Consolidation Therapy with Subcutaneous (SC) Alemtuzumab Results in Severe Infectious Toxicity in Previously Untreated CLL Patients Who Achieve a Complete Response (CR) after Fludarabine and Rituximab (FR) Induction Therapy: Interim Safety Analysis of the CALGB Study 10101.

Alemtuzumab (Campath-1H) is approved for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL). Given the increasing role of chemoimmunotherapy in the treatment of CLL, the Cancer and Leukemia Group B initiated a phase II study administering FR followed by alemtuzumab for remission consolidation to previously untreated, symptomatic CLL patients (pts). Pts received fludarabine 25 mg/m2 IV on days 1–5; rituximab 50 mg/m2 IV on day 1, 325 mg/m2 IV on day 3, and 375 mg/m2 IV on day 5 of cycle 1, and 375 mg/m2 IV on day 1 of cycles 2–6; every 28 days for up to 6 cycles. Four months after the last dose of fludarabine, pts with stable or responsive disease by NCI 96 response criteria received consolidation therapy with SC alemtuzumab 3 mg on day 1, 10 mg on day 3, 30 mg on day 5, and 30 mg thrice weekly thereafter for 6 weeks. Pts received standard pneumocystis (PCP) and Varicella Zoster Virus prophylaxis and were monitored weekly for Cytomegalovirus (CMV) reactivation by PCR, antigen test, or hybrid capture. We report safety data on the first 51 pts who received alemtuzumab. Median age was 60 years (range, 23–82), and 75% were male. Of 34 pts who attained an NCI 96 partial response (PR) after FR induction, 9 (26%) experienced unacceptable toxicity to alemtuzumab, as defined prospectively by the study. Eight grade 3 toxicities (4 opportunistic infections, 3 CMV reactivation, 1 hemorrhagic cystitis), and 1 grade 5 EBV lymphoproliferative disorder were observed. In contrast, 17 pts had CR after FR induction and 8 (47%) had unacceptable toxicity. Complications included grade 3 infections in 3 pts (2 CMV, 1 cryptococcus) and 5 grade 5 infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia). These infections occurred both during therapy and for up to 16 months following therapy. Analysis of alemtuzumab pharmacokinetics and genomic tumor features is currently ongoing. Continuous real-time safety monitoring prompted a study amendment to prohibit further pts in CR after FR induction from receiving alemtuzumab consolidation. Accrual of new pts to the trial is complete. Only pts in PR or with stable disease after FR induction continue to receive alemtuzumab consolidation, with close monitoring for infectious and other toxicities. Detailed response and outcome data will be reported when all pts have completed therapy. We conclude that alemtuzumab cannot be safely administered as consolidation therapy to pts who achieve an NCI 96 CR following induction chemoimmunotherapy. The safety and feasibility of alemtuzumab consolidation for pts in PR after FR induction remains under study, and such therapy should not be pursued outside of a clinical trial due to concerns about serious infectious morbidity and mortality.