Abstract Introduction Adult T-cell leukemia/lymphoma (ATLL), driven by HTLV-1, frequently presents with hypercalcemia, often attributed to PTHrP; however, RANKL/cytokine-mediated osteoclast activation can cause PTHrP-independent hypercalcemia that is refractory to standard therapy. Case Presentation A 49-year-old woman (BMI 45.7; prior sleeve gastrectomy) presented with lethargy, weakness, dyspnea, and severe hypercalcemia (total Ca 19.7 mg/dL). The patient also had a similar admission in another hospital for hypercalcemia. Hypercalcemia recurred despite aggressive IV fluids, repeated calcitonin, and zoledronic acid. PTH and PTHrP were suppressed; vitamin D was low. Imaging showed bilateral axillary/pelvic/inguinal lymphadenopathy and diffuse osteolytic vertebral lesions. Peripheral blood flow cytometry revealed an aberrant CD4+/CD7−/CD5− T-cell population (19% of leukocytes) with HTLV-1 seropositivity, supporting ATLL. Bone marrow was markedly hypocellular; FISH for common myeloid/lymphoid neoplasia was negative. Hospitalization was notable for transient thrombocytopenia, morbilliform rash responsive to topical steroids/antihistamines, prerenal AKI resolving with fluids, and electrolyte losses (K/Mg/Phos) requiring repletion. She remained hemodynamically stable on room air with persistent sinus tachycardia. Given refractory hypercalcemia and new ATLL diagnosis, she was transferred to a tertiary center for chemotherapy ± stem-cell transplant. Discussion ATLL-associated hypercalcemia may occur despite suppressed PTHrP, via RANKL-dependent osteoclastogenesis driven by HTLV-1/Tax signaling; diffuse osteolysis can accompany this physiology. Recognition of PTH/PTHrP-independent hypercalcemia is crucial when standard therapy fails. In bisphosphonate-refractory cases, denosumab (RANKL blockade) is an evidence-supported next step but risks prolonged hypocalcemia, necessitating careful ICU/step-down monitoring and calcium/vitamin D repletion strategies. This case emphasizes a diagnostic/therapeutic framework for severe recurrent hypercalcemia with lymphadenopathy and bone lesions culminating in ATLL. Conclusion Refractory hypercalcemia with suppressed PTH/PTHrP should prompt evaluation for HTLV-1-related ATLL and RANKL-mediated osteolysis. Early multidisciplinary management and consideration of denosumab may be lifesaving. This abstract is funded by: None
Akella et al. (Fri,) studied this question.