Researchers are combining chimeric antigen receptor (CAR) T-cell therapy with ibrutinib (Imbruvica) as a means of augmenting and deepening responses in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Two pilot studies presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition suggest this approach may be effective with lower rates of cytokine-release syndrome than typically seen with CAR T-cell therapy.
University of Pennsylvania Study
A pilot study at the University of Pennsylvania explored treatment with humanized anti-CD19 CAR T cells in 20 patients with CLL who responded to ibrutinib but did not achieve a complete response after at least 6 months of therapy with the Bruton tyrosine kinase inhibitor. The study did not include patients who failed to respond to ibrutinib therapy. After CAR T-cell infusion, the complete response rate was 43% and the bone marrow remission rate was 94%, including minimal residual disease negativity in 78%.1
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.— Saar I. Gill, MD, PhD
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“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 lead author Saar I. Gill, MD, PhD, of the 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 minimal residual disease–negative at 12-month follow-up.”
CD19-directed CAR T-cell manufacturing was successful for all patients. Of the 20 patients enrolled, 19 received CAR T-cell infusions (1 patient did not due to newly diagnosed adenocarcinoma). Fifteen patients were male, and the median age was 62 years (range = 42–76 years).
Five patients were receiving first-line ibrutinib. Among the remaining 14 patients, the median number of prior therapies was 2 (range = 1–16). A total of 17 patients had adverse prognostic markers; 11 had chromosome 17p abnormalities or TP53, and 3 had abnormalities of chromosome 11q22 or ATM. All patients had bone marrow involvement. Nine patients had enlarged nodes at baseline.
All patients received at least two doses of CAR T cells. During the study, patients continued to receive ibrutinib, and there was no mandate to stop this treatment.
“Cytokine-release syndrome was frequent but mild to moderate and did not commonly require anticytokine therapy,” Dr. Gill said. Of the 19 patients who received CAR T cells, 18 experienced cytokine-release syndrome—3 with Penn grade 3 or 4, and 15 with Penn grade 1 or 2. Two patients were treated with tocilizumab (Actemra). Five patients developed encephalopathy (1 case was grade 4). One patient died on day 14 due to cardiac arrhythmia during severe neurotoxicity. In total, 49 grade 3 and 22 grade 4 toxicities were reported.
At the time of the ASH meeting, 18 (95%) of the 19 patients were alive, and 16 of 18 remained in morphologic and/or flow cytometry–assessed complete response at last follow-up. The median follow-up was 18.5 months.
Among 18 evaluable patients, marrow responses showed morphologic complete response in 17 (94%); of these, 15 had no minimal residual disease; 14 of 18 were minimal residual disease–negative. At 12 months, among 11 evaluable patients, 10 were in morphologic complete response (91%) and 1 showed morphologic relapse. Of the 10 patients in morphologic complete response, 3 showed low minimal residual disease positivity and the rest remained minimal residual disease–negative. Of 3 patients previously treated with murine CD19 CAR T cells, 2 were in minimal residual disease–negative complete response at 12 months and 1 was refractory to humanized CD19 CAR T cells.
Among 14 patients evaluable by the -International Workshop on CLL criteria at 3 months, 6 patients had complete responses, 4 had partial responses, 3 had stable disease, and 1 had progressive disease.
Fred Hutchinson Cancer Research Center Study
In a retrospective analysis of 43 patients with relapsed or refractory CLL treated at Fred Hutchinson Cancer Research Center in Seattle, concurrent administration of ibrutinib with CD19-specific CAR T cells was feasible in most patients, achieving high response rates and deep responses.2 The study showed lower rates of grade 3 or higher cytokine-release syndrome than has been seen in previous studies. Based on these results, a prospective phase I/II study, called TRANSCEND-CLL-004 (ClinicalTrials.gov identifier NCT03331198) is currently ongoing.
Jordan Gauthier, MD, MSc
“In most cases, CLL is a slow-growing cancer involving B cells that express the CD19 antigen, and it is the most common leukemia in adults. Prognosis is poor in patients with relapsed or refractory disease despite currently available treatments, including chemotherapy, anti-CD20 antibodies, and molecular pathway inhibitors such as ibrutinib, idelalisib (Zydelig), and venetoclax (Venclexta),” explained lead author Jordan Gauthier, MD, MSc, of Fred Hutchinson Cancer Research Center in Seattle.
Based on the previous observation that CAR T-cell therapy can achieve durable responses in patients with relapsed or refractory CLL who had treatment failure on ibrutinib, Dr. Gauthier and colleagues hypothesized that concurrent administration of ibrutinib with CAR T cells might be beneficial in this setting, preventing disease flare and improving CAR T-cell function, while decreasing CAR T-cell–related toxicity, including cytokine-release syndrome. They conducted a retrospective analysis of 2 sequential cohorts totaling 43 patients with detectable disease after ibrutinib therapy.
The first cohort (n = 24) had discontinued ibrutinib, prior to leukapheresis or lymphodepletion, and then received a single CAR T-cell infusion. In the second cohort (n = 19), patients were treated concurrently with ibrutinib through leukapheresis, lymphodepletion, and CAR T-cell therapy. Most patients and disease characteristics were comparable between the two cohorts.
At 4 weeks, 41 patients were evaluable for response. Response rates were 83% in those receiving concurrent ibrutinib and 65% in those who did not have concurrent ibrutinib. Minimal residual disease was undetectable in the bone marrow on flow cytometry in 72% and 74%, respectively; by deep sequencing, minimal residual disease–negative status was found in 85% and 50% of patients with no marrow disease by flow cytometry, respectively.
“Better CD4-positive CAR T-cell expansion was observed in patients receiving concurrent ibrutinib. This might improve responses,” Dr. Gauthier suggested.
Lower rates of any-grade cytokine-release syndrome were observed with concurrent ibrutinib vs no ibrutinib: 74% and 92%, respectively. Rates of severe cytokine-release syndrome were 0% and 25%, respectively. Neurotoxicity of any grade was reported in 32% of those on concurrent ibrutinib vs 42% of the no-ibrutinib group; severe neurotoxicity was reported in 26% and 29%, respectively.
“All cases of grade 1 to 4 cytokine-release syndrome and neurotoxicity were reversible,” Dr. Gauthier said. ■
DISCLOSURE: Dr. Gill has equity ownership with Carisma Therapeutics, is a consultant/board member/advisor for Extellia, and has received research funding from Novartis. Dr. Gauthier reported no conflicts of interest.
1. Gill SI, Vides V, Frey NV, et al: Prospective clinical trial of anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia shows a high response rate. 2018 ASH Annual Meeting & Exposition. Abstract 298. Presented December 2, 2018.
2. Gauthier J, Hiramaya AV, Hay KA, et al: Comparison of efficacy and toxicity of CD19-specific chimeric antigen receptor T-cells alone or in combination with ibrutinib for relapsed and/or refractory CLL. 2018 ASH Annual Meeting & Exposition. Abstract 299. Presented December 2, 2018.
Joseph C. Alvarnas, MD
Commenting on the ibrutinib (Imbruvica)/chimeric antigen receptor (CAR) T-cell approach at a press conference, Joseph C. Alvarnas, MD, said: “Patients with CLL do not do as well on CAR T-cell therapy as those with B-cell acute lymphoblastic leukemia, and by combining ...!-->!-->