A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma

Abstract

This study assessed the safety and preliminary efficacy of escalated dose subcutaneous alemtuzumab in combination with rituximab in chronic lymphocytic leukemia. Twenty-eight patients with relapsed refractory chronic lymphocytic leukemia were treated on four dosing cohorts of weekly rituximab at 375 mg/m(2) and alemtuzumab doses that started at 30 mg three times per week and escalated to weekly dosing over four weeks, culminating with 90 mg weekly. One dose limiting toxicity of a rituximab infusion reaction was seen in cohort 2, but the regimen was otherwise well tolerated without evidence of differential toxicity by cohort. The overall response rate by National Cancer Institute-Working Group criteria was 61%, and the rate of complete bone marrow response was 43%, most of whom were negative for minimal residual disease. The addition of CT scan evaluation per International Workshop on Chronic Lymphocytic Leukemia 2008 criteria reduced the overall response rate to 14%. Median overall survival was 35 months, with 12 patients able to proceed to stem cell transplantation. Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80% of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab, and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance. We conclude that escalated subcutaneous doses of alemtuzumab given weekly are well tolerated and result in excellent bone marrow clearance of chronic lymphocytic leukemia, helping patients to proceed to stem cell transplantation. This study is registered at ClinicalTrials.gov (Identifier:00330252).

Trial registration: ClinicalTrials.gov NCT00330252.

Figures

Figure 1.

(A) Progression-free survival. Median 26 months. (B) Time to treatment failure. Median 8 months. (C) Overall survival. Median 35 months. All curves include the 28 enrolled patients.

Figure 2.

Median cell counts during and after alemtuzumab and rituximab therapy. (A) B (CD20), T (CD3) and NK (CD56+CD3−) cells. (B) T-cell subsets. (C) CD4 count subsets. Memory cells (CD45RO+) show earlier recovery. (D) CD8 count subsets. (E) NK cells.

Figure 3.

Maximum trough serum concentrations of rituximab (solid circles) and alemtuzumab (solid triangles) in patients evaluated at each dose cohort. No association is seen between drug levels and dose cohort.