A year old woman was
A 77-year-old woman was referred to our medical center for second opinion for refractory CMML-2. She had been incidentally found to have mild leukocytosis, anemia, and thrombocytosis on routine laboratory analysis. At diagnosis her white blood cell count (WBC) was 12×10/L, hemoglobin was 10.8g/dL, and platelet count was 420×10/L. Monocytes and eosinophils constituted 19% and 1% of total WBC, respectively. Bone marrow biopsy demonstrated hypercellularity, bone marrow dysplasia, and 14% blasts consistent with a diagnosis of CMML-2. Cytogenetics were 46,XX,del(7)(q22q32) and no other analysis to interrogate rearrangements was performed at that time.
After two cycles of 5-azacitidine, the patient proceeded to undergo matched unrelated donor allogeneic hematopoietic stem cell transplantation but subsequently had graft failure and relapsed in a CMML-2 state. Post-transplant therapies included 5-azacitidine, induction chemotherapy, and decitabine for which she did not respond. Broad spectrum molecular profiling was performed using the clinically available FoundationOne®Heme assay which analyzes the complete coding DNA sequences of 405 genes, selected introns of 31 genes involved in rearrangements, and the RNA sequence of 265 commonly rearranged genes to identify gene fusions. Findings included mutations in , , , , and a rearrangement. is a gene that encodes a phospholipid-binding protein that has not been previously reported to partner with . Given that SDPR is highly expressed in hematopoietic early progenitor aspirin solubility () , we hypothesized that the fusion of the SDPR promoter to the PDGFRB coding region would result in overexpression of PDGFRB as has been reported with other fusions. Her peripheral eosinophil count at the time of molecular profiling was 1.12k/L and bone marrow biopsy was consistent with secondary AML with 36% blasts. The patient was started on 400mg of imatinib and achieved a significant reduction in bone marrow blasts to 5%, consistent with a partial CR. Blood counts at time consisted of white blood cell count of 3k/µL, platelets of 108k/µL, hemoglobin of 8.5g/dL and hematocrit of 25.9%. The duration of response using imatinib was approximately 4 months prior to disease progression after which the patient transitioned to best supportive care with hydroxyurea and expired 3.5 months later.
CMML remains a lethal malignancy with limited treatment options. The incidence of rearrangements in myeloproliferative neoplasms (MPNs) is low; a recent study reported only 1.8% of 556 patients evaluated . While MPNs with rearrangements are phenotypically diverse, CMML with eosinophilia is a common morphologic diagnosis . We report a case of a refractory CMML case eosinophilia harboring a rearrangement leading to a favorable response with imatinib. This case demonstrates the utility of broad spectrum genomic profiling in refractory CMML cases as an opportunity to uncover additional treatment options.
Introduction The transcription factor GATA2 has a complex role in the development of hematopoiesis and lymphopoiesis but even in differentiation of non-hematopoietic progenitors. Haploinsufficiency of GATA2 leads to a variety of clinical and laboratory findings. It has been previously described that heterozygous mutations in GATA2 underlie different syndromes defined by monocytopenia and mycobacterial avium complex infection (MonoMAC), deficiency of dendritic cells, monocytes, B- and NK lymphocytes (DCML), lymphedema, deafness and myelodysplasia (Emberger syndrome) or familiar myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) [1–3]. Different types of mutations are known to cause loss of function of the mutated allele leading to haploinsufficiency of GATA2, and a correlation with certain clinical symptoms has been described in some cases [4–6]. Germline mutations of GATA2 are transmitted with autosomal dominant inheritance. However, even among hereditary cases, there is a great variation of clinical findings, time of manifestation and even severity of disease in patients with GATA2 mutations. Clinical characteristics in most patients include immunodeficiency with susceptibility to human papillomavirus (HPV) and non-tuberculous mycobacteria (NTM), predisposition to MDS/AML, pulmonary proteinosis (PAP) and congenital lymphedema. These symptoms might occur with or without preceding cytopenias and different medical specialties are involved in the diagnosis and management of these patients. The only curative treatment so far is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, it is crucial to diagnose patients with GATA2 mutations as early as possible.