Myelodysplastic Syndrome/Myeloproliferative Neoplasms with Ringed Sideroblasts and Thrombocytosis (MDS/MPN RS-T)–A Case Report with Literature Review on Diagnosis and Management

Myelodysplastic syndrome/Myeloproliferative neoplasms with ringed sideroblasts and thrombocytosis (MDS/MPN RS-T) is a rare disorder with mixed features of dysplasia and myeloproliferation. This is a relatively new independent entity included in the 2016 WHO classification as MDS/MPN with RS-T. The diagnostic criteria include erythroid lineage dysplasia, ≥15% Ringed Sideroblasts (RS), <1% blast cells in peripheral blood, <5% blast cells in the bone marrow, persistent thrombocytosis with platelet count ≥450×109/L, presence of SF3B1 mutation, absence of BCR-ABL1 gene fusion and rearrangement of PDGFRA, PDGFRB or FGFR1 or PCM1-JAK2. In MDS/MPN RS-T, two mutations are commonly seen JAK 2, which promotes myeloid proliferation, and SF3B1 gene, which causes myelodysplasia with ringed sideroblasts commonly observed in this syndrome. We present a relatively young 59-year-old woman diagnosed with MDS/ MPN RS-T based on the above guideline criteria. She has low-risk MDS, which favors a good prognosis; however, the presence of Essential Thrombocythemia (ET) favors a poor prognosis. Currently, there is no consensus on the specific management of this entity, given its rarity. She was referred to an allogeneic hematopoietic stem cell transplant center for curative treatment since she had become transfusion dependent. Before curative treatment, the patient was initiated on ruxolitinib as a bridging therapy to bone marrow transplant.

LSD1 Inhibition with IMG7289 (bomedemstat) Rebalances Megakaryopoiesis and Erythropoiesis in a Patient with MPN/MDS with Refractory Anemia with Ringed Sideroblast and Marked Thrombocytosis with JAK2 and SF3B1 Mutations

Lysine-specific demethylase-1 (LSD1) is a histone H3 K4 demethylase that plays a critical role in hematopoietic progenitor cell differentiation, in particular, the production of megakaryocytes and erythrocytes from their common classical bi-potent progenitor (MEP). LSD1 is recruited to chromatin by the transcription factor GFI1B to license the maturation of megakaryocyte-erythrocyte progenitor cells (MEPs). Anemia is a common and serious complication of primary myelofibrosis (PMF), which is often refractory to conventional therapy. We report here the effect of IMG-7289 (bomedemstat), an LSD1 inhibitor, on skewing the fate of MEPs favoring the production of red cells over platelets and producing a complete hematologic remission in a JAK2V617F-positive PMF patient who had developed a refractory anemia with ringed sideroblasts. A 63 year old woman presented in 2016 with a 1 year history of with fatigue significantly compromising her lifestyle. She denied fever, night sweats, or weight loss. The physical examination was unremarkable with no palpable splenomegaly. Laboratory studies showed a hemoglobin (Hb) of 11.3 g/dL, a total white blood cell count (WBC) of 20.3k/µL with leukoerythroblastosis with 1% circulating blast cells, and a platelet count of 1,192k/µL. A bone marrow biopsy (BMB) showed a hypercellular marrow with increased dysmorphic megakaryocytes but without dyserythropoiesis. There were no ringed sideroblasts with Perls stain, and silver staining showed grade 2 reticulin fibrosis. The karyotype was del(7)(q11.2) and genotyping identified a JAK2V716F allele (VAF not known). The patient was considered to have PMF. Initial treatment consisted of hydroxyurea but without any improvement in her symptoms. Financial constraints initially prevented access to ruxolitinib but the patient was eventually started on 15 mg BID in January 2018. She tolerated therapy well but discontinued therapy a year later owing to no improvement in her fatigue and opted for observation alone. Over the next year, her hemoglobin fell to the range of 9.0-9.5g/dl and she developed drenching night sweats. A BMB in August 2019 showed a hypercellular marrow with increased dysplastic megakaryocytes but now with 76% ringed sideroblasts. Reticulin stain showed grade 2-3 fibrosis. No other dysplastic features were observed. Additional genotyping was declined by insurance and the patient was considered to have an MPN/MDS overlap syndrome. Accordingly, the patient was enrolled in clinical trial IMG-7289-CTP-102 (NCT03136185), a study of the LSD1 IMG-7289. On entry, her Hb was 9.5 gm/dL with an absolute reticulocyte count of 129K/µL. The WBC was 22.7k/µL with 69% neutrophils and 11% monocytes. The platelet count was 1,585k/µL with a mean platelet volume (MPV) of 8.1 fL. Genotyping showed a JAK2V617F VAF of 27%, a new SF3B1K700E mutation with a VAF of 26%, and a DNMT3A mutation with a VAF of 95%. Spleen volume by imaging was 283.3 cm³. The starting IMG-7289 dose was 40 mg po QD. At week 12, the Hb rose to 13.8 g/dL while the absolute reticulocyte count fell to 40K/µL. The platelet count was 271k/µL with the MPV increasing to 10.5 fL. The WBC was 5.2k/µL with 58% neutrophils and 18% monocytes. The mutant JAK2 allele burden had dropped to 14%. The spleen volume was 223 cm³. The IMG-7289 dose was reduced to 35 mg QD after complaints of fatigue. At Week 24, Hb was 11.7 g/dL, WBC was 12.1k/µL and platelets were 743k/µL. The total symptom score (MPN SAF TSS) was reduced by 31% from baseline. The expected pharmacodynamic effects of LSD1 inhibition on hematopoiesis were evident in this patient: monocytosis with a decrease in neutrophils and a marked reduction in the platelet count. Most striking was the concurrent improvement in the patient's anemia which was associated with a persistent reticulocytosis present at the start of treatment but with a significant increase in red blood cells in the setting of a SF3B1 mutation. MEP fate decisions hinge on the balance between KLF1 and FLI1 with the former favoring an erythroid fate, the later, megakaryocytes. The transcription factor complex of FLI1, GATA1, FOG1 which recruits the LSD1-containing NuRD complex is essential for megakaryocyte function; IMG-7289 likely disrupts that complex favoring erythropoiesis over megakaryopoiesis. The inhibition of LSD1 may, therefore, in the setting of thrombocytosis and anemia, rebalance the fate of MEPs to ameliorate both abnormalities. Disclosures Yacoub: Novartis: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Roche: Other: Support of parent study and funding of editorial support. Rienhoff:Imago BioSciences: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Low-risk myelodysplastic syndrome managed with an erythroid-stimulating agent for 10 years

A 57-year-old man with a history of diabetes and coronary artery disease was referred to haematology for the evaluation of anaemia in the setting of non-cardiac chest pain, fatigue, dyspnoea and dizziness. Previous investigations into these recurrent symptoms focused on a re-evaluation of his known ischaemic heart disease, which required multiple percutaneous interventions with stenting several years ago. In the year leading up to his referral, the patient required two transfusions during separate hospitalisations. Previously, his chronic anaemia was attributed to chronic inflammation because of unrevealing micronutrient and endoscopic evaluations. The patient underwent a bone marrow biopsy, which demonstrated normal karyotype myelodysplastic syndrome with ringed sideroblasts. This patient was found to have favourable cytogenetics and low-risk disease. His anaemia and associated symptoms improved with the administration of an erythroid-stimulating agent. Now 75 years old, he has remained on single-agent therapy for 10 years without need of transfusion.

Presentation of a diagnostically challenging case of chronic eosinophilic leukemia with marrow dysplasia and ringed sideroblasts

Chronic eosinophilic leukemia, not otherwise specified can be challenging to differentiate from hypereosinophilic syndrome and myelodysplastic syndromes with elevated eosinophilia. We present a diagnostically challenging case of chronic eosinophilic leukemia, not otherwise specified that initially seemed like a myelodysplastic syndrome but progressed to eosinophilic tissue infiltration and overt eosinophilic dyspoiesis. In addition, we discuss the morphologic and molecular findings that can overlap among these entities that made the diagnosis difficult in the case presented.

Diagnostic Value of Flow Cytometry Standardized Using the European LeukemiaNet for Myelodysplastic Syndrome

Background: Myelodysplastic syndromes (MDS) and idiopathic cytopenia of undetermined significance (ICUS) are heterogeneous hematological disorders characterized by hematopoietic dysplasia and/or chromosomal aberrancy. Objectives: This study aimed to evaluate the diagnostic value of flow cytometry standardized using the European LeukemiaNet (ELN) for MDS and ICUS by analyzing samples obtained from patients with cytopenia based on morphological examination, cytogenetic analysis, and flow cytometry. Methods: We retrospectively analyzed bone marrow samples aspirated from 253 consecutive patients (median age: 66 years [range: 1–92]) to identify the cause of cytopenia. Results: Sixty patients presented with MDS, and 16 with ICUS. MDS subtypes were distributed as follows: MDS with single-lineage dysplasia (n = 10); MDS with multi-lineage dysplasia (n = 10); MDS with ringed sideroblasts (n = 4); MDS with excess blasts-1 (n = 9); MDS with excess blasts-2 (n = 13), MDS unclassified (n = 5); 5q-syndrome (n = 6); and MDS/myeloproliferative neoplasms (n = 3). Four representative ELN indexes were used. Two or more ELN MDS indexes were in the abnormal range in 35 MDS cases (58.3%) and 4 ICUS cases (25.0%). Conclusions: Morphological examination remains the standard for MDS diagnosis. Considering the low incidence of genetically proven ICUS (20.2–27.5%), the low sensitivity of ELN MDS indexes for ICUS is considered a valuable alternative.