Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure

Abstract

We previously reported durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients treated with CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell immunotherapy after ibrutinib failure. Because preclinical studies showed that ibrutinib could improve CAR T cell-antitumor efficacy and reduce cytokine release syndrome (CRS), we conducted a pilot study to evaluate the safety and feasibility of administering ibrutinib concurrently with CD19 CAR T-cell immunotherapy. Nineteen CLL patients were included. The median number of prior therapies was 5, and 17 patients (89%) had high-risk cytogenetics (17p deletion and/or complex karyotype). Ibrutinib was scheduled to begin ≥2 weeks before leukapheresis and continue for ≥3 months after CAR T-cell infusion. CD19 CAR T-cell therapy with concurrent ibrutinib was well tolerated; 13 patients (68%) received ibrutinib as planned without dose reduction. The 4-week overall response rate using 2018 International Workshop on CLL (iwCLL) criteria was 83%, and 61% achieved a minimal residual disease (MRD)-negative marrow response by IGH sequencing. In this subset, the 1-year overall survival and progression-free survival (PFS) probabilities were 86% and 59%, respectively. Compared with CLL patients treated with CAR T cells without ibrutinib, CAR T cells with concurrent ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines, despite equivalent in vivo CAR T-cell expansion. The 1-year PFS probabilities in all evaluable patients were 38% and 50% after CD19 CAR T-cell therapy, with and without concurrent ibrutinib, respectively (P = .91). CD19 CAR T cells with concurrent ibrutinib for R/R CLL were well tolerated, with low CRS severity, and led to high rates of MRD-negative response by IGH sequencing.

Conflict of interest statement

Conflict-of-interest disclosure: K.A.H. has served on advisory boards for Celgene. J.L. and D.L. are employees of and have equity ownership in Juno Therapeutics, a Bristol-Myers Squibb Company. M.S. has received research funding from Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, AbbVie, TG Therapeutics, Beigene, Acerta Pharma, and Merck and has served on advisory boards for AbbVie, Genentech, Astra Zeneca, Sound Biologics, Verastem, ADC Therapeutics, and Atara Biotherapeutics. S.R.R. holds equity ownership in, has served as an advisor for, and has patents licensed to Juno Therapeutics, a Bristol-Myers Squibb Company; is a founder of Lyell Immunopharma; and has served on advisory boards for Adaptive Biotechnologies and Nohla. D.G.M. has received research funding from Kite Pharma, Juno Therapeutics, a Bristol-Myers Squibb Company, and Celgene and has received honoraria for participation in advisory board meetings from Kite Pharma, Gilead, Genentech, Novartis, and Eureka. C.J.T. receives research funding from Juno Therapeutics, a Bristol-Myers Squibb Company, and Nektar Therapeutics; has patents pending and licensed to Juno Therapeutics, a Celgene company; has served on advisory boards and has equity ownership in Caribou Biosciences, Eureka Therapeutics, Precision Biosciences, ArsenalBio, and Myeloid Therapeutics; and has served on advisory boards for Aptevo, Juno Therapeutics, a Bristol-Myers Squibb Company, Kite, a Gilead Company, Humanigen, Nektar Therapeutics, Novartis, T-CURX, Allogene, AstraZeneca, and PACT Pharma. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Responses to CD19 CAR T cells with concurrent ibrutinib were associated with better in vivo expansion of CAR T cells. CAR T-cell transgene peak in blood was measured by quantitative polymerase chain reaction (FLAP-EF1α copies per microgram of genomic DNA in blood) according to response by the 2018 iwCLL criteria (A) and marrow response by flow cytometry (sensitivity 10−4) (B). Bold horizontal lines represent the median, the box represents the interquartile range (IQR), and the vertical lines represent quartiles ± 1.5 × IQR. Data are from patients evaluable for response (n = 18). The P values were calculated using the Wilcoxon rank-sum test (2-sided).

Figure 2.

OS and PFS probabilities after CD19 CAR T-cell immunotherapy with concurrent ibrutinib. OS and PFS probabilities in CLL patients according to response by the 2018 iwCLL criteria (A-B) and marrow response by IGH sequencing (sensitivity 10−6) (C-D). Data are from patients evaluable for response (n = 18). (C-D) Data from patients who achieved MRD-negative marrow response by flow cytometry (n = 13), categorized according to the presence (n = 2) or absence (n = 11) of the residual malignant clone in the marrow by IGH sequencing. The solid lines represent the Kaplan-Meier estimates; the dashed lines represent 95% CIs. The P values were calculated using the log-rank test.

Figure 3.

Lower CRS severity in the Con-ibr cohort. CRS grade according to the 2014 Lee et al consensus criteria. Bold horizontal lines represent the median, the box represents the interquartile range (IQR), and the vertical lines represent quartiles ± 1.5 × IQR. The P values were calculated using the Wilcoxon rank-sum test (2-sided).

Figure 4.

Robust CAR T-cell expansion in blood in the Con-ibr cohort. CD8+ (A) and CD4+ (B) CAR T-cell kinetics in blood between the day of CAR T-cell infusion and day 30. The bold curves are polynomial regression lines using the LOESS (locally estimated scatterplot smoothing) method, and the shaded areas show the 95% CIs of the estimates. CD8+ (C) and CD4+ (D) CAR T-cell peak counts in blood. CD8+ (E) and CD4+ (F) CAR T-cell peak counts in patients stratified by CRS grade, according to Lee et al consensus criteria. The P values were calculated using the Wilcoxon rank-sum test (2-sided). Bold horizontal lines represent the median, the box represents the IQR, and the vertical lines represent quartiles ± 1.5 × IQR. The figure shows data from patients treated with 2 × 106 CAR T cells per kilogram and Cy/Flu lymphodepletion (Con-ibr, n = 18; No-ibr, n = 18). Two patients who died before the peak of CAR T-cell expansion were excluded.

Figure 5.

Greater numbers of CAR T cells were associated with lower serum concentrations of cytokines strongly correlated with severity. Peak serum MCP-1 (A), soluble IL-2Rα (B), and IL-6 (C) concentrations (log10 pg/µL) in patients who received 2 × 106 CAR T cells per kilogram and Cy/Flu lymphodepletion (Con-ibr, n = 18; No-ibr, n = 18). Bold horizontal lines represent the median, the box represents the IQR, and the vertical lines represent quartiles ± 1.5 × IQR. Two patients who died before the peak of CAR T-cell expansion were excluded. The P values were calculated using the Wilcoxon rank-sum test (2-sided) and were adjusted for multiple comparisons using the Benjamini-Hochberg procedure. No-ibr, ibrutinib discontinued prior to lymphodepletion.