Atypical bone involvement in chronic lymphocytic leukemia: clinical response to BTK inhibition after chemotherapy failure

Abstract

Chronic lymphocytic leukemia (CLL) is an indolent lymphoid neoplasm typically presenting with lymphocytosis, lymphadenopathy, and splenomegaly. Bone involvement is extremely rare, especially in young patients, and is usually associated with refractory disease. We present the case of a 31-yearold male diagnosed with Rai stage IV chronic lymphocytic leukemia (CLL) in January 2023, initially treated with high-dose methylprednisolone and subsequently with seven cycles of fludarabine, cyclophosphamide, and rituximab (FCR), achieving complete clinical remission in September, with normalization of hematological parameters and absence of lymphadenopathy or splenomegaly on physical examination. During outpatient followup, he developed craniofacial deformities, gingival hyperplasia, and bilateral exophthalmos. Imaging revealed diffuse bone infiltration involving the scapulae, humeri, and sternoclavicular joints. Laboratory tests showed malignant hypercalcemia, associated with a non-traumatic pathological fracture of the right humerus. A skull bone marrow biopsy revealed a hypercellular marrow with 25% infiltration by CLL. Flow cytometry confirmed residual clonal B-cell population. The patient was treated with zoledronic acid and subsequently started on ibrutinib, leading to complete resolution of both bone and gingival lesions. This case illustrates an atypical and aggressive skeletal presentation of CLL in a young adult, with clinical progression despite standard chemoimmunotherapy. Extensive bone involvement may mimic other hematologic malignancies or metastatic tumors, posing a diagnostic challenge. Targeted therapy with Bruton’s tyrosine kinase (BTK) inhibitors, such as ibrutinib, proved effective in achieving disease control in this rare and complex clinical scenario.