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 $$\pm$$ ± 1.3 GBq 177Lu-PSMA-617 per cycle was administered, and mean cumulative activity was 24.6 $$\pm$$ ± 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.

Safety and Efficacy of 177Lutetium-PSMA-617 Radioligand Therapy Shortly after Failing 223Radium-Dichloride

“…Three patients developed visceral metastases under 223 Ra (one patient with adrenal, one with pulmonary and one with splenic metastases, respectively). Upon initiation of 177 Lu-PSMA-617, 16 patients had low (oligo-/multifocal; ≤20 lesions) and 12 patients had high (disseminiated/diffuse; >20 lesions) bone tumor burden (based on PROMISE miTNM and previous studies) [17][18][19].…”

“…In the VISION study, 68/529 (12.9%) patients developed grade ≥ 3 anemia, 42 (7.9%) thrombocytopenia and 13 (2.5%) leukopenia [9]. In a recent study by Groener et al, significant hematologic adverse events were observed in a total of 13/140 patients (9.3%) after 177 Lu-PSMA-617 [19]. Here, previous treatment with 223 Ra was not significantly associated with occurrence of hematotoxicity (OR: 0.93, 95% CI 0.27-3.20, p = 0.58).…”

“…High extent of metastatic bone involvement may increase the risk of myelotoxicity and is suggested as a negative prognostic factor for survival after RLT with 177 Lu-PSMA-617. Groener et al showed, that patients with disseminated/diffuse osseous involvement at baseline (n = 77/140) had a significantly higher incidence of hematotoxicity (OR 5.08, p = 0.04) [19]. Similarly, in a report on the subgroup of patients from the multicenter WARMTH study with known numbers of bone lesions, only patients with >20 bone lesions or diffuse bone marrow involvement developed significant thrombocytopenia (n = 18), no significant leukopenia was observed [30].…”

Lutetium-177-PSMA-617: A Vision of the Future

“…At median follow-up of 8 months, no cases of late-onset severe myelosuppression or myelodysplastic syndrome were reported. 25 Another study showed hematological safety of [ 177 Lu]Lu-PSMA-617 in patients with high bone tumor burden. 22 …”

Hematological Toxicity in Mice after High Activity Injections of 177Lu-PSMA-617

“…Hematologic adverse events have been reported more frequently than diminished renal function with 177 Lu-PSMA-617. For example, Rahbar et al reported grade 3-4 hematotoxicity in 12% of patients (3% leukopenia, 10% anemia, and 4% thrombocytopenia) in a multicenter trial, and Groener et al reported similar numbers (9.3%; 3.6% leukopenia, 7.1% anemia, and 4.3% thrombocytopenia) [9,10]. There are several risk factors for hematotoxicity, e.g., patients with high occurrence of bone metastases, previous chemotherapy with taxane, or pretreatment grade 2 cytopenia [10].…”