It is longstanding knowledge that rituximab has more than an additive effect when combined with traditional cytotoxic chemotherapy. Its ability to “add” to novel targeted agents is less well established and probably varies depending on the rituximab-novel agent combination and the disease under study. A recently published single-arm phase II study strongly suggests rituximab adds considerable efficacy to the BRAF inhibitor vemurafenib in relapsed hairy cell leukemia (HCL).
HCL is a strongly CD20+ indolent B-cell malignancy. The BRAF V600E kinase activating mutation is the defining pathogenic alteration. Vemurafenib is an orally available BRAF inhibitor with established single agent activity in relapsed HCL. Two phase II studies in relapsed HCL demonstrated an overall response rate of 91 percent, complete response (CR) rate of 35 percent, and partial response rate of 56 percent to single-agent vemurafenib. The median relapse-free survival was nine months for the entire population, 19 months in patients with a CR, and six months in patients with a partial response. Single-agent rituximab has a response rate of 25 percent in relapsed HCL. With this knowledge, Dr. Enrico Tiacci and colleagues hypothesized that adding rituximab to vemurafenib would improve the quality of the response in relapsed HCL.
The study enrolled 31 patients, with 30 evaluable for response and toxicity. The dosing strategy was to administer an induction cycle of vemurafenib at 960 mg by mouth twice daily for 28 days along with rituximab at 375 mg/m2 on days 1 and 14. Patients then received a two-week treatment break followed by repeating the same 28-day dose and schedule of vemurafenib and rituximab for induction cycle 2. Patients then received consolidation rituximab consisting of an additional four doses administered every two weeks. The CR rate was 87 percent (26/30), and the overall response rate was 90 percent (27/30), with three unevaluable patients deemed nonresponders. Remarkably, CRs were observed in the 10 patients who were refractory to purine analogues, the seven patients previously treated with a BRAF inhibitor, and in the five patients refractory to rituximab. The duration of response was also remarkably durable, with 78 percent of patients being progression-free at 37 months (Figure 1A). Of the seven patients previously treated with a BRAF inhibitor, the response duration to vemurafenib-rituximab was substantially better (median of 4 months vs. median not reached). When comparing these seven patients against the 19 patients who never received prior BRAF inhibitors, the relapse-free survival at 35 months was 57 percent versus 95 percent, suggesting that these patients are much better off receiving the combination rather than single-agent vemurafenib.
The magnitude of the apparent benefit is quite astonishing. Admittedly, this is just a small single-arm, phase II study, but if I were to encounter a patient with relapsed HCL in clinic next week, I would be inclined to offer vemurafenib plus rituximab using the same dose and schedule as used in this study. Repeat treatment with purine analogues is certainly an option, but one must be cognizant of the cumulative myelosuppression and immunosuppression likely to be encountered. And what should you do if your patient progresses after vemurafenib-rituximab? Certainly, retreatment could be considered. Additionally, moxetumomab pasudotox is U.S. Food and Drug Administration–approved in this setting. Finally, I would direct readers to an interesting phase II study published recently, testing ibrutinib in relapsed HCL.1 The best overall response was 54 percent, and the estimated 36-month progression-free survival was 73 percent.
Dr. Kahl indicated no relevant conflicts of interest.