New Data on CAR T-Cell Therapy in Hematologic Malignancies

Chimeric antigen receptor modified (CAR) T cells have emerged in recent years as a novel and highly effective treatment option for patients with different hematologic malignancies, including diffuse large B-cell lymphoma (DLBCL), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL). At the 2018 American Society for Hematology (ASH) Annual Meeting, new findings from several trials evaluating CAR T cells in these diseases were presented, including efficacy and safety with longer follow-up and the potential of treatment strategies combining CAR T cells with other therapies.

The CD19-targeting CAR T-cell tisagenlecleucel was the first CAR T-cell therapy approved in the United States. Long-term follow-up of two studies evaluating tisagenlecleucel in DLBCL and ALL showed durable responses. In the international phase II JULIET trial (Abstract 1684) involving adult, heavily-pretreated patients with relapsed or refractory DLBCL, tisagenlecleucel was associated with sustained high and durable objective response rates (ORR) at 19 months of follow-up. The ORR in these patients was 54%, including an impressive 40% rate of complete remission. ORR was consistent across prognostic subgroups and median duration of response in responders was not reached. Importantly, 54% of patients who initially achieved a partial response had converted to complete response with longer follow-up. Median overall survival (OS) among patients who received an infusion was 12 months and was not reached for those with complete response. Results from this study were simultaneously published in The New England Journal of Medicine. Similarly, results from the ELIANA trial (Abstract 895) in pediatric/young adult patients with ALL showed durable responses with high rates of OS and relapse-free survival (RFS) after an additional 11 months follow-up. In this population, the 18-month RFS and OS rates were 66% and 70%, respectively. Of note, in both studies there were no new safety findings with longer follow-up.

Axicabtagene ciloleucel (axi-cel), a second FDA-approved CD19-targeting CAR T-cell therapy, is being evaluated in ALL and DLBCL in the ZUMA clinical trial program. Updated results from the phase I ZUMA-3 trial presented at the ASH meeting (Abstract 897) showed that 78% of adult patients with relapsed/refractory ALL treated with single axi-cel infusion achieved undetectable minimal residual disease (MRD), an outcome associated with low risk of relapse and high long-term survival. Likewise, a 2-year follow-up from the phase I/II ZUMA-1 trial of 101 patients with refractory DLBCL (Abstract 2967) showed that axi-cel therapy yielded an 83% ORR, including complete response in 58% of patients. At a median follow-up of 27.1 months, 39% of responses are ongoing, and the median OS has not yet been reached. Median progression-free survival (PFS) was 5.9 months. These results were published in Lancet Oncology . In addition, ‘’real world’’ results from 274 patients that received axi-cel after its FDA approval mirror response rates reported in ZUMA-1 trial (Abstract 91) .

While CAR T-cells are highly effective in inducing durable responses, many patients with B-cell ALL will eventually relapse, despite initial remission and strategies needed to improve long-term outcomes. In the phase I/II PLAT-02 trial, treatment with the CD19-targeted CAR T-cell ScRI-CAR19v1 was associated with a 93% rate of MRD-negative CR at 21 days postinfusion and 1-year leukemia-free survival (LFS) of 76%. A retrospective analysis of this trial evaluated the impact of hematopoietic cell transplant (HCT) following CAR T-cell treatment in patients who sustained leukemic remission for more than 63 days following CAR T-cell therapy (Abstract 967). Patients who received HCT following CAR T-cell treatment had improved LFS compared to those who did not receive HCT (P = .01). It appears that patients with history of previous HCT did not benefit from second transplant post CAR T-cell therapy.

Finally, two smaller studies presented during the ASH meeting showed promising results for CAR T cells in combination with other treatments. In a phase I/II trial including 43 patients with relapsed/refractory CLL treated in two sequential cohorts (ibrutinib and no ibrutinib), concurrent administration of ibrutinib with CD19 CAR T-cell therapy (JCAR014) resulted in an ORR of 83%, compared to 56% in the cohort of patients not receiving ibrutinib (Abstract 299). In addition, responses in the ibrutinib cohort were deeper, with 85% having undetectable disease by deep sequencing. Interestingly, patients receiving the ibrutinib combination had lower rates of serious adverse events (AEs). Of note, there was no grade ≥3 cytokine release syndrome (CRS) in patients receiving ibrutinib, compared to 25% in the cohort not receiving ibrutinib.  A second trial (Abstract 556) evaluated the combination of a PD-1 inhibitior with a CD19 CAR T cell (CTL119) in 14 heavily pretreated pediatric patients, 13 with relapsed B-cell ALL and 1 with lymphoblastic lymphoma. The combination demonstrated clinical activity, with signs of CAR T- cell proliferation and B-cell aplasia seen following treatment. Overall, half of the patients maintained partial or complete responses. Importantly, immune-associated AEs were rare and tolerable and CRS symptoms occurred in only 3 of 14 patients treated with this combination. Both of these small, nonrandomized trials show promising outcomes for CAR T-cells in combination with other therapies and support further investigation of CAR T-cell–based combinations in the future.

For more information about these and other studies covered during the 2018 ASH meeting, please visit prIME Oncology’s Virtual Poster Session in Hematology and prIME Clinical Updates.

Schuster SJ, et al. Blood. 2018;132: Abstract 1684.

Grupp SA, et al. Blood. 2018;132: Abstract 895.

Wierda WG, et al. Blood. 2018;132: Abstract 897.

Neelapu SS, et al. Blood. 2018;132: Abstract 2967.

Nastoupil LJ, et al. Blood. 2018;132: Abstract 91.

Summers C, et al. Blood. 2018;132: Abstract 967.

Gauthier J, et al. Blood. 2018;132: Abstract 299.

Li AM, et al. Blood. 2018;132: Abstract 556.
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