Addition of granulocyte macrophage colony stimulating factor does not improve response to early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab

Abstract

Thirty-three previously untreated patients with high-risk chronic lymphocytic leukemia (CLL) were treated before meeting standard criteria with alemtuzumab and rituximab. Granulocyte macrophage colony stimulating factor (GM-CSF) was added to the regimen to determine whether it would improve treatment efficacy without increasing toxicity. High risk was defined as at least one of the following: 17p13-; 11q22.3-; unmutated IGHV (or use of VH3-21) together with elevated expression of ZAP-70 and/or CD38. Treatment was subcutaneous GM-CSF 250 μg Monday-Wednesday-Friday for 6 weeks from day 1, subcutaneous alemtuzumab 3 mg-10 mg-30 mg from day 3 and then 30 mg Monday-Wednesday-Friday for 4 weeks, and intravenous rituximab (375 mg/m(2)/week) for 4 weeks from day 8. Patients received standard supportive care and were monitored weekly for cytomegalovirus (CMV) reactivation. Using standard criteria, 31 (94%) patients responded to treatment, with nine (27%) complete responses (one with persistent cytopenia) and nine (27%) nodular partial responses. Median progression-free survival was 13.0 months and time to next treatment was 33.5 months. No patient died during treatment, seven (21%) had grade 3-4 toxicities attributable to treatment, and 10 (30%) had CMV viremia. Addition of GM-CSF to therapy with alemtuzumab and rituximab decreased treatment efficacy and increased the rate of CMV reactivation compared to a historical control.

Trial registration: ClinicalTrials.gov NCT00562328.

Figure 1. Progression Free Survival

These Kaplan Meier curves plot the progression free survival for patients on the MC0785 (alemtuzumab, rituximab, and GM-CSF) and MC038G (alemtuzumab and rituximab studies).

Figure 2. Time to Retreatment

These Kaplan Meier curves plot the percentage of patients that did not require retreatment for their CLL on the MC0785 (with GM-CSF) and MC038G (without GMCSF) studies.

Figure 3. Neutrophil Counts

Absolute blood neutrophil counts (median, 25^th, and 75^th quartiles) were plotted for patients treated with (solid squares) or without (open circles) GM-CSF. The vertical interrupted lines indicate duration of treatment. The median neutrophil counts (x 10⁹/L) were significantly higher for patients on MC0785 compared to MC038G for measurements at three time points during therapy with GM-CSF (marked by the vertical interrupted lines) at day 8 (3.5 vs. 2.7, p<0.001), day 22 (3.9 vs. 3.1. p=0.003), and day 29 (4.1 vs. 2.9, p=0.002) (Wilcoxon Rank Sum Test).

Figure 4. Monocyte Counts

Absolute blood monocyte counts (median, 25^th, and 75^th quartiles) were plotted for patients treated with (solid squares) or without (open circles) GM-CSF. The vertical interrupted lines indicate duration of treatment. The median monocyte counts (x 10⁹/L) were not significantly different for patients on MC0785 compared to MC038G during therapy with GM-CSF at day 8 (0.5 vs. 0.3, p=0.06), day 15 (0.1 vs. 0.1, p=0.178), day 22 (0.1 vs. 0.1, p=0.86) and day 29 (0.1 vs. 0.1, p=0.75) (Wilcoxon Rank Sum Test).