We know that CAR T-cells work pretty well for acute lymphoblastic leukaemia, work pretty well for non-Hodgkin lymphoma but the data for chronic lymphocytic leukaemia is not as robust. Some groups have actually shown some timid results with CAR T-cells and CLL. We’ve actually reported in the JCO last year pretty convincing results with using CD19 directed CAR T-cells for CLL, particularly in patients who progress or relapse or are refractory to a drug called ibrutinib. In this subset of patients we actually observed very durable responses but still we had a feeling that we had to go forward and potentially improve the response rates. There’s actually some preclinical and clinical data that suggests that combining ibrutinib with CAR T-cells may help mitigating toxicity, potentially improving the functionality of the CAR T-cells and, in addition, in some patients when you discontinue the ibrutinib just before CAR T-cells you can observe a rapid progression of tumour which we call a tumour flare which also may be detrimental for CAR T-cell therapy.
What did you do to investigate this?
What we did, this is not a prospective head-to-head comparison but we compared two retrospective cohorts that were sequentially treated on phase I/II trials. What we did, we had a group that we called the no ibrutinib group, there’s 24 patients in this group, and the common denominator is that all of those patients had interrupted ibrutinib at some point prior to leukapheresis or prior to lymphodepletion. In contrast, the ibrutinib group which are we interested in, all those patients were scheduled to start ibrutinib at least two weeks prior to leukapheresis and up to three months after infusions of CAR T-cells.
What did you find?
We found that we managed to obtain very high response rates of above 80% using the iwCLL 2018 criteria and this is four weeks after CAR T-cells, so very early on, compared to 65% in the control group that did not receive ibrutinib in combination. Obviously it’s hard to have statistical power in such a small study but we still find that very encouraging. In addition to these high rates of response we observed as well very deep responses using either flow cytometry or IGH sequencing. So these are the key findings when it comes to efficacy.
What is the potential impact of this research?
There’s one key finding I can maybe talk about which is the toxicity. Another important finding was that no patients in the ibrutinib group developed the severe form of cytokine release syndrome defined as a grade 3 or above using the Lee consensus criteria, so compared to about 20% of patients in the control group who developed the severe form of the toxicity. We find that very interesting, we don’t know exactly what’s the biology and what I will show tomorrow morning is that we observed that some cytokines that are strongly associated with the severe form of cytokine release syndrome were significantly reduced when we combined ibrutinib with CAR T-cells.
Do you have future plans to expand this research?
Juno and Celgene are considering expanding this analysis and there is currently a trial that will actually be presented tomorrow morning. One of the questions that is asked is to compare in a prospective, in a larger study, to investigate the impact of ibrutinib combined with CAR T-cells.
What is the take home message?
Ibrutinib combined with CAR T-cells led to high rates of response using the iwCLL criteria, to reduce the severe form of toxicity that is sometimes observed after CAR T-cell therapy.