Hematologic Toxicity or Tumor Biology Translational Pitfalls of ¹⁷⁷lu-Psma in Advanced Prostate Cancer

Prostate-specific membrane antigen (PSMA) – based theranostics has reshaped the treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) by integrating molecular imaging with targeted radionuclide therapy. Lutetium-177–PSMA (177Lu-PSMA) has demonstrated meaningful clinical benefit in selected patients; however, important translational challenges persist. These include optimal patient selection, prediction of hematologic toxicity, and differentiation between treatment-related adverse effects and manifestations of aggressive tumor biology, particularly in patients with extensive skeletal disease. To describe a case of mCRPC treated with 177Lu-PSMA complicated by severe pancytopenia, highlighting the translational challenges in distinguishing radionuclide-induced myelotoxicity from bone marrow infiltration by metastatic prostate cancer. A 63-year-old man presented with a clinical and radiologic profile highly suggestive of metastatic prostate cancer, with markedly elevated PSA levels (1749 ng/mL) and widespread bone and nodal disease. Cross-sectional imaging revealed diffuse osteoblastic and osteolytic lesions involving the axial and appendicular skeleton, multiple pathologic fractures, and retroperitoneal and pelvic lymphadenopathy. PSMA PET demonstrated intense radiotracer uptake across multiple skeletal sites, consistent with high-volume PSMA-avid disease. Histologic confirmation of the primary tumor was not feasible due to a concomitant low rectal tubulovillous adenoma with high-grade dysplasia, which precluded transrectal biopsy. Following surgical castration and subsequent biochemical progression, the patient was classified as having mCRPC. Given the extensive PSMA expression and lack of alternative systemic options due to limited performance status, 177Lu-PSMA therapy was initiated. After the first cycle, the patient developed progressive anemia, neutropenia, and thrombocytopenia, complicated by febrile neutropenia. Further radionuclide therapy was withheld due to concern for severe hematologic toxicity. Bone marrow evaluation was pursued to clarify the underlying mechanism of cytopenias in the setting of extensive skeletal disease. Bone marrow biopsy revealed morphologic and immunohistochemical features consistent with metastatic prostatic adenocarcinoma involving the marrow, supporting tumor infiltration as a contributing factor to the observed cytopenias. This case shows how difficult it can be to distinguish hematologic toxicity from 177Lu-PSMA therapy from bone marrow involvement caused by high-volume disease. Imaging-based selection alone may be insufficient to predict hematologic risk. Integrative translational strategies incorporating molecular imaging, baseline marrow assessment, and predictive biomarkers are essential to optimize patient selection and safely expand the clinical impact of theranostics in advanced prostate cancer.