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Ibrutinib plus CD19-specific CAR T-cell therapy may benefit patients with relapsed or refractory CLL
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SAN DIEGO — Administration of ibrutinib beginning 2 weeks prior to leukapheresis and continuing until 3 months after CD19-specific chimeric antigen receptor T-cell therapy appeared well tolerated among patients with relapsed or refractory chronic lymphocytic leukemia, according to retrospective study results presented at ASH Annual Meeting and Exposition.
The therapeutic approach resulted in high response rates and deep responses, and it also may reduce incidence of severe cytokine release syndrome, results showed.
“The next step is to hopefully validate these findings in a prospective phase1/phase 2 study,” Jordan Gauthier, MD, senior immunotherapy fellow at Fred Hutchinson Cancer Research Center, said during a press conference.
Gauthier and colleagues conducted a prior study that showed patients with relapsed or refractory CLL who failed ibrutinib (Imbruvica; Janssen, Pharmacyclics) achieved durable responses to JCAR014 (Juno Therapeutics), a CD19-specific CAR T-cell therapy.
However, in that study, ibrutinib — a Bruton tyrosine kinase inhibitor — was not administered during CAR T-cell immunotherapy.
Gauthier and colleagues hypothesized that continuation of ibrutinib through leukapheresis, lymphodepletion and CAR T-cell therapy could prevent tumor progression after ibrutinib withdrawal, improve CAR T-cell function and reduce incidence of cytokine release syndrome, according to study background.
Gauthier and colleagues conducted a phase 1/phase 2 study with two sequential cohorts of patients with relapsed/refractory CLL.
In one cohort, 19 patients received cyclophosphamide and fludarabine lymphodepletion followed by JCAR014 dosed at 2 x 106 CAR T cells/kg.
In the other cohort, 23 patients received cyclophosphamide and fludarabine lymphodepletion plus JCAR at the same dose with concurrent ibrutinib. Ibrutinib was dosed at 420 mg daily from at least 2 weeks prior to leukapheresis until at least 3 months after CAR T-cell infusion.
Study protocol allowed for dose reduction due to toxicity.
The ibrutinib and no-ibrutinib groups were balanced with regard to median age (65 years vs. 61 years), sex (men, 63% vs. 63%), progression on prior ibrutinib (94% vs. 95%), ECOG performance status, Richter’s transformation, complex karyotype, 17p deletion, receipt of prior hematopoietic cell transplant and other factors. One patient in each cohort was intolerant to prior ibrutinib.
Concurrent ibrutinib with cyclophosphamide, fludarabine and JCAR014 appeared well tolerated among most patients.
In the concurrent ibrutinib cohort, 13 (68%) of 19 patients received ibrutinib as planned without discontinuation.
Rates of grade 1 or worse cytokine release syndrome were similar between the ibrutinib and no-ibrutinib groups (76% vs. 89%). However, patients who received ibrutinib were less likely to experience grade 3 or worse cytokine release syndrome (0% vs. 25%; P = .03). Serum peak interleukin-6 (P = .03), soluble TIM-3 (P = .004), MCP-1 (P < .001) and soluble interleukin-2 receptor alpha (P < .001) concentrations also were lower in the ibrutinib cohort.
Researchers reported significantly higher peaks of CD4-positive CAR T-cell counts in the ibrutinib group.
In the ibrutinib group, one patient with grade 2 cytokine release syndrome developed fatal presumed cardiac arrhythmia, and one patient developed a subdural hematoma in the setting of trauma and thrombocytopenia. Researchers reported no difference in incidence of grade 3 or worse cytopenias.
Administration of concurrent ibrutinib did not affect neurotoxicity frequency or severity.
Sixteen patients (95%) who received concurrent ibrutinib and 23patients (96%) who did not completed response assessment.
Although they observed high rates of response in both groups, researchers reported no statistically significant difference between the ibrutinib and no-ibrutinib groups with regard to percentage of patients who achieved complete or partial remission (83% vs. 65%) or percentage of those with lymph node disease prior to treatment who achieved complete or partial remission (71% vs. 64%).
In addition, the percentage of patients with pretreatment bone marrow disease who had no disease by flow cytometry after CAR T-cell immunotherapy was comparable between the ibrutinib and no-ibrutinib groups (72% vs. 74%).
Among patients who had no disease in the bone marrow by flow cytometry after CAR T-cell therapy, the percentage who achieved minimal residual disease-negative response at 4 weeks by deep sequencing was higher in the ibruitinib group than the no-ibrutinib group (85% vs. 50%), although researchers could not reject the null hypothesis at an alpha level of .05.
Multivariable analysis showed that higher peak of CAR T cells and lower maximum standard uptake value prior to lymphodepletion were associated with greater probability of response by International Working Group on CLL criteria. – by Mark Leiser
Reference:
Gauthier J, et al. Abstract 299. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures : Gauthier reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.