Jordan Gauthier, MD, MSc
Retrospective data have demonstrated that concurrent treatment with ibrutinib (Imbruvica) and the chimeric antigen receptor (CAR) T-cell product JCAR014 elicits high responses and lower rates of severe toxicity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). However, prospective trials need to be conducted to confirm these findings, explained Jordan Gauthier, MD, MSc.
In the retrospective phase I/II trial, the combination demonstrated an overall response rate of 83% in patients with relapsed or refractory disease. Additionally, there was also higher in vivo expansion of CD4-positive CAR T cells and lower rates of severe toxicity versus outcomes for a similar group of patients who received JCAR014 without ibrutinib.
While CAR T cells have been successful in acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL), there has previously been less promise in CLL, said Gauthier, who led the retrospective trial.
In an interview with OncLive
, Gauthier, a senior clinical research fellow at Fred Hutchinson Cancer Research Center, discussed these results and where CAR T-cell research is headed for patients with CLL.
OncLive: Could you provide some background on this phase I/II trial?
: We’ve seen some very impressive results with CAR T cells in ALL and NHL, particularly with aggressive lymphoma. The results in CLL [are] not as good. We have, nonetheless, demonstrated that by using a CD19-specific CAR T-cell product, JCAR014, we could achieve some durable responses in patients refractory or having relapsed after ibrutinib. We tried to go a little further, and there is actually a body of data, preclinical and clinical data, that suggest ibrutinib and CAR T cells could be beneficial. Why is that? It could be beneficial because sometimes you stop ibrutinib just before the infusion of CAR T cells or before full depletion. If patients have what is called tumor flare, the lymph nodes get much bigger, and there’s rapid tumor progression. By continuing ibrutinib, it might be beneficial.
The other thing is that there is evidence that ibrutinib helps the CLL cells migrate from the lymph nodes into the peripheral blood, which potentially could make it easier for CAR T cells to cure them. The last thing is that there is actually evidence that ibrutinib might improve the functionality of the CAR T cells and improve the antitumor effect of the CAR T cells.
Last, there’s also evidence in a marine model that ibrutinib may prevent cytokine release syndrome (CRS), a kind of toxicity we see often after CAR T-cell therapy.
How was this trial designed?
This is a retrospective analysis of 2 sequentially treated cohorts on a phase I/II study. The first cohort, which we call the no-ibrutinib cohort, was 24 patients, and all of them had interrupted ibrutinib at some point prior to leukapheresis or prior to lymphodepletion. In contrast, the other cohort that we call the concurrent ibrutinib cohort consisted of 19 patients, and all of them were scheduled to receive ibrutinib at least 2 weeks prior to leukapheresis up to 3 months after the infusion of CAR T cells.
What were the findings?
The key finding is that we observed high rates of response by the 2018 International Workshop on CLL criteria. Eighty-three percent of patients in the concurrent ibrutinib group responded versus 65% in the no ibrutinib cohort, so [there were] high rates of response, and that’s after 4 weeks of CAR T-cell infusion. Next, we also noted very deep responses by using flow cytometry and deep sequencing. In particular, in patients who had no disease detectable by flow, 80% of them had no disease detectable by deep sequencing, so these were very deep responses.