Primary myelofibrosis in a patient with sickle cell disease
Authors: Sarah E. Green, Zeba N. Singh, Maria R. Baer
Journal: American Journal of Hematology (2021)

A 76-year-old woman had been diagnosed with sickle cell disease at age 60 years after presenting with a splenic infarct. She did well until age 73 years, when she developed progressive transfusion-dependent anemia, leukocytosis and thrombocytosis. Hemoglobin electrophoresis in the absence of hydroxyurea treatment showed 70% hemoglobin S, 27% hemoglobin F and 3% hemoglobin A2, consistent with sickle cell-beta zero thalassemia with hereditary persistence of fetal hemoglobin. She was treated with hydroxyurea for anemia thought to be due to sickle cell disease, but it was discontinued due to gastrointestinal toxicity. She was subsequently referred to the University of Maryland for Hematology consultation. Comorbidities included hypertension, atrial fibrillation and congestive heart failure with preserved ejection fraction and moderate pulmonary hypertension. Liver and spleen were not palpable. Hemoglobin was 9.7 g/dL (recently transfused), white blood cell count (WBC) 12.2 × 109/L with 59% neutrophils, 9% bands, 1% metamyelocyte, 4% myelocytes, 3% basophils, 4% eosinophils, 10% monocytes and 9% lymphocytes, platelet count 1237 × 109/L, 97 nucleated red blood cells (NRBCs) per 100 WBC, absolute reticulocyte count 18 × 109/L (5.25%), lactate dehydrogenase (LDH) 2631 units/L, total bilirubin 2.0 mg/dL with direct bilirubin 0.5 mg/dL and creatinine 0.72 mg/dL. Peripheral smear showed anisopoikilocytosis, with target, sickle and teardrop cells, and scattered schistocytes, polychromatophilia, NRBCs and Howell-Jolly and Pappenheimer bodies, as well as occasional myeloblasts, giant platelets and rare megakaryocyte nuclear fragments (Image 1 A–C). Bone marrow biopsy was 60% to 70% cellular with grade 3 myelofibrosis (Image 1 D), without increased blasts. Karyotype was normal. A type 1 frameshift mutation in calreticulin (CALR), c.1099_1150del52 (p.Leu367Thrfs*46), was found, with an allele frequency of 51%, as well as a DNMT3A mutation, c.2196dup (pGlu733*), with an allele frequency of 4%. A diagnosis of primary myelofibrosis1 was made based on presence of grade 3 myelofibosis and a CALR mutation and not meeting criteria for other myeloid malignancies (major criteria), as well as elevated LDH and leukoerythroblastosis (minor criteria); anemia and leukocytosis were also present as minor criteria, but could also be attributed to sickle cell disease. Though presentation was confounded by coexisting sickle cell disease, myelofibrosis was best categorized as intermediate-risk (older age, severe anemia and dense fibrosis, but presence of CALR mutation and lack of unfavorable cytogenetic changes or mutations), and symptom-directed therapy was indicated.2 In the setting of transfusion-dependent anemia with an inappropriately low endogenous erythropoietin level (80 mIU/mL), epoietin 60 000 units subcutaneously weekly was initiated. The risk of stimulating production of sickle cells was thought to be low, given the high percentage of hemoglobin F. Cytoreductive therapy to control thrombocytosis was thought to be indicated in the setting of older age and cardiovascular disease. Given previous intolerance of hydroxyurea, pegylated interferon alfa-2a was initiated to control thrombocytosis, resulting in a gradual decrease in her platelet count. Outside blood counts 8 months after starting epoietin and pegylated interferon alfa-2a were hemoglobin 9.2 g/dL, WBC 41.5 × 109/L (including NRBCs) and platelet count 270 × 109/L. She subsequently relocated and no further follow-up information is available. This patient's course illustrates lack of symptoms and late diagnosis of sickle cell disease in association with hereditary persistence of fetal hemoglobin, development of a myeloid neoplasm in an older patient with sickle cell disease in the absence of hydroxyurea therapy, and management of anemia and thrombocytosis associated with myelofibrosis in the setting of sickle cell disease. Higher hemoglobin F levels are associated with a lower rate of acute painful episodes and of complications including acute chest syndromes, osteonecrosis and leg ulcers, and reduced disease severity.3 An increased risk of leukemias has been reported in patients with sickle cell disease,4 attributed to ongoing increased cellular turnover in the bone marrow and chronic inflammation,5, 6 but primary myelofibrosis has not been previously reported in sickle cell disease, to our knowledge. Of note, primary myelofibrosis and other myeloproliferative neoplasms may be under-diagnosed in patients with sickle cell disease because of shared manifestations, including anemia, abnormal red blood cell morphology, leukocytosis, thrombocytosis and elevated LDH levels. Recent data indicate that epoietin therapy may be safe and effective in patients with sickle cell disease, with increases in Hgb levels and without increased incidence of vaso-occlusive crises or venous thromboembolism.7, 8 Epoietin was well tolerated in our patient with sickle cell disease with hereditary persistence of fetal hemoglobin. Of note, our patient's presentation preceded the availability of voxelotor to treat anemia in patents with sickle cell disease.7 Additionally, pegylated interferon alfa-2a9 was well tolerated and effective in decreasing thrombocytosis associated with myelofibrosis in our patient. Supported by NIH-NCI grant P30 CA134274. The authors declare no conflict of interest. Notapplicable (single case report). Data sharing is not applicable to this article as no new data were created or analyzed in this study.