Renier J. Brentjens, MD
The use of chimeric antigen receptor (CAR) T-cell therapies for the treatment of hematologic malignancies is still in its early stages, but when the FDA approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta) in 2017, this gave hope to oncologists and patients with some types of leukemia and lymphoma who have exhausted all other options. The findings and approvals for this approach were so welcome that the American Society of Clinical Oncology (ASCO) named CAR T-cell therapy as the Advance of the Year as part of the Clinical Cancer Advances 2018: ASCO’s Annual Report on Progress Against Cancer.1
These new drugs are categorized as adoptive cellular therapies. In the 2 agents approved thus far, the patients’ T cells are reengineered to target cancer cells expressing CD19 in certain B-cell leukemias and lymphomas. Study results show certain patients respond well, particularly compared with historical averages, but because experience with this novel therapy is still limited, there are questions about response durability.
The clinical trials have focused on initial clinical outcomes and long-term studies are not yet available. There also may be some questions about the reported responses being for the patients treated, rather than a percentage of the intentto-treat population. So, it is still not known how often these treatments provide complete remission, how long patients can expect to remain in remission, and how the durability of the treatment matches the high cost of treatment.
Recent Findings for CAR Therapies
Tisagenlecleucel was the first FDA-approved CAR T-cell therapy; the agency approved it in August 2017 to treat children and young adults (up to 25 years) with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.2
The therapy was approved based on outcomes among 63 patients who received a single dose of tisagenlecleucel during the phase II single-arm international ELIANA trial. Among the infused patients, 83% achieved a remission, including 63% with a complete remission (CR).
In updated results from the study published in February 2018, investigators reported an overall remission rate of 81%, including 60% with a CR, among 75 patients who had received a tisagenlecleucel and had at least 3 months’ follow-up.3
The rates of event-free survival (EFS) and overall survival (OS) were 73% and 90%, respectively, at 6 months. At 12 months, the EFS rate was 50% and the OS was 76%. In addition, tisagenlecleucel was evident in the blood for up to 20 months following infusion and the median duration of remission was not reached. These results compared favorably with historical findings for approved therapies for relapsed B-cell ALL, where response rates have ranged from 20% to 39%, investigators noted.
Similarly, long-term data from a phase I trial involving 53 adults with relapsed B-cell ALL who received an infusion of autologous T-cells expressing 19-28z CARs showed high response rates.4
These results showed 83% of patients achieved a CR; after a median follow-up of 29 months, the median EFS was 6.1 months and the median OS was 12.9 months.
The initial response rate for CAR therapy is very high, according to Renier J. Brentjens, MD, PhD, but the relapse rate is significant, he said. “Depending on which study you’re looking at, we’re getting more longterm follow-up now, and it looks like maybe half of the patients can relapse and some of those patients relapse with a disease that no longer expresses the CD19 target,” he said in an interview with OncologyLive®
. Brentjens, a leading researcher into CAR therapies, is director of Cellular Therapeutics at Memorial Sloan Kettering Cancer Center in New York, New York.
Terry J. Fry, MD, principal investigator on several CAR T-cell trials at the Pediatric Oncology Branch at the National Cancer Institute (NCI), said in an article published by the NCI, that “even in those who experience a complete response, up to a third will see their disease return within a year.”5
In most cases of B-ALL, CD22 is expressed in addition to CD19, so researchers at the NCI are testing CAR T cells that target this protein. The results of a small phase I study of 21 children and young adults (17 previously treated with CD19- directed immunotherapy) were promising. CRs were obtained in 73% of the patients and median remission duration was 6 months.6