Filgrastim and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia TS Lin 1 , IW Flinn 2 , MS Lucas 1 , P Porcu 1 , J Sickler 2 , ME Moran 1 , DM Lucas 1 , NA Heerema 3 , MR Grever 1 and JC Byrd 1 1 The Division of Hematology-Oncology, The Ohio State University, Columbus, OH, USA; 2 The Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, MD, USA; and 3 Department of Pathology, The Ohio State University, Columbus, OH, USA Alemtuzumab (anti-CD52; Campath-1H) is effective in fludar- abine-refractory chronic lymphocytic leukemia (CLL), but is associated with infection and early onset neutropenia. To reduce toxicity, filgrastim (G-CSF) was administered concur- rently with alemtuzumab. In total, 14 CLL patients (median age 59) with a median of 3.5 prior regimens (range 1–12) received i.v. alemtuzumab, stepped up from 3 to 30 mg the first week, then 30 mg thrice weekly for 12 weeks. Filgrastim 5 lg/kg was administered daily 5 days before and throughout alemtuzumab therapy. Six patients developed cytomegalovirus (CMV) react- ivation 3–6 weeks into treatment; six patients developed fever, three neutropenia, and one pneumonia. The patient with CMV pneumonia died; ganciclovir cleared CMV in the other patients. Five patients developed early neutropenia (weeks 2–5). Four patients developed delayed neutropenia (weeks 10–13) unas- sociated with CMV reactivation. Nine patients ceased therapy because of infectious and hematologic toxicity. Five partial responses were noted, all in patients with lymph nodes 45 cm, lasting a median of 6.5 months (range 5–13). Filgrastim and alemtuzumab were given concurrently with manageable infu- sion toxicity and clinical activity, but the efficacy of this regimen was limited by delayed neutropenia of unclear etiology and CMV reactivation. Filgrastrim should not be administered prophy- lactically during alemtuzumab therapy outside clinical trials. Leukemia (2005) 19, 1207–1210. doi:10.1038/sj.leu.2403782 Published online 28 April 2005 Keywords: CLL; alemtuzumab; filgrastim; G-CSF; cytomegalovirus; CMV Introduction Alemtuzumab (Campath-1H), a humanized anti-CD52 anti- body, 1,2 is active in fludarabine-refractory chronic lymphocytic leukemia (CLL), with a 33% response rate in a large pivotal trial that gained FDA marketing approval. While such patients are predisposed to infections even in the absence of treatment, infections occurred in 55% of patients (27% grade 3–4) in the pivotal study, and 13% developed septicemia. 3 Such infections are likely secondary to underlying disease, profound cellular immune suppression, and early neutropenia associated with alemtuzumab therapy. 2 In an attempt to decrease alemtuzumab- induced neutropenia and potentially enhance neutrophil antibody dependent cellular cytotoxicity, we performed a phase I/II study of combined granulocyte-colony stimulating factor (G-CSF; Filgrastim) and alemtuzumab in relapsed and refractory CLL. Materials and methods Patients with relapsed CLL were enrolled and provided written consent to participate in this institutional review board- approved protocol. Filgrastim 5 mg/kg was administered sub- cutaneously daily 5 days before and continuously through the 12-week alemtuzumab treatment period. Alemtuzumab was administered identically to the CAM211 study and used similar prophylaxis for pneumocystis carinii pneumonia and varicella zoster that continued for 6 months post-therapy. 3 The alemtu- zumab dose was stepped up from 3 to 30 mg during the first week, and then given 30 mg thrice weekly for 12 weeks. Blood counts were monitored weekly. Cytomegalovirus (CMV) was monitored weekly with a semiquantitative DNA hybrid capture assay. 4 Interphase cytogenetics were performed as previously published. 5 CLL response was assessed by NCI 96 criteria. 6 Toxicity was graded according to NCI Common Toxicity criteria. 7 Results Patient demographics In total, 14 patients with a median age of 59 years (range 47–74) were enrolled. In total, 10 patients were male (71%), 11 had bulky lymph node enlargement 45 cm (79%), and eight were Rai stage III/IV (57%). Prior therapy included a median of 3.5 regimens (range 1–12), with 13 patients (93%) refractory to fludarabine. Five patients had del(17)(p13.1). These features are summarized in Table 1. Nonhematologic toxicity Filgrastim was well tolerated. Alemtuzumab infusion toxicity was manageable; all patients received full dose alemtuzumab within 1 week of starting therapy. While all patients experienced grade 1–2 infusion toxicity, no patient experienced grade 3–5 infusion toxicity, and all infusion toxicity resolved within 24 h. However, two patients experienced severe, grade 3 fatigue, and both patients were removed from study by week 5 due to disease progression or infection. Rapid decrease in blood CLL cells concurrent with increased LDH was noted in a subset of patients with the initial three doses of alemtuzumab. While no patient developed overt tumor lysis syndrome, one patient developed grade 4 hyperuricemia. Grade 3 laboratory abnormalities included hypophosphatemia (4), elevation in alkaline phospha- tase (3), hyperglycemia (2), hyperkalemia (1), hypokalemia (1), and hyponatremia (1); all laboratory abnormalities were transient. These toxicities are summarized in Table 2. Infectious toxicity Two patients were hospitalized for neutropenic fever; CMV was not implicated in either patient. One of these two patients died of fusarium and polymicrobial sepsis; no organism was isolated Received 21 October 2004; accepted 17 March 2005; Published online 28 April 2005 Correspondence: Dr TS Lin, Division of Hematology and Oncology, The Ohio State University, 320 West 10th Avenue, Columbus, OH 43210, USA; Fax: þ 1 614 293 7526; E-mail: lin-1@medctr.osu.edu Leukemia (2005) 19, 1207–1210 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu