Anti-CD19 CAR T-Cell Therapy Induces Significant Remission Rates in B-Cell ALL

Renier J. Brentjens, MD

Chimeric antigen receptor T-cell therapy targeting CD19 demonstrated a greater than 80% complete remission (CR) rate across relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) patients with multiple levels of disease burden, according to data presented at the 2016 Society of Hematologic Oncology annual meeting.

“What is exciting about these findings is that in some patients, these remissions are very durable,” Renier J. Brentjens, MD, who presented the findings, said in an interview with OncLive.

“This has been validated in subsequent studies that demonstrated similar results with similar technology. It gives us a broad validation that this is a cellular approach that may have some utility in treating a disease that is extremely difficult to treat,” added Brentjens, a medical oncologist, and director of Cellular Therapeutics at Memorial Sloan-Kettering Cancer Center (MSK).

The phase I findings included 51 adult patients with relapsed/refractory B-ALL treated with 19-28z CAR-T cells at MSK. All 51 patients were evaluable for toxicity assessment and 50 patients were evaluable for response assessment with greater than 1 month of follow-up.

Patients were separated into cohorts by disease burden at the time of T-cell infusion; 31 (61%) had morphologic disease and 20 (39%) had minimal disease. Follow-up occurred after a median of 8.5 months (range, 1-54 months), with 29 of 50 (58%) patients with at least 6 months of follow-up and 17 of 50 patients (34%) with over 1 year of follow-up.

In the group of patients with morphologic disease, 8 had previously received 2 prior lines of therapy, 8 had received 3 lines of therapy, and 15 had received 4 or more lines of therapy. The CR rate among 30 evaluable patients was 77% (n = 23). The minimal residual disease (MRD)—negative CR rate was 90% (19/21; 2 patients not evaluable for MRD assessment). The mean time to a CR in this patient population was 20 days.

Among patients with minimal disease, 12 had 2 prior lines of therapy, 5 had 3 prior lines, and 3 had 4 or more prior lines. The CR rate in these patients was 90% (n = 18) with a 78% (14/18) MRD-negative CR rate. The mean time to CR was 25 days.

Thirty-nine percent (16/41) of patients proceeded to allogeneic hematopoietic stem cell transplantation after achieving CR as part of a post CAR-T cell infusion clinical course. Forty-five percent (15/33) of those with MRD-negative CRs relapsed, and 4 of those 15 were CD19 negative/undetectable. Nine (27%) of the 33 MRD-negative CR patients remained disease-free for more than 1 year.

The overall survival after a median follow-up of 13 months was not yet reached in the minimal disease cohort and 9 months in the morphologic cohort (P = .25).

These findings, as well as previous similar findings, demonstrate that the CAR-T cell approach targeting CD19 is the best option for relapsed/refractory B-ALL patients, said Brentjens.

“There are multiple phase II multicenter trials that are designed to allow for early FDA approval for this technology in various B-cell malignancies, including ALL and non-Hodgkin lymphoma, said Brentjens. “There are obviously issues related to the production of these cells and limited centers where this therapy can be offered, but I think it is very likely that in the foreseeable future, at least for a population of patients with B-cell malignancies, we will have an FDA approval and be able to treat with these CAR T-cells. I think this will become a standard of care for patients with relapsed/refractory ALL.”

The treatment did result in some significant toxicities, but with proper management these can be managed and are not an obstacle to expanding this therapy to multiple centers, said Brentjens.

Common adverse events included cytokine release syndrome (CRS), which resulted in fever, hypertension, respiratory insufficiency, and neurological changes (delirium, global encephalopathy, aphasia, and seizure-like activities or seizure).

In the morphologic cohort 13 (42%) patients (42%) had severe CRS, 11 (35%) had grade 3/4 neurological toxicities, and 7 (23%) had severe CRS and grade 3/4 neurological toxicities. Four (13%) patients in this cohort died on study.

Side effects were not as severe in the minimal disease cohort, indicating that toxicity may be associated in part to disease burden at the time of treatment, said Brentjens. In this cohort, 1 (5%) patient had severe CRS, 4 (20%) had grade 3/4 neurological toxicities, and 1 (5%) had severe CRS and grade III/IV neurological toxicities.

“Having a sense of caution when utilizing these types of therapies is necessary,” said Brentjens. “What we noticed in our patients that we didn’t notice in our preclinical studies is the fact that if this therapy is extremely effective, the T cells expand massively, logarithmically. Very much like in a really bad infection, the patients can have symptoms related to a massive immune response.”

Next Steps

“However there are ways of modulating that,” he added. “We think that starting out in lower doses in patients that have more tumor is a way to minimize those toxicities.”While the results with CAR T-cells in B-ALL are extremely promising, a portion of patients do not experience a CR and some patients who do experience a CR eventually relapse, said Brentjens. Combination treatments are being investigated to further optimize the treatment.

“It is very clear, especially with checkpoint inhibition and small molecules like the BTK inhibitors, that there are logical combinations for CAR T-cells that probably have acceptable toxicities and certainty warrant investigation,” he said. “These studies are already ongoing at some centers and will be opening up at other centers very soon. It is reasonable to expect that the response rates will improve with such combinations.”

CAR T-therapy targeting CD19 is also being investigated in other types of B-cell lymphomas, including chronic lymphocytic leukemia and other non-Hodgkin lymphomas.

Although results so far have not been as striking as in ALL, there is promise, said Brentjens.

“It is not entirely clear why it works so well in a disease like ALL while it doesn’t work as well in other B-cell cancers,” said Brentjens. “But the technology can be tweaked and the T-cell modifications can be adjusted in such a way that these cells are more potent in those diseases. This is already being tested in the clinical setting.”