The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort

Abstract

Most studies of immunosuppressive therapy (IST) in myelodysplastic syndromes (MDS) are limited by small numbers and their single-center nature, and report conflicting data regarding predictors for response to IST. We examined outcomes associated with IST and predictors of benefit in a large international cohort of patients with MDS. Data were collected from 15 centers in the United States and Europe. Responses, including red blood cell (RBC) transfusion independence (TI), were assessed based on the 2006 MDS International Working Group criteria, and overall survival (OS) was estimated by Kaplan-Meier methods. Logistic regression models estimated odds for response and TI, and Cox Proportional Hazard models estimated hazards ratios for OS. We identified 207 patients with MDS receiving IST, excluding steroid monotherapy. The most common IST regimen was anti-thymocyte globulin (ATG) plus prednisone (43%). Overall response rate (ORR) was 48.8%, including 11.2% (95% confidence interval [CI], 6.5%-18.4%) who achieved a complete remission and 30% (95% CI, 22.3%-39.5%) who achieved RBC TI. Median OS was 47.4 months (95% CI, 37-72.3 months) and was longer for patients who achieved a response or TI. Achievement of RBC TI was associated with a hypocellular bone marrow (cellularity < 20%); horse ATG plus cyclosporine was more effective than rabbit ATG or ATG without cyclosporine. Age, transfusion dependence, presence of paroxysmal nocturnal hemoglobinuria or large granular lymphocyte clones, and HLA DR15 positivity did not predict response to IST. IST leads to objective responses in nearly half the selected patients with the highest rate of RBC TI achieved in patients with hypocellular bone marrows.

Treatment of myelodysplastic syndrome in the era of next‐generation sequencing

“…HLA‐DR15 positivity has been considered to strengthen the indication, especially in patients >50 years of age and with a long duration of transfusion dependency . A recent retrospective cohort study of 125 MDS patients indicated that the presence of SF3B1 mutation was associated with lower response rates, but this finding did not reach statistical significance . In this study, only a hypocellular bone marrow remained a significant predictor of achieving red blood cell transfusion independence.…”

“…Immunosuppressive therapy with anti‐thymocyte globulin and cyclosporine can lead to transfusion independency in about one‐third of MDS patients, and durable objective responses according to the modified 2006 MDS International Working Group criteria in nearly 50% . Commonly, younger lower‐risk patients have been selected for this treatment option, due to the presence of an activated immune response in these patients, with oligoclonal T cells inhibiting haematopoiesis in a similar way as in aplastic anaemia .…”

MDS overlap disorders and diagnostic boundaries

“…First, among a subset of patients with lower-risk MDS, immune activation and inflammation drive the selection of somatically mutated clones, potentiating the response to immunosuppressive therapies (ISTs). 56,57 Second, up to 15% of patients with severe AA (SAA) will have their disease evolve into MDS and/or acute myeloid leukemia (AML). 58,59 Distinguishing AA from hMDS may be challenging, because patients with these diseases share many clinical features, such as bone marrow hypocellularity that hinders accurate evaluation of morphologic dysplasia, clonal cytogenetic and/or genetic abnormalities, and clinically meaningful responses to ISTs.…”

Disordered Immune Regulation and its Therapeutic Targeting in Myelodysplastic Syndromes

“…Immunosuppressive therapy in this large cohort showed overall response rate of 45%, leading to transfusion independence in 39% of patients. [61] A correlation of response with MDS subtype or other factors was not observed. Over the past decade more has been discovered regarding the role of the immune system in MDS and with these discoveries comes the advent of directed immunotherapies.…”