The Benefit of Adding Rituximab to Ibrutinib in Relapsed/Refractory CLL
Ibrutinib has proved to be an effective targeted therapy in patients with relapsed/refractory CLL (Byrd JC, et al. N Engl J Med. 2014;371:213-223; Jain N, O’Brien S. Hematol Oncol Clin North Am. 2013;27:851-860; Barrientos J, Rai K. Leuk Lymphoma. 2013;54:1817-1820). Moreover, a phase 2 clinical trial of ibrutinib in combination with rituximab in 40 high-risk patients with CLL demonstrated an ORR of 95% (Burger JA, et al. Lancet Oncol. 2014;15:1090-1099).
Kim and colleagues reported on a randomized study of ibrutinib versus ibrutinib plus rituximab in patients with relapsed CLL to assess whether the addition of rituximab to ibrutinib can abrogate ibrutinib-induced lymphocytosis and accelerate the response of predictive biomarkers, including plasma levels of chemokines CCL3 (MIP-1?) and CCL4 (MIP-1?), which are known to reflect the activation status of CLL cells (Blood. 2014;124. Abstract 1998).
At the time of this report, 104 patients with previously treated CLL, or treated or untreated high-risk disease (del17p or TP53 mutation) had been randomized to receive ibrutinib (Arm A) or ibrutinib plus rituximab (Arm B) for 6 cycles. The absolute lymphocyte counts (ALCs) were determined repeatedly over the course of the study.
In Arm A, consistent with a known pattern of lymphocytosis with ibrutinib, ALC rose immediately after the initiation of treatment and then began to stabilize. However, in Arm B, no statistically significant changes in ALC were observed during this initial period. In 52 patients who had ?4 months of follow-up, there was a downward trend in ALC in both groups, with a more rapid decrease in Arm B (P = .03) and with an initial lymphocytosis apparent in patients in Arm A but not in Arm B. Further analysis showed that patients in Arm B had a higher percentage of patients with normal or normalizing ALC after 4, 6, and 9 months of treatment.
Both treatment regimens resulted in significant reductions in CCL3, CCL4, and ?2-microglobulin levels within 1 week, with no significant differences between the 2 groups. Amounts of CD3+ and CD3+/CD4+ T-cells decreased significantly in patients in Arm B but not in Arm A (P = .007 and P = .002, respectively), and patients treated with combination therapy had significantly higher reductions in CD3+, CD3+/CD4+, and CD3+/CD8+ T-cells compared with patients treated with ibrutinib alone.
Thus, the addition of rituximab to ibrutinib abrogates the transient lymphocytosis associated with ibrutinib monotherapy and is associated with faster clearing of leukemia cells from the bloodstream in patients with relapsed CLL. In addition, a significant reduction in chemokine ligands CCL3 and CCL4 was observed in both treatment arms within 1 week of therapy.