Ibrutinib/CAR T Cell Combo Active in CLL

Jordan Gauthier, MD, MSc

Concurrent treatment with ibrutinib (Imbruvica) and the CD19-targeted chimeric antigen receptor (CAR) T-cell therapy JCAR014 was well tolerated and led to an overall response rate (ORR) of 83% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to retrospective phase I/II findings presented at the 60th American Society of Hematology Annual Meeting.¹

The combination approach showed that there was also higher in vivo expansion of CD4-positive CAR T cells and lower rates of severe toxicity, specifically rates of grade ≥3 cytokine release syndrome (CRS), compared with outcomes for a similar group of patients who received JCAR014 without ibrutinib.

“In this retrospective analysis of 43 CLL patients with refractory or relapsed disease in 2 sequential cohorts, the concurrent administration of ibrutinib with CD19-specific CAR T cells was feasible in most patients, induced high responses and deep responses early on, and was associated with higher in vivo expansion of CD4 CAR T cells and lower rates of severe toxicity,” said lead study author Jordan Gauthier, MD, MSc, a senior fellow in the Clinical Research Division at Fred Hutchinson Cancer Research Center in Seattle, Washington, who presented these data at the meeting.

Previous data have shown that, when administered after progression on ibrutinib, JCAR014 elicited durable responses in relapsed/refractory patients with CLL.² However, investigators hypothesized that administration of ibrutinib throughout leukapheresis, lymphodepletion, and CAR T-cell therapy could prevent tumor flare following ibrutinib withdrawal, mobilize disease into the blood from the lymph nodes, improve CAR T-cell function, and decrease CAR T-cell—related toxicity, such as CRS.

In this phase I/II study, 43 evaluable patients with relapsed/refractory CLL were treated with cyclophosphamide and fludarabine lymphodepletion followed by JCAR014 at 2 x 10⁶/kg.

To be eligible for enrollment, patients must have received first-line therapy, failed combination chemotherapy and anti-CD20 therapy or been ineligible for such treatment, and had persistent disease following ibrutinib. The cohort of patients with CLL from the prior study (n = 24) were used as a retrospective comparison against the cohort who received concurrent ibrutinib; their ibrutinib treatment had been discontinued prior to the start of CAR T-cell infusion.

In the second cohort, 19 patients received the BTK inhibitor at 420 mg daily from at least 2 weeks prior to leukapheresis until at least 3 months following CAR T-cell infusion. Dose reduction was permitted for toxicity. Responses were evaluated according to 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, CRS was graded by consensus criteria, and neurotoxicity and additional adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events v4.03.

Although this was not a head-to-head comparison, Gauthier said that most patient and disease characteristics were comparable between the 2 cohorts. The median age in the ibrutinib and no-ibrutinib cohorts were 65 and 61 years, respectively. The number of prior therapies given in each cohort was 5. Seven patients from both cohorts had Richter’s transformation, 29 had a complex karyotype, and 25 patients had a chromosome 17p deletion. Five patients previously underwent hematopoietic cell transplantation.

Prior disease progression was reported in 16 and 18 patients in the ibrutinib and no-ibrutinib cohorts, respectively; additionally, 1 patient in each cohort had prior intolerance to ibrutinib. Time to intolerance or ibrutinib failure prior to CAR T-cell therapy was longer and the pre-leukapheresis lactate dehydrogenase level was lower with ibrutinib versus no ibrutinib, and the median follow-up in responders was 98 and 764 days, respectively.

Data showed that the ORRs were 83% and 65% in the ibrutinib and no-ibrutinib cohorts, respectively. In those with no marrow disease detected via flow cytometry, the ORR was 72% in those who received ibrutinib versus 74% without ibrutinib. However, in patients with no marrow disease detectable by deep sequencing, the ORRs were 85% versus 50%, respectively.

Data also showed that there was better in vivo CD4-positive CAR T-cell expansion in those who received concurrent ibrutinib (P = .03) and was comparable with CD8-positive T cells (P = .20).

Results showed that combination therapy with ibrutinib and JCAR014 was well tolerated in most patients. Dose reduction or discontinuation of ibrutinib occurred in 6 patients (32%) at a median of 21 days following JCAR014 infusion.

All-grade CRS and neurotoxicity were reported in 74% (n = 14) and 32% (n = 6), respectively, of patients receiving concurrent ibrutinib versus 92% (n = 22) and 42% (n = 10) in those who did not receive the BTK inhibitor (P = .21; P = .42). Severe cases of CRS occurred in 0% of patients on the concurrent ibrutinib cohort and in 25% (n = 6) of those not treated with ibrutinib (P = .03).

There was 1 death in each cohort; 1 was presumed as cardiac arrhythmia in the ibrutinib cohort and CRS/neurotoxicity in the no-ibrutinib cohort. “To our knowledge, these are the most encouraging results that have been seen to date in humans with a combination of CAR T cells and a targeted agent,” said Gauthier. “While the CAR T cells expanded robustly in both groups and led to high rates of response, we did not observe a single case of severe CRS in patients receiving ibrutinib during CAR T therapy.”

These findings must be validated in a larger, prospective trial, Gauthier concluded. In the ongoing, prospective phase I/II TRANSCEND-CLL 17004 study (NCT03331198), investigators will evaluate the safety and efficacy of the CD19-targeted JCAR017 CAR T-cell therapy alone and in combination with ibrutinib in patients with relapsed or refractory CLL or small lymphocytic lymphoma.

Ibrutinib was approved by the FDA as a frontline treatment for patients with CLL in March 2016; prior to that, it was approved for previously treated patients.

References

1. 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, California. Abstract 299.
2. Turtle CJ, Hay KA, Hanafi LA, et al. Durable molecular remission 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.

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