Adding Ibrutinib to CAR T-Cell Therapy Increases Response Rates in CLL

Jordan Gauthier, MD, MSc

Jordan Gauthier, MD, MSc

Adding ibrutinib (Imbruvica) to chimeric antigen receptor (CAR) T-cell therapy led to improved responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to preliminary findings presented at the 2019 Transplantation and Cellular Therapy Meetings.

Jordan Gauthier, MD, of Fred Hutchinson Cancer Research Center, presented the findings from the trial, which investigated concurrent administration of ibrutinib and the investigational CAR T-cell agent JCAR014. The results showed an overall response rate of 83% as compared with 65% for patients who discontinued ibrutinib before starting JCAR014. Complete response in marrow occurred in a similar proportion of patients when assessed by flow cytometry but was substantially higher with concurrent therapy when assessed by deep sequencing.

“Concurrent administration of ibrutinib with CD19 CAR-T cells for relapsed/refractory CLL was feasible in most patients, and led to high response rates at 4 weeks,” said Gauthier.

“We observed higher in vivo expansion of CD4-positive CAR T-cells [with concurrent therapy], which may deepen responses. Concurrent ibrutinib and CAR T-cell therapy was associated with lower rates of severe cytokine release syndrome (CRS), which was associated with lower serum concentrations of cytokines,” added Gauthier.

The phase I/II study, which involved a total of 43 patients with relapsed/refractory CLL, had its genesis in the recognition that patients who discontinue ibrutinib because of disease progression or intolerance have a poor prognosis. Tyrosine kinase inhibitors have a limited duration of activity in high-risk CLL.

Gauthier and colleagues previously reported durable responses to CD19-targeted CAR T-cell therapy after ibrutinib failure.²They hypothesized that concurrent treatment with ibrutinib and CAR T-cell therapy would improve the response rate with less toxicity by preventing tumor flare, mobilizing CLL cells into the blood from lymph nodes, improving CAR T-cell function, and attenuating CRS.

All 43 patients discontinued ibrutinib prior to leukapheresis or lymphodepletion with cyclophosphamide and fludarabine. Subsequently, 24 patients received JCAR014 alone and 19 received ibrutinib concurrently with the CAR T-cell therapy. Patient and disease characteristics were similar in the 2 groups, said Gauthier.

All but 6 patients in the concurrent group received ibrutinib as planned. Reasons for discontinuation included thrombocytopenia, neurotoxicity and associated complications, disseminated intravascular coagulation associated with CRS, and disease progression in a single case. One patient died suddenly of presumed cardiac arrhythmia. Duration of concurrent ibrutinib treatment to discontinuation ranged from 4 to 207 days.

By International Working Group on CLL criteria, 15 of 18 (83%) evaluable patients in the concurrent group achieved objective responses as compared with 15 of 23 (65%) in the no-ibrutinib group (P= .38).

Rates of complete response in marrow by flow cytometry were 72% with ibrutinib and 74% without. Deep sequencing showed complete marrow responses in 11 of 13 (85%) evaluable patients in the concurrent arm versus 7 of 14 (50%) in the no-ibrutinib group (P= .10). Nodal response rates were 71% with ibrutinib and 64% without, and responses by PET criteria were 80% and 69%, respectively, neither of which achieved statistical significance.

The addition of ibrutinib led to improved in vivo expansion of CD4-positive CAR T cells (P= .03). CAR T-cell expansion was a significant predictor of global response (P= .003), nodal response (P= .004), and complete response in bone marrow (P<.001).

The overall incidence of CRS did not differ significantly between the ibrutinib (74%) and no-ibrutinib (92%) groups. However, no patient who received concurrent ibrutinib developed grade &ge;3 CRS as compared with 25% of the no-ibrutinib group (P= .03).

&ldquo;Despite robust CAR T-cell expansion, levels of cytokines associated with severe CRS were lower in the concurrent ibrutinib cohort,&rdquo; said Gauthier.

Rates of treatment-associated neurotoxicity were similar (32% vs 42%) as were rate of grade &ge;3 neurotoxicity (26% vs 29%). One fatal adverse event occurred in each group.

Looking ahead, Gauthier suggested that cardiac monitoring for arrhythmias might warrant consideration for patients who develop CRS while on ibrutinib. Enrollment has already begun in a follow-up prospective study of JCAR014, including a phase I evaluation of concurrent ibrutinib.

References:

1. Gauthier J, Hirayama AV, Hay KA, et al. Efficacy and toxicity of CD19-specific chimeric antigen receptor T cells alone or in combination with ibrutinib for relapsed and/or refractory CLL Presented at: TCT Meetings; February 20-24, 2019; Houston, TX. Abstract 10.
2. Turtle CJ, Hay KA, Hanafi LA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-Specific chimeric antigen receptor-modified T cells after failure of ibrutinib.J Clin Oncol. 2017;35(26):3010-3020. doi: 10.1200/JCO.2017.72.8519.