Response to erythropoiesis‐stimulating agents in patients with WHO‐defined myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T)

To the Editor, In the 2016 iteration of the World Health Organisation (WHO) classification of myeloid neoplasms, myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) has been included as a unique entity, defined by the presence of erythroid lineage dysplasia in the presence or absence of multilineage dysplasia and persistent thrombocytosis (platelet count ≥450 9 10/l), without other disease-defining genetic abnormalities (Arber et al., 2016). Frequent somatic alterations in patients with MDS/MPN-RS-T include SF3B1 (85%), JAK2V617F (50%), TET2 (25%), ASXL1 (20%), DNMT3A (15%) and SETBP1 (10%) (Patnaik et al., 2016a). With an estimated median overall survival of approximately 76 months, outcomes are better than in patients with MDS-RS and single lineage dysplasia, but inferior when compared to patients with essential thrombocythemia (Broseus et al., 2012). Due to ineffective erythropoiesis related to locking of intracellular iron in mitochondria and accelerated erythroid precursor apoptosis, anaemia is a major source of morbidity, not only due to complications associated with impaired oxygen transport but also due to red blood cell (RBC) transfusion-associated iron overload (Patnaik & Tefferi, 2019). Erythropoiesis-stimulating agents (ESAs) are commonly used to reverse this erythroid maturation arrest and decrease the RBC transfusion frequency, but literature on specific response rates in patients with MDS/MPN-RS-T is limited (Patnaik & Tefferi, 2019). This is especially relevant as patients with MDS/MPN-RS-T are already at an increased risk for thrombosis, which may be compounded by the use of concomitant ESA (Broseus et al., 2012). We conducted a single institution retrospective study to assess ESA responses among WHO-defined patients with MDS/MPN-RS-T. After Institutional Review Board approval, adult patients with WHO-defined MDS/MPN-RS-T, diagnosed from years 2002 to 2014 at our institution, were included in the study. Diagnostic bone marrow (BM) aspirate and trephine biopsy morphology and cytogenetics were reviewed to ensure compliance with the latest WHO criteria (Arber et al., 2016). Twenty-four (60%) study patients underwent next generation sequencing (NGS) for the following genes: IKZF1, PTPN11, SH2B3, SUZ12, ZRSR2, ASXL1, CALR, CBL (exons 8, 9), CEBPA (exon 1), CSF3R (exons 14, 17), DNMT3A (exons 4, 8, 13, 15, 16, 18, 19, 20, 22 and 23), EZH2 (exons 8, 17 and 18), FLT3 (exons 14, 20), IDH1 (exon 4), IDH2 (exon 4), JAK2 (exons 12, 14), KIT, MPL (exon 10), NPM1 (exon 11), NRAS (exons 2, 3), RUNX1 (exons 3, 4 and 8), SETBP1 (exon 3), SF3B1 (exons 13, 15 and 17), SRSF2 (exon 1), TET2 (exons 3, 9, 10, 11), TP53 (exons 5, 6, 7, and 8) and U2AF1 (exons 2, 6) obtained on BM mononuclear cells, at diagnosis, or at first referral, by previously described methods (Patnaik et al., 2016a). Treatment details, including the type of ESAs used, the dose administered, side effects and the reason for discontinuation were retrospectively abstracted. Erythroid responses were assessed using the 2015 IWG (International Working Group) MDS/MPN response criteria (Savona et al., 2015). Forty patients with WHO-defined MDS/MPN-RS-T, who received ESA treatment at any time during their disease course, were included in the study; median age 72 1 years (range, 52–93 3), 45% male. Table I describes the clinical and laboratory characteristics of these patients. The median haemoglobin (Hb) at diagnosis was 9 2 gm/dl (range, 6 6– 12 1); median baseline Hb level (prior to ESA treatment) was 9 gm/dl (range, 6 6–12 1 – Hb levels were spuriously high in six patients due to recent RBC transfusions and levels prior to referral were not available) and median baseline erythropoietin (EPO) level (available in 15 patients – nine responders, six non-responders) 44 iu/l (range, 8–500). Seventeen (43%) patients had a bone marrow reticulin stain evaluation at diagnosis, with seven (41 2%) patients showing evidence of bone marrow fibrosis (six grade 1, one grade 2). Median LDH level at diagnosis was 152 5 (range: 145–270) U/l; however, this information was only available for four patients. Abnormal karyotype was seen only in three (7 5%) patients, with abnormalities including der(13;14)(q10;q10), -Y and inv (3)(q21;q26). Eleven (31%) patients were RBC transfusiondependent (TD) prior to start of ESA therapy. None of the 40 ESAs-treated patients were on concomitant cytoreductive therapy for thrombocytosis. Twenty-one (53%) patients were treated with epoietin-a (EA), 15 (38%) with darbepoietin-a (DA), and four (10%) received both drugs sequentially. Median administered doses were 40,000 iu weekly (range, 20 000–80 000) for EA and 200 mcg every two weeks (range, Correspondence