Expanding the immune armoury against myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are heterogeneous clonal myeloid neoplasms characterized by bone marrow dysplasia and consequent cytopenias. Several prognostic scoring systems based on clinical and cytogenetic factors are utilized for risk stratification of patients with MDS. Individuals in the intermediate-2 or high score groups based on the International Prognostic Scoring System (IPSS) and in the intermediate, high, and very high score groups according to the revised IPSS (IPSS-R) constitute higher-risk MDS. Patients in higher-risk groups typically have a median overall survival (OS) of <2 years despite treatment. Goals of treatment in MDS are improvement in symptom burden, alleviation of transfusion needs, and reduction in risk of progression to acute myeloid leukaemia (AML) or death. Hypomethylating agents (HMA) are the current mainstay of standard of care treatment in higher-risk MDS, with a response rate of only about 50%. Duration of response with HMA is short, nearly all patients relapsing within two years even with an optimal front-line response, supporting novel combination therapy in the front-line setting in order to improve the overall response rates, the quality (i.e., degree of haematopoietic improvement and depth of remission), and the durability of responses. Furthermore, the outcome is dismal after HMA failure, with a median OS of less than six months in most patients. Notably, even in lower-risk MDS patients, median OS is less than one year upon HMA failure. Additionally, an HMA failure prognostic model has been developed to stratify lowerversus higher-risk disease; however, OS remains approx. one year even in the “lower-risk” setting. Currently, there is a lack of any approved therapeutic option in HMArefractory patients, underscoring the urgent need for developing effective new therapies for this difficult to treat patient population. Over the last decade, immune checkpoint inhibitors have revolutionized the treatment landscape in many malignancies. High transcriptomic expression for immune checkpoint proteins, such as programmed cell death 1 (PD1), programmed cell death ligand 1 (PDL1), and cytotoxic T lymphocyte antigen 4 (CTLA4), has been noted in samples from patients with MDS. Further, upregulation of these regulatory proteins was observed in patients on treatment with HMA and after HMA failure. Unfortunately, single-agent immune checkpoint therapy has been underwhelming with overall very low if any objective response in MDS patients (0% and 15% with nivolumab and ipilimumab, respectively) with the exception of CTLA-4 inhibition in patients with extramedullary leukaemia. Combination therapy of nivolumab or ipilimumab with azacitidine (AZA) in front-line MDS patients did not show any clear synergy or survival signal. Additionally, the combination of AZA with nivolumab (anti-PD1) has been evaluated in patients with relapsed/refractory AML in a phase II study. The overall response rate (ORR) was 33%, and complete remission (CR)/complete remission with incomplete count recovery was observed in 22% of patients. The presence of CD3and CD8-positive infiltrates on flow cytometry of blood and marrow samples was predictive of treatment response in this study population. In the current issue, Chien et al. describe the results of their phase II study of combination treatment with AZA and pembrolizumab (anti-PD1 agent) in patients with intermediate-1 or higher-risk (IPSS) MDS in a heterogeneous cohort of HMA-na€ıve (n = 17) and failure (n = 20) patients. All patients received AZA (75 mg/m) for seven days every 28 days, along with pembrolizumab 200 mg every 21 days. The primary end-point was ORR and safety profile after six cycles of treatment. Combination treatment had an ORR of 76% in previously untreated patients and 25% in the HMA failure cohort. Although the overall response improved with combination therapy compared to historical data with AZA Correspondence: David A. Sallman, Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA. E-mail: david.sallman@moffitt.org commentary