Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab

Abstract

Background: Patients with chronic lymphocytic leukemia (CLL) usually are treated only for progressive disease. However, the discovery of biologic predictors of a high risk of disease progression, together with the development of newer, more targeted therapies, could change this paradigm. In this phase 2 study, the authors tested the safety and efficacy of early treatment for patients with high-risk CLL using alemtuzumab and rituximab.

Methods: Patients were eligible for treatment if they were 1) previously untreated, 2) had no National Cancer Institute-Working Group 1996 criteria for treatment, and 3) had at least 1 marker of high-risk disease 17p13-, 11q22-, or a combination of unmutated IgVH and CD38+/ZAP70+). Treatment consisted of subcutaneous alemtuzumab (initial dose escalation followed by 30 mg on Monday, Wednesday, and Friday for 4 weeks) and intravenous rituximab (375 mg/m(2) per week x4 doses). All patients received Pneumocystis pneumonia and herpes virus prophylaxis and were monitored for cytomegalovirus reactivation.

Results: Twenty-seven of 30 patients (90%) responded to therapy with 11 (37%) complete responses (CRs). Five patients (17%) patients who had a CR had no detectable minimal residual disease. The median response duration was 14.4 months, and only 9 patients required retreatment for progressive disease at the time of the current report (median follow-up, 17.6 months). Study patients had a significantly longer time from diagnosis to first treatment for CLL according to conventional indications than a comparison cohort with similar biologic risk profiles.

Conclusions: The therapy regimen used was safe and effective for early treatment of patients with high-risk CLL. Further studies will be required to determine whether this early treatment strategy decreases morbidity and mortality for high-risk CLL.

Figure 1. Effect of Treatment on Neutrophil and Monocyte Counts

Peripheral blood absolute neutrophil (ANC, upper data points, black) and monocyte (AMC, lower data points, gray) counts were done in the routine clinical laboratory. The graph shows median and 25–75 quartiles for each time point. The nadir ANC was a median count of 1.68 × 10⁹/L (range, 0.15 – 3.65). The nadir AMC was a median count of 0.08 × 10⁹/L (range 0 – 0.29).

Figure 2. Effect of Treatment on T Lymphocytes

The CD4+ (black data points) and CD8+ (gray data points) T lymphocyte subsets counts were calculated from the absolute lymphocyte count and flow cytometric analysis for expression of CD3, CD4, and CD8. The median nadir count for CD4+ T cells was 0.0001 × 10⁹/L (range 0 – 0.0034) and for CD8+ T cells was 0.0003 × 10⁹/L (range 0 – 0.032).

Figure 3. Effect of Treatment on NK cell counts

The NK lymphocyte counts were calculated using the absolute lymphocyte count and flow cytometric analysis of cells within the lymphocyte gate for expression of CD16. The median nadir count for NK cells was 0.0004 × 10⁹/L (range 0 – 0.0078).

Figure 4. Circulating CLL B Lymphocyte Counts

The number of circulating CLL cells was calculated after initiation of treatment from the absolute lymphocyte count and percentage of cells on flow cytometry in the lymphocyte gate defined on forward and side scatter that expressed CD19.

Figure 5. Duration of response to therapy

The median duration of response in the 27 responders was 14.4 months (95% CI: 9.3 –22.5 months)

Figure 6. Time from Diagnosis of CLL to First Treatment for Progressive Disease

Time from diagnosis to first treatment for progressive CLL (using NCI-WG96 criteria) was plotted for patients treated on this study and a comparison cohort from the Mayo Clinic CLL Database with the same high risk features for progressive CLL who did not receive early therapy. Time to first treatment for progressive disease was significantly longer in patients who received alemtuzumab and rituximab therapy.