Feasibility of CXCR4-Directed Radioligand Therapy in Advanced Diffuse Large B-Cell Lymphoma

Abstract

We have recently reported on our experience with C-X-C-motif chemokine receptor 4- (CXCR4-) directed radioligand therapy (RLT) in multiple myeloma and acute leukemia. Six patients with heavily pre-treated relapsed diffuse large B cell lymphoma (DLBCL) (3 males, 3 females; aged, 54±8 years) underwent CXCR4-directed RLT in combination with conditioning chemotherapy and allogeneic stem cell transplantation (SCT). In 2 patients, radioimmunotherapy (RIT) targeting CD20 or CD66 was added to enhance anti-lymphoma activity. Endpoints were incidence and severity of adverse events, progression-free and overall survival. RLT as well as additional RIT were well-tolerated without any acute adverse events or changes in vital signs. Successful engraftment was recorded after a median of 11 days (range, 9-13 d). In the 4 patients who were available for follow-up (one patient died of CNS aspergillosis 29 days, another of sepsis in aplasia 34 days after after RLT), CXCR4-directed RLT resulted in partial response in 2/4 cases (both treated with additional RIT) and mixed response in the remaining 2 subjects. Response duration was rather short-lived with median progression-free survival of 62 days (range, 29-110 d) and median overall survival of 76 days (range, 29-313 d). CXCR4-directed RLT (in combination with additional RIT) as a conditioning regimen prior to allogeneic SCT in DLBCL is feasible.

Side Effects of CXC-Chemokine Receptor 4–Directed Endoradiotherapy with Pentixather Before Hematopoietic Stem Cell Transplantation

“…The treatment-related data of some patients have been previously described in feasibility studies of CXCR4-directed endoradiotherapy with pentixather (15)(16)(17). Those data have thus not been analyzed in a structured retrospective manner before now.…”

“…177 Lu-pentixather has already been proven capable of successfully eradicating CXCR4-positive tumor cells without completely and irreversibly destroying the supporting HSPC niche in a preclinical endoradiotherapy mouse model-a capability that is a prerequisite for the reconstitution of the hematopoietic system after therapy. Moreover, first-in-human experiences of CXCR4-directed endoradiotherapy with pentixather in patients with advanced-stage multiple myeloma, acute myeloid leukemia, and non-Hodgkin lymphoma have shown the feasibility of this therapy in combination with high-dose chemotherapy and autologous or allogeneic hematopoietic stem cell transplantation (HSCT) (10,(15)(16)(17). However, because of the high expression levels of CXCR4 on HSPCs and its crucial function in their regulation, the safety of CXCR4-directed endoradiotherapy has to be further studied.…”

Possibility of cancer-stem-cell-targeted radioimmunotherapy for acute myelogenous leukemia using 211At-CXCR4 monoclonal antibody

“…Recently, clinical experience with 177 Lu-and 90 Y-labeled pentixather for the CXCR4-targeted radionuclide therapy for advanced-stage DLBCL, MM, and AML, has been reported 32,33 . The latest report at present showed a partial response in two of six patients who underwent additional radioimmunotherapy with a 188 Re-anti-CD66 antibody or 90 Y-anti-CD20 antibody (ibritumomab tiuxetan) 33 . In these studies, radionuclide therapies were performed in addition to high-dose chemotherapy, followed by allogeneic hematopoietic stem cell transplantation.…”

Theranostics: Leveraging Molecular Imaging and Therapy to Impact Patient Management and Secure the Future of Nuclear Medicine

“…That imaging agent is the most extensively investigated CXCR4 radioligand to date (73,74). Its theranostic twin, pentixather, radiolabeled with either 177 Lu or 90 Y, has also been studied (Table 2) (75)(76)(77). Because of physiologic expression of CXCR4 in the bone marrow, and substantial retention of radioactivity in renal parenchyma, side effects include myelosuppression and deterioration in renal function.…”