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Maintenance therapy after allo-HSCT in patients with MDS

Mar 29, 2021

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


Main finding

Retrospective case-control cohort analysis of low dose Aza after allo-HSCT for AML and MDS4

Aza maintenance following reduced-intensity allo-HSCT gave comparable EFS and OS to myeloablative transplant.

Phase III randomized study of posttransplant Aza maintenance vs observation in high-risk AML/MDS patients5

No significant difference in median RFS, OS, or incidence of relapse between patients who received Aza maintenance compared with those who had no intervention after allo-HSCT.

PANOBEST phase I/II trial of panobinostat, an HDAC inhibitor, as maintenance after allo-HSCT in patients with high risk MDS or AML6

Cumulative incidence of relapse at 2 years with panobinostat maintenance was 20%, NRM was 5%, and RFS was 75%. Low relapse rate not associated with chronic GvHD, suggesting panobinostat does not impair peripheral tolerance and may mitigate GvHD.

Phase I study of CC-486 maintenance therapy after allo-HSCT in AML and MDS7

CC-486 maintenance was well tolerated, with low rates of relapse, disease progression, and GvHD.

Prospective phase II study of prophylactic low-dose Aza and DLI following allo-HSCT for high-risk MDS/AML8

At median follow-up of 49 months, 2-year disease free survival was 65%. Aza was well tolerated as a prophylactic treatment and compared favorably with patients who received no maintenance.

allo-HSCT, allogeneic hematopoietic stem cell transplant; AML, acute myeloid leukemia; Aza, azacitidine; DLI, donor lymphocyte infusions; EFS, event-free survival; GvHD, graft-versus-host disease; HDAC, histone deacetylase; OS, overall survival; MDS, myelodysplastic syndromes; NRM, non-relapse mortality; RFS, relapse-free survival.


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.

  1. Onida F. The role of maintenance therapy after allogeneic HSCT in MDS. Oral presentation #E9-3. 47th Annual Meeting of the EBMT; Mar 14, 2021; Virtual.
  2. Platzbecker U, Middeke JM, Sockel K, et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol. 2018;19(12):1668-1679. DOI: 1016/S1470-2045(18)30580-1
  3. Rautenberg C, Bergmann A, Pechtel S, et al. Wilm's Tumor 1-guided preemptive treatment with hypomethylating agents for molecular relapse of AML and MDS after allogeneic transplantation. Bone Marrow Transplant. 2021;56(2):442-450. DOI: 1038/s41409-020-01039-2
  4. Ali N, Tomlinson B, Metheny L, et al. Conditioning regimen intensity and low-dose azacitidine maintenance after allogeneic hematopoietic cell transplantation for acute myeloid leukemia. Leuk Lymphoma. 2020;61(12):2839-2849. DOI: 1080/10428194.2020.1789630
  5. Oran B, de Lima M, Garcia-Manero G, et al. A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients. Blood Adv. 2020;4(21):5580-5588. DOI: 1182/bloodadvances.2020002544
  6. Bug G, Burchert A, Wagner EM, et al. Phase I/II study of the deacetylase inhibitor panobinostat after allogeneic stem cell transplantation in patients with high-risk MDS or AML (PANOBEST trial). Leukemia. 2017;31(11):2523-2525. DOI: 1038/leu.2017.242
  7. de Lima M, Oran B, Champlin RE, et al. CC-486 Maintenance after stem cell transplantation in patients with acute myeloid Lleukemia or myelodysplastic syndromes. Biol Blood Marrow Transplant. 2018;24(10):2017-2024. DOI: 1016/j.bbmt.2018.06.016
  8. Guillaume T, Malard F, Magro L, et al. Prospective phase II study of prophylactic low-dose azacitidine and donor lymphocyte infusions following allogeneic hematopoietic stem cell transplantation for high-risk acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant. 2019;54(11):1815-1826. DOI: 1038/s41409-019-0536-y