Hypophosphatemia in Midostaurin-Treated FLT3 Acute Myeloid Leukemia

Introduction: Midostaurin is a first in class, multiple protein kinase inhibitor approved in 2017 for treatment of FLT3-mutated acute myeloid leukemia with conventional therapy. It has activity against multiple protein receptors including the mutated and wild type FMS-related tyrosine kinases. Other kinase inhibitors have been previously described to contribute to hypophosphatemia and 5% of patients were found to have hypophosphatemia in a phase 3 trial of midostaurin. There have been no cases describing the course or nature of hypophosphatemia in midostaurin use. We present the first case of hypophosphatemia attributed to midostaurin use with resolution after discontinuation. Case Description: A 51-year-old female with hypertension presented with encephalopathy and fevers and was found to have acute myeloid leukemia positive for the FLT3 IDT mutation. She underwent cytoreduction with hydrea and induction with “7+3” cytarabine and anthracycline alongside midostaurin. Before induction therapy, phosphorous ranged from 3-4 mg/dL. By day 3, phosphorus was 1.0 mg/dL, requiring daily oral and intravenous replacement. On day 4, phosphorus was 0.8 mg/dL. Serum creatinine was at a baseline of 0.5 mg/dL, ionized calcium was 1.10mmol/L, serum calcium was 6.8 mg/dL. PTH was 222 pg/mL, Vitamin D level was 37 ng/mL, and uric acid was 1.2 mg/dL. Spot urine electrolytes were obtained. Urine creatinine was 26 mg/dL, urine phosphorus was 52.8 mg/dL, and urine potassium was 20.5 mg/dL. Urine sodium was 114 mg/dL. There was no glucosuria. The fractional excretion of phosphate was 59.7%. Midostaurin was switched to gilternitinib after day 15 and phosphorus and calcium levels improved without further supplementation. Discussion: We describe the first case of hypophosphatemia attributed to midostaurin use. Like other kinase inhibitors, the exact mechanism of midostaurin related hypophosphatemia is unknown. Theories include PTH mediated hyperparathyroidism, FGF23 interaction, and proximal tubule wasting. Based on our patient’s elevated fractional excretion of phosphate, the acuity and refractory nature of her phosphate depletion, she likely had at least contributions from proximal tubular injury. Use of midostaurin should have careful electrolyte monitoring and evaluation, with investigation of etiology if hypophosphatemic. In our patient, discontinuation was followed by resolution of the hypophosphatemia.