Treatment of Myelodysplastic Syndrome (MDS) with Cytokine Immunotherapy for Low-Risk MDS.
Authors: Kadia Tapan M. , Kantarjian Hagop , Verstovsek Srdan , Newman Beth , Garcia-Manero Guillermo , Borthakur Gautam 
Published: April 2020

Patients with low- or intermediate 1- (Int-1) risk MDS, as defined by the International Prognostic Scoring System (IPSS) are generally asymptomatic at presentation, but nonetheless have an expected median survival of only 3.5 to 5.7 years. Highly effective and preferably non cytotoxic therapies are needed to prolong their survival and reduce their risk of transformation to acute myelogenous leukemia (AML). Cytokine modulating therapies including hematopoietic growth factors, steroids, and immune modulating agents have shown activity in low risk MDS. We have developed a phase II clinical trial of cytokine immune-therapy for patients who have not previously been treated with cytotoxic therapy, with low to intermediate risk MDS or ≤10% marrow blasts according to the following treatment plan: Erythropoietin (EPO) 40,000 units SQ weekly, (with escalation to 60,000 units weekly and then twice weekly if the hemoglobin response is inadequate); G-CSF 300 mcg SQ twice weekly, titrated to maintain an ANC between 1 and 10 x 109/dL; oral prednisone starting at 60mg PO daily tapered over 4 weeks; Cyclosporin A given at a dose of 300mg daily for at least 6 months. Treatment was continued until relapse, progressive disease, or lack of response after 6 months of therapy. Responses are evaluated according to the International Working Group (IWG) criteria. Being an efficacy study, the primary outcome is rate of complete remission (CR), although all responses are being considered and reported. We have 14 evaluable patients thus far, with a median age of 67 (46–79). Two-thirds of the patients are male and all had MDS with diploid cytogenetics. Twelve patients (86%) were classified as Int-1, 2 (14%) were low risk, and 1 (7%) was Int-2. The median number of prior therapies was 1 (0–3). So far 2 (14.3%) CRs, 2 (14.3%) PRs, and 4 (28.6%) hematologic improvements have been observed for an overall response rate of 57%. The median time to response was 3 (1–16) months, and the median duration of response was 2 (1–29) months. Of the 2 patients in CR, one required 6 months of therapy before achieving CR and continues to have normal counts with a followup of 33 months. The second patient was treated for 16 months with decreasing transfusion requirements until CR. She now continues on the study, in a CR with incomplete platelet recovery (CRp), with no transfusion requirements and no significant toxicities with a followup of 23 months. Overall, the regimen was well tolerated. Eleven (79%) of the patients required a cyclosporin A dose reduction, mostly due to renal insufficiency. The most common grade 3 toxicities are diarrhea and renal insufficiency, and 1 patient each with fatigue and confusion. No grade 4 toxicities have been seen. Correlation of response with EPO levels, HLA DR15 expression, and CD55/59 expression is ongoing. A cytokine immune-therapy program using a combination of growth factors, steroids, and immune suppression is well tolerated and effective with durable responses in a low to intermediate risk population of patients with MDS.