Bone Marrow Recovery and Subsequent Chemotherapy Following Radiolabeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 in Men with Metastatic Castration-Resistant Prostate Cancer

Abstract

Radioimmunotherapy (RIT) has demonstrated efficacy with acceptable toxicity leading to approval in non-Hodgkin’s lymphoma, but has been slower to develop for the treatment of advanced solid tumors. Prostate cancer (PC) represents a good candidate for RIT based upon high exposure to circulating antibodies at common disease sites with a specific, highly expressed cell-surface antigen of prostate-specific membrane antigen. Four phase I and II trials utilizing 177Lu- or 90Y-J591 have been reported. Long-term toxicity and chemotherapy administration was analyzed. As expected, the only serious toxicity observed was myelosuppression. Grade 4 thrombocytopenia occurred in 33.3% without significant hemorrhage and grade 4 neutropenia occurred in 17.3% with 0.07% febrile neutropenia. Nearly all subjects (97.3%) recovered to grade 0 or 1 platelets and all had complete neutrophil recovery. The majority (81.3%) received chemotherapy at any time, with 61.3% receiving chemotherapy following RIT. Ten subjects underwent bone marrow biopsies at some point in their disease course following RIT for low counts; all had diffuse PC infiltration without evidence of myelodysplasia or leukemia. As expected, myelosuppression occurs following therapeutic doses of RIT for men with metastatic castration-resistant PC. However, toxicity is predictable and self-limited, with the majority of patients who do not refuse able to receive cytotoxic chemotherapy following RIT.

Phase 1/2 study of fractionated dose lutetium‐177–labeled anti–prostate‐specific membrane antigen monoclonal antibody J591 (177Lu‐J591) for metastatic castration‐resistant prostate cancer

“…The long circulation times of monoclonal antibody–based radioimmunotherapy is a disadvantage when it comes to myelosuppression, but is advantageous for continuous delivery and uptake of radionuclides by tumor over many days. In contrast to the high incidence of low‐grade xerostomia in prospective studies of 177 Lu‐targeted radioligand therapy, we have not observed this phenomenon (nor targeting of salivary glands by imaging) . Renal toxicity is a potential late side effect of PSMA radioligand therapy .…”

“…Renal toxicity is a potential late side effect of PSMA radioligand therapy . No long‐term follow‐up has been performed with PSMA‐targeted radioligand therapy, but we have not observed any significant acute or delayed nephrotoxicity in our studies with many years of follow‐up …”

“…In the present study, we detail the severity, duration, and consequences of our hematologic adverse events, include an analysis of subsequent therapy with our OS results, and are comfortable with the proportion of patients with high‐grade thrombocytopenia and the need for platelet transfusions. Furthermore, we have published our long‐term follow up of 150 patients treated with 177 Lu‐J591 or 90 Y‐J591, with all patients having complete neutrophil count recovery and 97.3% with platelet count recovery to grade 0‐1; 177 Lu‐J591 radioimmunotherapy did not prevent subsequent chemotherapy …”

“…Furthermore, we have published our longterm follow up of 150 patients treated with 177 Lu-J591 or 90 Y-J591, with all patients having complete neutrophil count recovery and 97.3% with platelet count recovery to grade 0-1; 177 Lu-J591 radioimmunotherapy did not prevent subsequent chemotherapy. 24 Targeting of PSMA with radiopharmaceuticals has increased with the use of PSMA ligands, initially for imaging and subsequently for treatment. Although no direct comparisons can be made due to different patient populations with access to different additional treatments and different methodology, it is of interest to put our study into current context.…”

“…In contrast to the high incidence of low-grade xerostomia in prospective studies of 177 Lu-targeted radioligand therapy, we have not observed this phenomenon (nor targeting of salivary glands by imaging). [6][7][8]10,11,24,28 Renal toxicity is a potential late side effect of PSMA radioligand therapy. 29 No long-term follow-up has been performed with PSMA-targeted radioligand therapy, but we have not observed any significant acute or delayed nephrotoxicity in our studies with many years of follow-up.…”