Allogeneic HSCT in patients with MDS

Still, allogeneic HSCT remains the only curative option for a small subset of medically fit patients with higher-risk MDS. Patient stratification for allogeneic HSCT is mainly based on MDS risk scores, age and comorbidities. In general, the earlier the transplantation takes place during the disease course the better the chances of long-term cure. On the other hand, patients with less advanced disease should not be exposed to the substantial risk of NRM associated with this procedure. According to a decision model published a decade ago [1] patients with int-2 or high-risk MDS by IPSS criteria should be considered for HSCT at the time of diagnosis if a HLA-matched donor is available at this time. Notably, this analysis was restricted to MDS patients below the age of 60 years undergoing HLA-matched sibling bone marrow transplantation following intensive conditioning. Nevertheless, recent retrospective analyses have suggested that allogeneic HSCT in older HR-MDS patients undergoing RIC is superior compared to treatment with HMA, although the observed benefit occurred with a certain delay following HSCT.[2,3] In patients with an anticipated short-term benefit with hypomethylating agents (HMA) only, allogeneic HSCT should be planned as early as possible and exposition to HMA should be limited with the goal to achieve the highest potential reduction in disease burden prior to transplantation. Most importantly, recent large analyses have shown that the survival of patients with failure to HMA is dismal with a median survival of less than 6 months.[4] In fact, only a subset of patients subsequently undergoing allogeneic HSCT achieved long-term disease control afterwards compared to other conventional treatment options. Therefore, especially in these patients, if eligible, allogeneic HSCT should be planned as early as possible but monitoring of disease recurrence after HSCT is also highly recommended.[5] Allogeneic HSCT can, but does not necessarily result in cure. In fact, the risk of relapse is mainly determined by the disease stage at the time of transplantation.[5] Most importantly, the relapse rate of patients is significantly influenced by the cytogenetic risk exceeding 50% in patients with very poor-risk karyotype according to the IPSS-R.[6] This is also true for certain molecular aberrations [7,8] which clearly shows that a given prognostic factor in MDS retains its significance even in the presence of therapies potentially altering the course of the disease.

Finally, given the absence of randomized clinical studies HSCT treatment decisions are very often challenging thus further supporting the inclusion of patients into clinical protocols.

Tab. 1: Recommendations for the use of allogeneic HSCT in MDS patients:

Indication	Regimen	Comments
IPSS INT-2/HIGH or INT-1 with high-risk features (fibrosis, poor-risk mutations (e.g. RUNX1, ASXL1, TP53), severe RBC-TD	Prefer reduced-intensity conditioning regimens, Consider standard conditioning in patients < 60 years of age	– Carefully select patients (disease-risk/comorbidities/alternatives) – Start donor search at diagnosis – Avoid mismatched donors – Facilitate therapeutic debulking prior to HSCT but not at the expense of toxicity potentially precluding subsequent HSCT – Avoid clinically significant GVHD – Monitor disease recurrence – Treat patients within clinical trials

Reference List:

[1] Cutler CS, Lee SJ, Greenberg P et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004;104:579 – 585.

[2] Koreth J, Pidala J, Deeg HJ et al. A decision analysis of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation for older patients with de-novo myelodysplastic syndrome (MDS): early transplantation offers survival benefit in higher-risk MDS. Journal of Clinical Oncology 2013;31:2662 – 2670.

[3] Platzbecker U, Schetelig J, Finke J et al. Allogeneic Hematopoietic Cell Transplantation in Patients Age 60 – 70 Years with De Novo High-Risk Myelodysplastic Syndrome or Secondary Acute Myelogenous Leukemia: Comparison with Patients Lacking Donors Who Received Azacitidine. Biology of Blood and Marrow Transplantation 2012;18:1415 – 1421.

[4] Prebet T, Gore SD, Esterni B et al. Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure. Journal of Clinical Oncology 2011;29:3322 – 3327.

[5] Platzbecker U. Who benefits from allogeneic transplantation for myelodysplastic syndromes?: new insights. Hematology Am.Soc.Hematol.Educ.Program. 2013;2013:522 – 528.

[6] Deeg HJ, Scott BL, Fang M et al. Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDS. Blood 2012;120:1398 – 1408.

[7] Bejar R, Stevenson K, Abdel-Wahab O et al. Clinical Effect of Point Mutations in Myelodysplastic Syndromes. New England Journal of Medicine 2011;364:2496 – 2506.

[8] Thol F, Koenecke C, Kade S et al. Prognostic Effect of Mutations in the Splicing Gene Machinery in 339 Patients with MDS or Secondary AML Following MDS After Allogeneic Hematopoietic Stem Cell Transplantation. Blood 2012;120:

[9] Itzykson R, Thepot S, Quesnel B et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood 2011;117:403 – 411.