Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL

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Abstract

Purpose:

A phase I/II study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).

Patients and Methods:

In phase I, we tested sequentially two cell populations for CAR transduction: (i) central memory (Tcm) or (ii) naïve, stem, and central memory (Tn/mem) T cells. The study employed an activity constrained for toxicity design to determine the recommended phase II dose (RP2D), which was tested in phase II.

Results:

The Tcm cohort was closed early due to lack of activity. The 200 ×106 Tn/mem-derived CD19-CAR T-cell dose was found to be safe and active, and was declared the RP2D. At RP2D, 58 participants underwent leukapheresis and 46 received CD19-CAR T cells. Median age for treated participants was 38 years (range, 22–72). Twenty-nine (63%) participants had relapsed post-allogeneic hematopoietic cell transplantation (alloHCT), 18 (39%) had Philadelphia-like (Ph-like) genotype, and 16 (35%) had extramedullary disease (EMD) at lymphodepletion (LD). Three (7%) participants had grade 3 cytokine release syndrome (CRS), and none had grade ≥ 4 CRS. Eight (17%) participants had grade ≥ 3 neurotoxicity, including one fatal cerebral edema. Forty (87%) patients achieved complete remission (CR)/CR with incomplete hematologic recovery, 2 (4%) progressed, and 4 (9%) were unevaluable for response. Among 42 response-evaluable participants, 16/17 with Ph-like ALL and 13/15 with EMD at LD responded. Twenty-one (53%) responders underwent alloHCT consolidation, which was associated with improved relapse-free survival (adjusted HR = 0.16; 95% confidence interval, 0.05–0.48; P = 0.001).

Conclusions:

Tn/mem-derived CD19-CAR T cells were safe and active, including in Ph-like ALL and EMD.

See related commentary by El Marabti and Abdel-Wahab, p. 694

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Most cited references 47

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Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Shannon Maude, Theodore Laetsch, Jochen Buechner … (2018)

In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

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Chimeric antigen receptor T cells for sustained remissions in leukemia.

Shannon Maude, Noelle Frey, Pamela Shaw … (2014)

Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab. Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).

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ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Daniel W. Lee, Bianca D. Santomasso, Frederick L. Locke … (2019)

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.