Dose Escalation Study To Evaluate Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and Safety of Alemtuzumab for Consolidation Therapy in Patients with Chronic Lymphoycytic Leukemia: Phase I/II Trial of the German CLL Study Group (GCLLSG).

Introduction: Alemtuzumab has shown considerable activity in both relapsed/refractory chronic lymphocytic leukemia (CLL) and frontline treatment setting. In a prior randomised phase III trial we have demonstrated that consolidation with alemtuzumab significantly improves progression-free survival and the rate of molecular remissions in CLL patients after fludarabine based chemotherapy. However, significant toxicity including severe infections were observed. This ongoing phase I/II trial investigates the maximum tolerated dose (MTD) of alemtuzumab consolidation in patients with CLL after 2^nd line chemotherapy.

Methods: 12 patients (pts) in complete or partial remission after induction chemotherapy with either fludarabine plus cyclophosphamide (FC) or fludarabine plus cyclphosphamide plus rituximab (FCR) were eligible to receive alemtuzumab consolidation 90 to 150 days after last chemo infusion. Alemtuzumab was administered in 2 different cohorts either intravenously (iv, cohort A) or subcutaneously (sc, cohort B), once weekly for 8 weeks. Dose escalation was started with 10 mg iv/sc and increased in 10 mg intervals per dose level, each dose level including a minimum of 3 pts. All pts received standard premedication and infection prophylaxis. Blood samples were taken to determine pharmacokinetics in week 4 and 8. MRD was evaluated in peripheral blood and bone marrow by 4-colour flow cytometry at week 8 and 3-monthly thereafter.

Results: 10 pts (median age 68 years) in complete or partial remission (1 CR, 1 nPR, 8 PR) after FC/FCR were treated with alemtuzumab in cohort A. Due to 2 dose limiting toxicities (DLT) at dose level 2 (20 mg iv, 1 FUO requiring iv antibiotics, 1 exacerbated erythema exsudativum multiforme) the MTD of alemtuzumab was determined at 10 mg iv. In cohort B, so far 2 patients (1 CR, 1 PR) have been treated with 10 mg alemtuzumab sc and no DLT has been observed. Besides the 2 DLT overall toxicity was tolerable in both cohorts with 8 CTC grade III cytopenias reversible in less then 2 weeks, 1 FUO and 2 subclinical CMV reactivations. All infections were successfully treated. After the last dose of alemtuzumab (week 8) the clinical response status of 4 pts converted from PR to CR. Up to a median follow up of 22 months 3 pts presented with PD, 2 of them died due to disease progression. MRD negativity (< 1 × 10E-4) was achieved in 3/10 pts in cohort A and 1/2 pts in cohort B. The median PFS of all pts was 19.9 months. For the majority of patients examined alemtuzumab plasma concentrations in week 4 and 8 showed rapid accumulation with stable levels after administration in the range of 100 to 300 ng/ml.

Conclusion: Consolidation with alemtuzumab in CLL pts after 2^nd line therapy is safe and able to achieve response improvement including MRD negativity. Dose escalation of alemtuzumab has determined a MTD of 10 mg, if administered intravenously. Ongoing trial activity is attempting to determine the MTD, pharmacokinetic and clinical efficacy of subcutaneous alemtuzumab consolidation.