Higher dose of CAR T cells may be more effective in advanced chronic lymphocytic leukemia
A higher dose of anti-CD19 chimeric antigen receptor T cells may lead to more complete responses among patients with relapsed or refractory chronic lymphocytic leukemia, according to results of a dose-optimization study published in Journal of Clinical Oncology.
Although there was no statistically significant difference in OS between dose groups, patients who received a higher dose of CAR T-cells and achieved complete response to therapy achieved longer OS and PFS with manageable toxicity.
This group of researchers had conducted a previous pilot trial of CAR T cells for CLL, published in Science Translational Medicine, that showed “remarkable responses in some patients with CLL,” according to David L. Porter, MD, director of cell therapy and transplant at University of Pennsylvania’s Abramson Cancer Center and Cell Therapy Next Peer Perspective Board Member.
“There were no obvious dose-response or dose-toxicity associations and doses varied among patients,” he told Healio. “We wanted to define an optimal cell dose that maximized response while minimizing toxicity.”
The trial enrolled 42 patients with relapsed or refractory CLL between January 2013 and June 2016. After lymphodepletion chemotherapy, 38 patients received anti-CD19 CAR T-cell infusions. Twenty-eight patients in the treatment cohort had been randomly assigned to receive a low (5 × 107 cells/kg) or high (5 × 108 cells/kg) dose of CAR T cells. Twenty-four patients were eligible for evaluation, plus eight patients who received the high dose after an interim analysis.
Among the 32 evaluable patients (mean age 61.3 years; range, 48.8-76.1; 78% men) in the survival analysis, 19 received the high dose and 13 received the low dose.
Determining the efficacy of anti-CD19 CAR T cells at each dose and the optimal dose for further study served as the primary objective. Researchers defined the primary endpoint as the proportion of patients with complete response to therapy at 3 months after infusion. Secondary endpoints included overall response rate, PFS, OS and toxicity.
Median follow-up was 31.5 months (range, 2-75).
The analysis showed a complete response rate of 28% (90% CI, 16-44) and an ORR of 44% (90% CI, 29-60).
The ORR for the 19 patients in the high-dose group was 53% (90% CI, 32-73), including a 37% complete response rate (n = 7). Among the 13 patients in the low-dose group, two patients (15%; 90% CI, 3-40) achieved complete response and two achieved partial response.
Researchers observed no statistically significant difference in median OS between the low- and high-dose groups. However, patients who achieved complete response had longer OS compared with those who did not (P = .035), regardless of dose. Median OS was not reached among complete responders vs. 64 months among those without a complete response; median PFS was 40.2 months among complete responders vs. 1 month among those without a complete response (P < .0001).
“Response rates appeared higher for recipients of the higher cell dose,” Porter told Healio. “Given the small number of patients treated, the study was not designed to show statistical significance, but we felt the differences were indeed clinically meaningful.”
“Median OS had not been reached in patients who achieved a complete response, and most remissions were sustained,” Porter continued. “Many patients who achieve a complete response do extremely well. The major impediment is inducing complete responses in more patients.”
Toxicity results appeared comparable between the two groups. The most common treatment-related adverse events were cytokine release syndrome (CRS, 63%) and leukopenia (92%). Five patients in the high-dose group had grade 3 to grade 4 CRS. The rate of grade 1 or grade 2 CRS among the entire study group was 48%, with 11% of patients experiencing grade 3 to grade 4 CRS, according to American Society for Transplantation and Cellular Therapy criteria.
Headaches (16%) were the most common neurotoxicity. Three patients experienced grade 3 neurotoxicity.
Porter said patients who received the higher dose of cells were more likely to achieve complete response without excessive toxicity. This led his group to choose the higher dose as the optimal dose for patients with CLL in future clinical trials.
“I think this study confirms the potency of CAR T cells for CLL and highlights the remarkable durability of responses,” Porter told Healio. “This certainly lends support for developing and applying CAR T-cell therapy for patients with relapsed and refractory CLL, and potentially for those patients earlier in the course of their disease.” – by Drew Amorosi
Reference:
Porter DL, et al. Sci Transl Med. 2015;doi:10.1126/scitranslmed.aac5415.
For more information:
David L. Porter, MD, can be reached at david.porter@pennmedicine.upenn.edu.
Disclosures: Porter reports consultant/advisory roles with Gerson Lehrman Group, Glenmark, Incyte, Janssen, Kite/Gilead and Novartis; research funding from Novartis; and a patent as inventor for CTL019. He also reports his spouse is employed by Genentech/Roche. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Over the past 2 years, anti-CD19 CAR T cells have rapidly become an important treatment option for adults with relapsed or refractory large B-cell lymphoma and children and young adults with advanced acute lymphocytic leukemia. It is anticipated that the FDA will approve new indications for anti-CD19 CAR T-cell therapy in the near future.
In this long-term follow-up report, the investigators have convincingly demonstrated that anti-CD19 CAR-T can result in durable complete remission and prolonged survival among patients with advanced CLL who experienced disease progression despite a median of 3.5 previous treatment regimens. Based on this study, CAR T-cell therapy should be considered as one of the evolving treatment options for patients with advanced CLL.
On the other hand, the study is limited by the dramatic changes in the treatment landscape for CLL. This study was performed before the era of Bruton tyrosine kinase inhibitors, BCL-2 inhibitors and newer monoclonal antibodies. Only a small percentage of the patients in this study had received these newer agents.
Nevertheless, I was very impressed with the durability of the response among patients who achieved a complete response. Median PFS was 40.2 months for patients who achieved complete remission and 1 month for those who did not.
Future studies will focus on defining the role of CAR T-cell therapy in CLL. Combining newer agents, improving patient selection and giving CAR T cells earlier during the course of the disease hopefully will result in higher complete response rates and minimal residual disease negativity, both of which were predictive of improved survival.
The adverse effects of CAR T-cell therapy, specifically neurotoxicity and cytokine release syndrome, were significant in this study. However, with increasing experience providing this treatment, both toxicities have become manageable and should no longer be obstacles to treating patients who may benefit from the therapy.
CAR T-cell therapy will soon be added to the list of treatments available to patients with advanced CLL.
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