Ibrutinib/JCAR014 Combo Shows Potential in Relapsed/Refractory CLL

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.

OncLive: Could you provide some background on this phase I/II 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.Gauthier: 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.

How was this trial designed?

What were the findings?

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.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.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.

What are the implications of these findings?

Are there any questions that came out of this research that still need to be answered?

What is the main takeaway of these data?

The last key finding is that in the concurrent ibrutinib cohort, not a single patient developed a severe form of CRS.This is retrospective data; this is not a head to head respective comparison, so it’s difficult to extrapolate too much, but we are hoping that we can confirm those findings. There is actually an ongoing trial which is called the TRANSCEND trial in CLL that will try to address that question with bigger numbers of patients, the question being, “Is ibrutinib beneficial combined with CAR T-cell therapy in CLL?”Yes, we see differences, but we don’t know why these differences happen. We’d like to understand more of the biology underlying these findings. In particular, we looked at the cytokines that usually correlate with severe CRS. We observed that the cytokines are much lower levels in the concurrent ibrutinib cohort, which may provide a bit of a hint as to what is going on, but much more research should be done. Up to now, the short answer is that the exact mechanisms are unknown.Obviously, it’s a bit harder to find room for CAR T cells because CAR T-cell therapies are complex. Venetoclax (Venclexta)-based combinations can lead to very good results, deep responses, and durable responses as well, particularly when administered earlier on in the course of the disease. With CAR T cells, these are still very early data, we need more follow-up, and hopefully we can find exactly where CAR T-cell therapy stands for CLL. This is a little too early now I think.

Are there any other strategies besides CAR T-cell therapy in CLL that you’re particularly interested in?

There’s [also] 1 thing in the biology, 1 of the key findings that we found in patients in the concurrent ibrutinib group had significantly better expansion of the CD4-positive CAR T cells, and we think that may partially explain why we saw higher rates of response as well.Just as I mentioned, there’s a little bit [of interest] in this new agent, in particular combining venetoclax and ibrutinib. This combination therapy seems very promising, in particular in high-risk patients when administered as a first-line therapy. It’s been shown that some of these responses seem durable as well.

Gauthier J, Hirayama AV, Hay KA, et al. Efficacy and toxicity of CD19 CAR-T cells alone or in combination with ibrutinib for relapsed and/or refractory CLL. Presented at 60th American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 299.