“Primum non nocere”: the addition of granulocyte-macrophage colony stimulating factor to alemtuzumab in chronic lymphocytic leukemia

Abstract

In the article “ Addition of granulocyte-macrophage colony stimulating factor does not improve response to early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab, ” Zent and colleagues treated 33 patients with chronic lymphocytic leukemia (CLL) in a small, but important phase II clinical trial [1]. Th e current study followed an earlier clinical trial at the Mayo clinic in which 30 patients with CLL meeting the same eligibility criteria were treated with the combination of rituximab and alemtuzumab, without granulocyte-macrophage colony stimulating factor (GM-CSF) [2]. Th is report outlines the clinical responses and toxicities seen in the current study (MC0785) and compares the results to those seen in the prior study (MC038G). Th e main hypothesis of the current study was that the addition of GM-CSF would increase the number of circulating immune eff ector cells to potentially improve the effi cacy of rituximab and alemtuzumab by enhancing antibody dependent cell-mediated cytotoxity (ADCC). Unexpectedly, combination immunotherapy with GM-CSF in patients with early stage high-risk CLL resulted in lower response rates compared to those obtained with rituximab and alemtuzumab alone, and the addition of GM-CSF increased the incidence of cytomegalovirus (CMV) reactivation. Th is trial was designed with the idea that GMCSF improves response rates to immunotherapy. In studies evaluating rituximab in CLL and follicular lymphoma, the addition of GM-CSF does appear to improve responses [3,4]. In contrast, a prior clinical trial reported by Lin et al ., evaluating the combination of G-CSF and alemtuzumab in CLL, did not yield encouraging results and also was associated with higher than expected rates of CMV reactivation [5]. Th e results of the current study support this earlier experience, indicating that myeloid growth factors are deleterious when combined with alemtuzumab. Why did the response rate fall when GM-CSF was added to the combination of alemtuzumab and rituximab? Of course, the two Mayo Clinic phase II studies were not designed to be compared in this fashion. Th is possibility aside, the addition of GM-CSF may have reduced the effi cacy of alemtuzumab, for example by reducing CD52 expression on CLL cells, increasing circulating free CD52, altering the number or activity of eff ector cells, or shifting the immune