CAR T-Cell Therapy Augments Response to Ibrutinib in Chronic Lymphocytic Leukemia

Results with chimeric antigen receptor (CAR) T-cell therapy have been less robust in chronic lymphocytic leukemia (CLL) compared with B-cell acute lymphocytic leukemia and diffuse large B-cell lymphoma. Preliminary studies presented at ASH 2018 ­suggested that a strategy of using CAR T-cell therapy to augment the response to ibrutinib (Imbruvica) holds promise in patients with CLL.

This approach also appears to reduce the rate of cytokine release syndrome that can occur with CAR T-cell therapy. CAR T-cell therapy plus ibrutinib will be studied further in patients with CLL, the researchers said.

CTL019 Augmenting Suboptimal Response to Ibrutinib

Anti-CD19 CAR T-cell therapy (CTL019) was given to 20 patients with CLL who had a suboptimal response to 6 months or more of ibrutinib therapy. After infusion of CAR T-cell therapy, the complete response rate was 43%, and the bone marrow remission rate was 94%, including minimal residual disease (MRD) negativity in 78% of patients. Patients whose CLL did not respond to ibrutinib were not enrolled in this study.

“The takeaway message from this study is that this strategy has high efficacy that compares favorably with other studies of CAR T-cells in progressive CLL. In previous studies of CAR T-cell therapy in CLL, complete response rates ranged from 21% to 29%,” stated Saar I. Gill, MD, PhD, Physician and Assistant Professor of Medicine, Division of Hema­tology and Oncology, University of Pennsylvania, Philadelphia.

“We saw high response rates, higher bone marrow clearance, and durability of response. We see that more than 50% of patients are still MRD-negative at 12 months, which is the last follow-up,” Dr Gill added.

The median follow-up is now 18 months, and patients are continuing to be followed. The 20 patients who participated in the study had several disease relapses before enrollment, including 3 whose disease relapsed during previous CAR T-cell therapy. CD19 CAR T-­cells were successfully manufactured for all patients; all 19 patients received an infusion with CAR T-cell therapy.

A total of 5 patients received first-line ibrutinib therapy. Among the remaining 14 patients, the median number of previous therapies was 2 (range, 1-16). Seventeen of 19 patients had adverse prognostic markers, and 9 patients had enlarged lymph nodes at baseline.

During the study, patients continued to receive ibrutinib therapy, with no mandate to stop treatment.

“Cytokine release syndrome was frequent but mild to moderate and did not commonly require anti-cytokine therapy,” Dr Gill said. Overall, 18 of the 19 patients had cytokine release syndrome: 3 patients had grade 3 or 4 cytokine release syndrome; 15 patients had grade 1 to 2 cytokine release syndrome; and 2 patients received treatment with tocilizumab (Actemra) for cytokine release syndrome.

In total, 5 patients had encephalopathy (1 grade 4); 1 patient died on day 14 from cardiac arrhythmia during severe neurotoxicity. Overall, 49 grade 3 and 22 grade 4 adverse events were reported.

At the time of the ASH 2018 presentation, 18 of the 19 patients were alive, and 16 patients remained in morphologic and/or flow complete response at last follow-up.

Among the 18 evaluable patients, bone marrow responses showed morphologic complete response in 17 (94%); 14 patients were MRD-negative. At 12 months, among 11 evaluable patients, 10 were in morphologic complete response and 1 had morphologic relapse. Of 10 patients who had morphologic complete response, 3 had low MRD positivity and the rest remained MRD-negative.

Among 3 patients who had received treatment with murine CD19 CAR T-cells, 2 had MRD-negative complete response at 12 months and 1 patient had disease refractory to humanized CD19 CAR T-cell therapy.

At 3 months, 6 complete responses and 4 partial responses were reported, and 3 patients had stable disease.

Concurrent Ibrutinib and CAR T-Cell Therapy

Concurrent administration of ibrutinib with CD19 CAR T-cell therapy was feasible with high response rates and deep responses, according to a retrospective analysis of 43 patients with relapsed or refractory CLL who received treatment at the Fred Hutchinson Cancer Research Center in Seattle, WA.

The rate of grade 3 or 4 cytokine release syndrome events was higher with the combination of ibrutinib plus CAR T-cell therapy than what had been reported in previous CAR T-cell therapy studies. A prospective phase 1/2 study will explore this combination.

The “prognosis is poor in relapsed or refractory CLL patients despite currently available treatments, including chemotherapy and an anti-CD20 antibody and molecular pathway inhibitors, such as ibrutinib, idelalisib [Zy­delig], and venetoclax [Venclexta],” said lead investigator Jordan Gauthier, MD, Senior Fellow, Clinical Research Division, Fred Hutchinson Cancer ­Research Center.

“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,” Dr Gautheir added.

This retrospective analysis included 2 sequential cohorts of 43 patients with detectable CLL after ibrutinib therapy. The first cohort (N = 24) had no recent exposure to ibrutinib therapy and underwent leukapheresis, lymphodepletion, and then received a single infusion of CAR T-cell therapy. The second cohort of 19 patients received CAR T-cell therapy and concurrent ibrutinib. Baseline and disease characteristics were comparable between the 2 cohorts.

At 4 weeks, 41 patients were evaluated for response to treatment. The response rates were 83% in those given concurrent ibrutinib and CD19 CAR T-cell therapy compared with 65% in those who did not receive concurrent treatment.

No bone marrow disease, or MRD, was detectable by flow cytometry in 72% of patients who received concurrent therapy and 74% of patients who did not receive concurrent treatment. Using deep sequencing, 85% of patients who received concurrent treatment had MRD-negative status versus 50% of patients who did not receive concurrent treatment.

Better CD4-positive CAR T-cell expansion was observed in patients who received concurrent ibrutinib and CAR T-cell therapy. “This might improve responses,” Dr Gauthier suggested.

Lower rates of severe cytokine release syndrome were observed with concurrent therapy versus CAR T-cell therapy alone (0% and 25%, respectively). Severe neurotoxicity was reported in 26% and 29% of patients, respectively.

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