratio with careful patient selection. Characteristics of both disease and patient are important, alongside any prognostic indicators that may be present. Patients who are high risk according to the International Prognostic Scoring System (IPSS) are usually candidates for allo-HSCT at the time of diagnosis, whereas those with intermediate/low risk may be eligible if other risk factors are present, such as life-threatening cytopenias, transfusion dependency, or high-risk mutations, or if non-transplant strategies fail.

Point mutations are common in patients with MDS, particularly in those with low or intermediate-1 IPSS risk. In the presence of high-risk mutations, such TP53, EZH2, ETV6, RUNX1, and ASXL1, intensive surveillance or early allo-HSCT are recommended. Somatic mutations can continue to influence outcomes after allo-HSCT, with ASXL1, RUNX1, and TP53 conferring a higher probability of relapse and shorter survival.

Preventing relapse following allo-HSCT

Factors to consider regarding relapse prevention in patients with MDS undergoing allo-HSCT include any disease-specific therapy, conditioning treatment type and intensity, strategies for graft-versus-host disease (GvHD) prophylaxis, and the use of pre-emptive or maintenance therapies. However, there is little data available on the impact of maintenance therapies in particular.

Measurable residual disease (MRD) negativity, achievement of complete molecular remission, and absence of high-risk mutations, especially TP53, are associated with better prognosis and improved survival following allo-HSCT. Interestingly, the RELAZA2 trial demonstrated that pre-emptive therapy with the HMA azacitidine can prevent or at least delay hematological relapse in MRD-positive patients with MDS or acute myeloid leukemia who are at high risk of relapse.² Promising results have also been obtained from the use of MRD monitoring as a means to detect molecular relapse and trigger initiation of pre-emptive HMA therapy.³

Maintenance therapy studies

The ideal maintenance agent should demonstrate anti-disease activity, an acceptable toxicity profile (particularly with respect to myelotoxicity), favorable influence on donor cells, the ability to be administered early after transplant, and also increase immunogenicity of malignant cells. Histone deacetylase (HDAC) inhibitors and HMAs have been proposed to fulfil this role as they:

• increase expression of tumor-associated antigens;
• increase expression of killer cell immunoglobulin-like receptor ligands on hematopoietic cells;
• recover reduced expression of human leukocyte antigens on tumor cells;
• increase expression of known minor antigens;
• affect microRNA function and inhibit oncogenes; and
• have immunomodulatory activity

First generation studies of maintenance therapies which have been undertaken are described in Table 1. Although these are not mutation-targeted, they have demonstrated efficacy and feasibility.

Table 1. First generation studies of maintenance therapies after allo-HSCT¹

Conclusion

The optimal setting for allo-HSCT in MDS appears to be achievement of MRD negative complete remission, absence of high-risk cytogenetics, and a good prognostic score. Posttransplant interventions, such as maintenance therapy, may be guided by monitoring MRD as a molecular marker of disease recurrence after allo-HSCT. First generation trials of maintenance therapies suggest HMAs offer feasibility and efficacy, however next generation studies are required to investigate the potential of molecular targeted, graft manipulation and genetically modified effector cells.