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CAR T-cells EHA 2019
My Thoughts on the Latest Results With CAR T-Cell Therapy From EHA 2019

Released: July 10, 2019

Expiration: July 08, 2020

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The results of several key clinical trials with CAR T-cell therapy were presented in June at the 2019 EHA Congress. In this commentary, I highlight my choices of the most interesting findings from this meeting.

Acute Lymphoblastic Leukemia (ALL)
The efficacy and safety of CD19-directed CAR T-cell therapy in pediatric ALL is well established, with one such agent—tisagenlecleucel—approved in both the EU and the US for this setting. However, the efficacy and safety of CD19-directed CAR T-cell therapy in adults with ALL is less well characterized.

At the 2019 EHA Congress, Shah and colleagues presented the end of phase I results of the phase I/II ZUMA‑3 trial with KTE-X19, an investigational CD19-directed CAR T-cell therapy, in adults with relapsed/refractory ALL. KTE-X19 uses the same CAR construct as axicabtagene ciloleucel, but the manufacturing process involves further enrichment of lymphocytes. The primary phase I objective of this study was to evaluate dose‑limiting toxicities (DLTs) and safety of KTE-X19. The median age of the enrolled patients was 46 years (range: 18-77 years). Three doses of KTE-X19 were tested in 3 cohorts: 2 x 106 cells/kg (n = 6), 1 x 106 cells/kg (n = 23), and 0.5 x 106 cells/kg (n = 16). No DLTs were reported in 3 evaluated patients. However, 2 patients (4%) died from treatment-related adverse events—1 from multiorgan failure secondary to cytokine-release syndrome (CRS) and another who developed a stroke in the context of CRS and neurologic events (NE). Among patients who received KTE-X19 at 1 x 106 cells/kg, the incidence and severity of CRS and NE appeared lower in a subset treated with a revised adverse event management approach that consisted of using tocilizumab only for CRS and initiating steroids for grade ≥ 2 NE rather than grade ≥ 3 NE. In terms of efficacy, the CR rate was 67%, 84%, and 50%, from the highest to the lowest dose of KTE-X19. All patients in the 1 x 106 cells/kg cohort who achieved a CR were MRD negative. Although only 6 patients received a stem cell transplant, transplant after KTE‑X19 did not appear to improve outcomes beyond treatment with KTE-X19 alone. The phase II portion of ZUMA-3 is currently ongoing at the recommended phase II dose of 1 x 106 cells/kg using the revised adverse event management approach.

Wayne and colleagues presented results of the phase I ZUMA-4 trial of KTE‑X19 in pediatric and adolescent patients with relapsed/refractory ALL. The aim of this study was to evaluate the safety, efficacy, and pharmacokinetics of KTE‑X19 in this group of patients. One cohort received KTE-X19 at 2 x 106 cells/kg (n = 4) and a second cohort received 1 x 106 cells/kg (n = 20), with the latter dose administered either at a lower cell density in a 68-mL volume or at a higher cell density in 40 mL. There were no DLTs observed and treatment-emergent toxicity was consistent with previous reports. The overall rate of CR plus CR with incomplete hematologic recovery across KTE-X19 doses was 73% with 15 of 16 evaluable responding patients achieving MRD negativity. These findings are encouraging, but unfortunately, no data on disease-free survival were presented. Based on these results, the phase II portion of ZUMA‑4 is now enrolling patients at the KTE-X19 dose of 1 x 106 cells/kg in a 40-mL volume.

Large B-Cell Lymphomas
Autologous CD19-directed CAR T-cell therapy has also shown marked efficacy in patients with relapsed/refractory large B-cell lymphoma. Both the EU and US have approved tisagenlecleucel and axicabtagene ciloleucel for adults with relapsed/refractory large B-cell lymphoma after 2 or more lines of previous systemic therapy. Currently, there are several ongoing clinical trials comparing the efficacy and safety of CD19-directed CAR T-cell therapy vs autologous hematopoietic stem cell transplant (auto-HSCT). Because patients older than 65 years of age might not be fit enough to undergo auto-HSCT, the outcomes associated with CD19-directed CAR T-cell therapy in older patients are of particular interest.

Neelapu and colleagues presented an analysis of safety and efficacy with axicabtagene ciloleucel from the phase I/II ZUMA-1 trial in patients stratified by age (≥ 65 vs < 65 years). The median age for the older subgroup was 69 years (range: 65-76 years) compared with 55 years (range: 23-64 years) for the younger subgroup. No age‑related differences in efficacy or safety of axicabtagene ciloleucel were observed, suggesting that older age should not be a deciding factor for whether patients are candidates for CAR T-cell therapy.

The efficacy and safety of CD19-directed CAR T-cell therapy in the subset of patients with B-cell non-Hodgkin lymphoma (NHL) and secondary central nervous system (CNS) lymphoma is of particular interest given the poor prognosis of this population. Abramson and colleagues reported preliminary results in 9 patients with secondary CNS lymphoma receiving lisocabtagene maraleucel (previously JCAR017) in the ongoing phase I TRANSCEND NHL 001 trial. Four of these 9 patients had responses, with all best responses being CRs; indeed, 2 were ongoing at the time of their last visits, which occurred at 270 and 545 days after infusion. No excess NEs were noted, with 1 patient experiencing grade 3 NE and grade 2 CRS. The authors concluded that lisocabtagene maraleucel appears to be safe in patients with secondary CNS lymphoma and that further evaluation in this setting is warranted.

Chronic Lymphocytic Leukemia (CLL)
Encouraging early findings with CAR T-cell therapy in CLL were also reported by Siddiqui and colleagues at the EHA 2019 Congress. The phase I/II TRANSCEND CLL 004 trial evaluated lisocabtagene maraleucel in patients with relapsed/refractory CLL or small lymphocytic lymphoma who were ineligible for or had progressed on ibrutinib. Of importance, more than one half of the 23 patients in this analysis also had previously received venetoclax. No unexpected toxicities were reported and the incidence of CRS and NE was comparable to previous studies. At a median follow-up of 9 months, lisocabtagene maraleucel was associated with an ORR of 82%, including 46% with a CR or CR with incomplete hematologic recovery. Although most responses were achieved by Day 30, some patients showed deepening responses over time. Of note, 83% of patients with CR at 6 months remained in CR at 9 months, including 3 patients who maintained CR beyond 12 months. The phase II portion of this study is currently enrolling patients.

Implementation of CAR T-Cell Therapy in Europe
Finally, 2 general sessions at the 2019 EHA Congress discussed the results of the activity survey of CAR T-cell therapy in Europe that was launched by the European Society for Blood and Marrow Transplantation (EBMT). Overall, 351 patients have been treated with CAR T-cell therapy across 22 European countries. Of these patients, approximately one third are children or adolescents, and the remainder are adults. Most patients had ALL (42%) or NHL (34%), with a small number having multiple myeloma (5%), solid tumors, or acute myeloid leukemia. Currently, there are 21 active CAR T-cell therapy clinical trials in Europe, including 7 sponsored by academic institutions. Of note, there are 7 institutions with CAR T-cell production in-house and 3 CAR T-cell therapies that have been developed by European academic institutions. Updated results of the EBMT activity survey will be available soon, and I encourage clinicians to consider CAR T-cell therapy for their patients with hematologic malignancies.

To learn how 5 multidisciplinary experts would manage patients experiencing adverse events associated with CAR T-cell treatment, please see “Expert Guidance on Multidisciplinary Management of CAR T-Cell Toxicities.” 

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