Ibrutinib May Boost Efficacy of CAR T Cells

The efficacy of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)—one of the most common adult leukemias—has been discouraging thus far. However, findings from 2 trials presented during the 2018 annual American Society of Hematology meeting in San Diego, CA, December 1–4, indicate that these patients may benefit from receiving the BTK inhibitor ibrutinib (Imbruvica; Janssen) alongside their own engineered T cells.

With CAR T-cell therapy in CLL, “a major limitation has been disappointing complete response rates,” said David Porter, MD, of the University of Pennsylvania in Philadelphia, senior investigator of one of the trials. Concurrent administration of ibrutinib, however, “led to high response rates and was also associated with a decrease in the severity of cytokine release syndrome [CRS],” said Jordan Gauthier, MD, of Fred Hutchinson Cancer Research Center in Seattle, WA, who presented findings from the second trial.

Gauthier and colleagues evaluated 43 patients with CLL who were given JCAR014 (Celgene), an investigational CD19-targeting CAR T-cell therapy. Of these, 24 had discontinued prior ibrutinib after disease progression; the other 19 received ibrutinib before, during, and for at least 3 months after CAR T-cell infusion. An analysis at 4 weeks showed a trend toward higher overall response rates in the concurrent ibrutinib group: 83%, versus 65% for those given only JCAR014. In the ibrutinib arm, 85% experienced deep molecular responses—undetectable bone marrow disease, via immunoglobulin heavy chain sequencing—compared with 50% in the no-ibrutinib arm. These results were also consistent with better CD4+ CAR T-cell expansion in the ibrutinib arm.

Additionally, severe CRS, a complication of CAR T-cell therapy, developed in 25% of patients who received only JCAR014, but did not occur among patients given concurrent ibrutinib.

Porter's study, meanwhile, followed 19 patients who received both ibrutinib and CTL119, the humanized counterpart of tisagenlecleucel (Kymriah; Novartis). Of these, 18 had undetectable bone marrow disease, determined via morphology, at 3 months, and at a median follow-up of 18.5 months, overall survival was 95%. Only 3 patients developed severe CRS.

“The results with concurrent ibrutinib are encouraging—given the very high response rates, CAR T cells could become a beneficial therapy for patients with high-risk CLL,” said Jennifer Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, who was not involved in either study.

Porter said it will be important to determine whether longer courses of ibrutinib—6 months or more, in his study—are more beneficial than shorter courses such as the 2-week treatment period in Gauthier's trial.

“Understanding exactly what ibrutinib contributes to CAR T-cell therapy, and when, is essential to optimizing benefits while minimizing unnecessary exposure and risk,” agreed Brown. She noted that although ibrutinib appears to reduce the likelihood of immunotherapy-induced severe CRS, 2 patients who received the drug died from cardiac arrhythmia, one in each trial.

The benefits of concurrent ibrutinib and CD19-directed CAR T-cell therapy are now being investigated in a larger phase I/II trial, said Gauthier, which may help address some of these questions. –Kristin Harper