Lenalidomide therapy in patients with myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
Authors: Maura Nicolosi, Mythri Mudireddy, Rangit Vallapureddy, Naseema Gangat, Ayalew Tefferi, Mrinal M. Patnaik
Journal: American Journal of Hematology (2017)

Based on the 2016 iteration of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia, myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with ring sideroblasts (RS) and thrombocytosis (MDS/MPN-RS-T), previously termed as refractory anemia with RS and thrombocytosis (RARS-T), is now formally categorized as a MDS/MPN overlap neoplasm.1 This entity is characterized by the presence of refractory anemia, thrombocytosis (platelet count ≥ 450 × 109), bone marrow (BM) RS, along with proliferation of large atypical megakaryocytes similar to those observed in BCR-ABL1 negative MPN.2 The median age at diagnosis ranges from 71 to 75 years, with ≈20% of patients demonstrating clonal cytogenetic abnormalities. Gene mutations encountered include SF3B1 (∼85%), JAK2V617F (∼50%), TET2 (∼25%), ASXL1 (∼20%), DNMT3A (∼15%) and SETBP1 (∼10%), with anemia (hemoglobin <10 gm/dL), abnormal karyotype and ASXL1/SETBP1 mutations, independently and adversely impacting survival.3, 4 There currently exist no formal treatment or response criteria for patients with MDS/MPN-RS-T; however, there are case reports demonstrating safety and efficacy of lenalidomide in affected patients.5 Lenalidomide is an immunomodulatory agent active in several hematological malignancies, including lower risk MDS patients with isolated del(5q) and with a normal karyotype.6, 7 In a prior case report, lenalidomide was used in two patients with MDS/MPN-RS-T and resulted in transfusion independence in both, along with a complete molecular response (JAK2V617F negative) in one patient.5 Here in, we describe our experience with lenalidomide therapy in three patients with MDS/MPN-RS-T (Table 1). JAK2V617F (74%) SF3B1 (46%) JAK2V617F (40%) SF3B1 (25%) SUZ12 (30%) ATM (56%) ASXL1 (39%) SF3B1 (44%) SRSF2 (39%) Darbepoetin alfa Hydroxyurea Anagrelide The first patient was a 49-year-old male who was diagnosed to have MDS/MPN-RS-T in December 2010, when he presented with thrombocytosis (935 ×109/L) and anemia (hemoglobin 10.7 gm/dl). His bone marrow was hypercellular (100%) with clusters of abnormal megakaryocytes and 60%–70% ring sideroblasts. He had a normal karyotype and was found to have mutations involving SF3B1 (K700E) and JAK2V617F. In January 2011, he initiated lenalidomide at a dose of 10 mg daily with an improvement in his thrombocytosis, and in fact after eight cycles obtained his best response with a platelet count of 585 ×109/L (partial platelet response). He maintained this response for an additional 8 months. Unfortunately, after 15 cycles he developed recurrent thrombocytosis and progressive anemia, and the lenalidomide was discontinued. Follow up molecular studies on this patient were not available. The second patient was a 73-year-old male diagnosed with MDS/MPN-RS-T in August 2011, when he presented with transfusion-dependent anemia and thrombocytosis (669 ×109/L). His bone marrow was hypercellular (70%) and demonstrated clusters of small hypolobated megakaryocytes with 20% to 30% ring sideroblasts. He too had a normal karyotype and molecular studies revealed mutations involving SF3B1 (H662Q), JAK2V617F, SUZ12 (D605V) and ATM (D1853V). He was initially treated with erythropoiesis stimulating agents and did not respond. In February 2012, he was treated with lenalidomide 10 mg daily. After 2 cycles of lenalidomide he had a complete hematological response and became red cell transfusion independent; (hemoglobin increase from 6.7 g/dL to14 g/dL). However, in spite of being transfusion independent he did not have any morphological improvement on his follow up bone marrow examinations. He received a total of 19 cycles of lenalidomide, following which he lost his erythroid response and had to come off therapy. The third patient was an 85-year-old female who was diagnosed in 2013 to have MDS/MPN-RS-T, when she presented with transfusion dependent anemia, extreme thrombocytosis (1203 ×109/L), and a leukocyte count of 3 × 109/L. Her bone marrow was hypercellular (80%) and demonstrated clusters of megakaryocytes, with 40–50% ring sideroblasts. Cytogenetic analysis revealed a normal karyotype, while molecular testing identified ASXL1 (G651Wfs*7), SETBP1 (G870S) and SRSF2 (R94dup) mutations. She was negative for SF3B1 and JAK2V617F. She was initially treated with erythropoiesis stimulating agents and hydroxyurea with a suboptimal response. She was started on lenalidomide at an initial dose of 5 mg daily and after two cycles had a partial platelet response (558 ×109/L). She however remained transfusion dependent and had to stop therapy after two cycles due to worsening congestive cardiac failure. We document the utilization of lenalidomide in three patients with WHO defined MDS/MPN-RS-T. Lenalidomide therapy was relatively well tolerated without significant side effects. Treatment with lenalidomide was able to produce partial platelet responses in all three patients; while one patient had a major erythroid response and became red cell transfusion independent after two cycles of therapy. In this patient, however, in spite of the major erythroid response there was no morphological improvement in the bone marrow. Due to the sub-optimal responses in the other two patients follow up bone marrow studies were not done. Our study was limited by the absence of serial molecular assessments on therapy due to non-availability of samples. In conclusion, while lenalidomide therapy does produce hematological responses in patients with MDS/MPN-RS-T, these are often sub-optimal, without significant changes in bone marrow morphology and are often not durable. Newer, effective therapies are much needed for these patients. Current publication is supported in part by grants from the 'The Gerstner Family Career Development Award" and the Mayo Clinic Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA'. National Center for Advancing Translational Sciences, KL2 TR000136 This publication was supported by CTSA Grant Number KL2 TR000136 from the National Center for Advancing Translational Science (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. None of the authors have any conflict of interest to disclose in regards to the current manuscript.