Hematologic safety of 177Lu-PSMA-617 radioligand therapy in patients with metastatic castration-resistant prostate cancer

Abstract

Background: Myelosuppression is a potential dose-limiting factor in radioligand therapy (RLT). This study aims to investigate occurrence, severity and reversibility of hematotoxic adverse events in patients undergoing RLT with ¹⁷⁷Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). The contribution of pretreatment risk factors and cumulative treatment activity is taken into account specifically.

Methods: RLT was performed in 140 patients receiving a total of 497 cycles. A mean activity of 6.9 [Formula: see text] 1.3 GBq ¹⁷⁷Lu-PSMA-617 per cycle was administered, and mean cumulative activity was 24.6 [Formula: see text] 15.9 GBq. Hematological parameters were measured at baseline, prior to each treatment course, 2 to 4 weeks thereafter and throughout follow-up. Toxicity was graded based on Common Terminology Criteria for Adverse Events v5.0.

Results: Significant (grade ≥ 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade ≤ 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT. Myelosuppression was significantly more frequent in patients with pre-existing grade 2 cytopenia (OR: 3.50, 95%CI 1.08-11.32, p = 0.04) or high bone tumor burden (disseminated or diffuse based on PROMISE miTNM, OR: 5.08, 95%CI 1.08-23.86, p = 0.04). Previous taxane-based chemotherapy was associated with an increased incidence of significant hematotoxicity (OR: 4.62, 95%CI 1.23-17.28, p = 0.02), while treatment with ²²³Ra-dichloride, cumulative RLT treatment activity and activity per cycle were not significantly correlated (p = 0.93, 0.33, 0.29).

Conclusion: Hematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous ²²³Ra-dichloride treatment show no significant contribution to incidence rates.

Keywords: 177Lu-PSMA-617; Hematologic adverse events; Hematotoxicity; Metastatic castration-resistant prostate cancer; PSMA.

Fig. 1

Violin plots for hemoglobin, white blood cell counts (WBC), and platelets at baseline and upon maximum deterioration (A). Incidence of grade ≥ 3 hematologic adverse events by risk factor: extent of bone tumor burden with 1) none, uni-/oligo-/multifocal (≤ 20) or 2) disseminated and diffuse bone metastases, chemo-naïve or after previous taxane-based chemotherapy, patients previously receiving ²²³Ra-dichloride or patients with previous hematological decline (CTCAE grade) (B)

Fig. 2

Cycle-based analysis (n = 497): (A) association of absolute change in hemoglobin, white blood cells (WBC) and platelets after each treatment cycle with cycle activity, linear trendline, (B) association of toxicity grade after each treatment cycle and cumulative treatment activity, (C) Sankey diagrams for change in CTC grade after each treatment cycle