The effects of erythropoiesis‐stimulating agents on the management of chemotherapy‐induced anemia and tumor growth in diffuse large B‐cell lymphoma patients

Abstract

Erythropoiesis‐stimulating agents (ESAs), such as erythropoietin (EPO) and darbepoetin, may alleviate anemia in diffuse large B‐cell lymphoma (DLBCL) patients. However, many cancer cells express EPO receptors (EPOR), through which exogenously administered ESAs potentially promote cancer cell growth. We conducted preclinical/phase II studies to investigate the safety and efficacy of ESAs for managing chemotherapy‐related anemia in DLBCL patients. We examined EPOR expression in germinal center B‐cell (GCB)‐ and activated B‐cell (ABC)‐DLBCL cell lines, and investigated the effects of ESAs on cell proliferation, and rituximab‐mediated complement‐dependent cytotoxicity (CDC). The clinical study enrolled 50 histologically confirmed DLBCL patients receiving rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R‐CHOP) who had hemoglobin levels <10.0 g/dl after a maximum of three R‐CHOP cycles and received ≥4 doses of fixed‐dose darbepoetin (360 μg) once every 3 weeks. EPOR mRNA was detected in all GCB‐DLBCL cell lines, but little/none was detected in ABC‐DLBCL cell lines. GCB‐DLBCL and ABC‐DLBCL cell proliferation was unaffected by EPO or darbepoetin. Rituximab‐mediated CDC of DLBCL cell lines with/without EPOR expression was not affected adversely by EPO. In the clinical study, baseline mean hemoglobin was 9.19 g/dl; the overall mean change in hemoglobin was 1.59 ± 1.3 g/dl (16 weeks). Forty‐eight percent of enrolled patients achieved a hematopoietic response. Our study shows that ESAs do not affect the growth of DLBCL cells or rituximab‐mediated CDC under the experimental conditions that we used, and the appropriate use of ESAs may be effective and safe for DLBCL patients with anemia after R‐CHOP.

Erythropoietin and its derivatives: from tissue protection to immune regulation

“…The preclinical researches make it possible for further exploration on EPO biology in cancer. Although the expression of CD131 on cancer cells remains unclear, the expression of EPOR has been verified both on mRNA and protein level [69][70][71][72][73][74] . Studies focus on EPOR signaling in cancer cells, which interacts with apoptotic pathway, hypoxia pathway and anticancer agents.…”

“…When EPOR signaling was blocked by EPOR knockdown or soluble EPOR against EPO, it inhibited tumor growth and invasion, and resulted in cell apoptosis 71,[75][76][77] . Interestingly, in most studies, EPO stimulation had no significant effects on tumor proliferation, survival or invasion under normoxia 69,[71][72][73][74]77,78 ; only in few cases, such as in melanoma, EPO was reported to stimulate tumor growth both in vivo and in vitro on eIF4Edependent pathway 79 . However, under hypoxia EPO significantly promoted cell proliferation 76,77 .…”

“…Rituximab, which functioned through complement-dependent cytotoxicity (CDC), was not affected by EPO in diffuse large B-cell lymphoma 74 . However, the anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab was partially antagonized by concurrent treatment of EPO, which activated Jak2/Src signaling and inactivated PTEN 69 .…”

Erythropoietin receptor is a risk factor for prognosis: a potential biomarker in lung adenocarcinoma

“…EPOR was originally discovered and described in erythroid progenitor cells, but it is also present in non-hematopoietic cells (tissues, organs) such as adipose tissues [17], bone progenitor cells [18], neurons [19], endothelial cells [20] and intestinal tract [21]. It is also widely present in various cancer cells and tumor tissues, such as head and neck squamous cell carcinoma [22], diffuse large B-cell lymphoma [23], rhabdomyosarcoma [24], breast cancer [25], hepatocellular carcinoma…”

Erythropoietin receptor is a risk factor for prognosis: a potential biomarker in lung adenocarcinoma

“…EPOR was originally discovered and described in erythroid progenitor cells, but it is also present in non-hematopoietic cells (tissues, organs) such as adipose tissues [17], bone progenitor cells [18], neurons [19], endothelial cells [20] and intestinal tract [21]. It is also widely present in various cancer cells and tumor tissues, such as head and neck squamous cell carcinoma [22], diffuse large B-cell lymphoma [23], rhabdomyosarcoma [24], breast cancer [25], hepatocellular carcinoma [26] and laryngeal malignancy [27]. Studies have shown that it is upregulated in gastric adenocarcinoma [28], liver cancer [29], prostate cancer [30], glioma [31] and other cancers.…”