SAT-499 Denosumab for Treatment of Hypercalcemia in Myelofibrosis

Abstract

Introduction Hypercalcemia is a rare complication of myeloproliferative neoplasms. As a result, the underlying mechanisms and optimal treatment options remain under investigation. We present a case of hypercalcemia in post-essential thrombocythemia (ET) related myelofibrosis that was responsive to treatment with denosumab 60mg. Clinical Case A 65-year-old woman with ET for 10 years and recent progression to myelofibrosis (confirmed by bone marrow biopsy) was admitted for failure to thrive. Significant labs include: Ca 11.5 mg/dL (n: 8.5-10.5 mg/dL), corrected Ca 13.2 mg/dL, phosphorous 3.7 mg/dL (n: 2.4-4.7 mg/dL), PTH 5 pg/mL (n: 16-87 pg/mL), 25-OH Vitamin D 20.2 ng/mL (n: 30-100 ng/mL), 1,25 Vitamin D: 6.5 pg/mL (n: 19.9-79.3 pg/mL), PTHrP <2 pmol/L (n: <2 pmol/L), Vitamin A 9.4 ug/dL (n: 36.4-108.0 ug/dL), bone specific alkaline phosphatase 58 ug/L (n: 8.1-31.6 ug/L), TSH 0.16 uIU/mL (n: 0.34-5.60 uIU/mL), pancytopenia on CBC with 3% blasts on differential, LDH 3157 U/L (n: 100-200 U/L), and uric acid 7.4 mg/dL (n: 2.7-7.3 mg/dL). There were no lytic lesions on CT head/chest/abdomen/pelvis. Corrected Ca levels improved to 11 mg/dL after i.v. fluids and calcitonin. Denosumab 60 mg was administered on day 9 of hospitalization when corrected Ca reached 14.5 mg/dL. Cholecalciferol 1000 IU daily was started. Ca levels normalized three days after denosumab. However, clinical course then rapidly deteriorated with transformation into acute leukemia with hemophagocytic lymphohistiocytosis (HLH), tumor lysis syndrome, septic shock, and acute renal failure. Venous ionized Ca levels dropped to 0.80 mmol/L (n: 1.14-1.29 mmol/L) six days after denosumab dose. She required i.v. calcium gluconate, oral Ca, and adjusted Ca bath in dialysis to correct hypocalcemia. The patient died on day 19 of hospitalization. Conclusion While hypercalcemia is uncommon in myelofibrosis, it needs to be recognized as a potential complication. Although the underlying pathogenesis remains unknown, suggested mechanisms include: ectopic 1,25 Vitamin D production, osteolytic metastases, immobilization, and RANKL activation. Our patient did not have known bone metastases, prolonged periods of immobility or elevated 1,25 Vitamin D levels. However, our patient’s response to denosumab supports a RANKL mediated process. It is likely that there is an extensive release of cytokines in myelofibrosis even in the absence of osteolytic lesions. This would shift the RANKL/OPG balance towards osteoclast differentiation and subsequent hypercalcemia. Our case illustrates effective treatment of hypercalcemia in myelofibrosis with denosumab 60 mg. Low dose denosumab can be considered for treatment in myelofibrosis patients with a high risk of acute clinical decompensation. However, more research to elucidate the underlying mechanism and optimal treatment of hypercalcemia in myeloproliferative disorders is necessary.