Therapy-Related Myeloid Neoplasms After [¹⁷⁷Lu]Lu-PSMA Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer: A Case Series

[¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA) therapy has a favorable toxicity profile in patients with metastatic castration-resistant prostate cancer (mCRPC). Therapy-related myeloid neoplasm (t-MN) has been described after [¹⁷⁷Lu]Lu-DOTATATE but has not, to our knowledge, yet been reported after [¹⁷⁷Lu]Lu-PSMA. This case series describes 5 patients with mCRPC who developed t-MN after [¹⁷⁷Lu]Lu-PSMA at our institution. <b>Methods:</b> In this single-center retrospective analysis, we reviewed all patients with mCRPC treated with [¹⁷⁷Lu]Lu-PSMA. Patients who developed biopsy-proven t-MN during or after [¹⁷⁷Lu]Lu-PSMA treatments are summarized with descriptive statistics. <b>Results:</b> From August 26, 2015, to December 31, 2022, 5 of 381 (1.3%) patients treated with [¹⁷⁷Lu]Lu-PSMA were subsequently diagnosed with t-MN. Their median age at cycle 1 (C1) was 78 y (range, 65-80 y). The median time from C1 to t-MN diagnosis was 33.6 mo (range, 6.0-58.8 mo). Previous treatments included docetaxel (<i>n</i> = 5), external-beam radiotherapy to metastases (<i>n</i> = 5), abiraterone (<i>n</i> = 4), enzalutamide (<i>n</i> = 3), and cabazitaxel (<i>n</i> = 3). On PSMA PET/CT, 4 (80%) patients had predominantly bone metastases and 1 (20%) had predominantly nodal metastases. They were treated with [¹⁷⁷Lu]Lu-PSMA-617 (<i>n</i> = 3) or [¹⁷⁷Lu]Lu-PSMA-I&T (<i>n</i> = 2). A median of 7 cycles (range, 4-12 cycles) of [¹⁷⁷Lu]Lu-PSMA was administered, with a median total cumulative activity of 49.2 GBq (range, 31.3-79.0 GBq). Prostate-specific antigen reduction of at least 50% or at least 80% from baseline was seen in 5 (100%) and 4 (80%), respectively. All had prostate-specific antigen progression preceding t-MN diagnosis. t-MN diagnosis included myelodysplastic syndrome with single-lineage dysplasia (<i>n</i> = 2), myelodysplastic syndrome with excess blasts 1 (<i>n</i> = 1), acute promyelocytic leukemia (<i>n</i> = 1), and acute myeloid leukemia (<i>n</i> = 1). At t-MN diagnosis, all patients presented with at least grade 2 cytopenia, involving one or more blood cell lines. Marrow genetic analysis revealed unfavorable karyotypes or mutations in all patients. Most patients received supportive care after t-MN diagnosis. Survival was 8.1, 31.3, 43.0, 56.0, and 60.4 mo from C1 and 1.8, 2.1, 6.8, 10.3, and 12.4 mo from t-MN diagnosis. <b>Conclusion:</b> In the mCRPC population after chemotherapy, we describe a low incidence of t-MN after [¹⁷⁷Lu]Lu-PSMA therapy. Ongoing follow-up is necessary to further define the true incidence of t-MN or other unexpected delayed toxicities, particularly with earlier use of [¹⁷⁷Lu]Lu-PSMA in the disease course.