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.
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.
Asterisk with author names denotes non-ASH members.