Exploring CAR T-Cell Therapy as a Bridge to HCT in ALL

Researchers at the National Institutes of Health (NIH) are exploring whether CAR T-cell therapy can enhance the effectiveness of treatment with hematopoietic cell transplant (HCT) among patients with relapsed/refractory acute lymphoblastic leukemia (ALL).

CAR T-cell therapy can induce next generation sequencing (NGS) negativity, suggesting a “synergistic” relationship with HCT that could enhance patient outcomes.

Results were presented at the 2018 American Society of Pediatric Hematology/Oncology Conference from an interim analysis of patients treated on a phase I trial that led investigators to conclude that CAR T-cell therapy may help patients “bridge” to HCT, especially patients who are NGS-negative. However, that conclusion is based on results from just 4 patients.

“We have seen that CAR-induced remissions may serve as an effective bridge to transplant,” said Haneen Shalabi, DO, cellular therapy fellow, Pediatric Oncology Branch, NIH. “Consolidative HCT following CAR may synergistically improve [event-free survival] and [overall survival] for this high-risk population.”

She added that there were no instances of acute or chronic graft-versus-host disease (GVHD) or transplant-related mortality (TRM) recorded.

Previous studies performed at the NIH have shown that anti-CD19 CAR T-cell therapy induced minimum residual disease (MRD)-negative remission with high disease-specific survival following HCT. The researchers conducted this follow-up study to explore CAR T cell persistence, depth of remission, and GVHD after transplantation.

Twenty-four children and young adults with relapsed/refractory CD22-positive ALL who had had a complete remission (CR) following treatment in the phase I study of CD22-41BB were included in the results. Of these patients, 20 patients did not undergo HCT following CAR T-cell treatment, and 15 of these patients then relapsed. The median time to relapse was 3 months (range, 2-12). Nineteen (95%) of twenty patients had undergone prior HCT and 11 (55%) had received prior anti-CD19 CAR therapy.

Four patients proceeded to HCT at a median of 70 days (range, 54-117) after CAR T-cell treatment. All 4 had undergone prior CD19 immunotherapy and 3 had CD19-negative disease.

The median patient age was 13 years (range, 12-30), 3 of the 4 were male, and 3 underwent total body irradiation (TBI)-based conditioning.

Two patients were receiving their first HCT, and those patients remained in an MRD-negative CR for 1 year following CAR T-cell treatment. Three patients had detectable CAR T cells on their pretransplantation bone marrow, leading investigators to suggest “the possibility of ongoing antileukemia surveillance prior to initiation of the conditioning regimen.”

One patient remains in ongoing remission at 15 months after transplantation.

Shalabi said that, when they considered using CAR T cells as a bridge to stem cell transplant, investigators wanted to examine the depth of CAR-induced remissions. NGS-based MRD analysis was available for 8 patients on the CD22 protocol. All were MRD-negative by flow cytometry, while 2 had NGS positive disease. NGS testing demonstrated disease burden reduction over time.

“The impact of CAR persistence peri-transplant still requires further analysis,” she said.

Investigators also wanted to determine if CAR persistence was necessary in the peri-transplant setting for better outcomes. Seventy-five percent of patients who received the CD22-41BB CAR regimen had detectable CAR when they began the preparative regimen. Shalabi said there was no evidence that CAR persistence had any effect on post-HCT outcomes, though she noted that the small sample size may have played a role in that result.

She said that, eventually, investigators determined that not all CARs were created equal.

“Shorter-acting CARs may be preferred when persistence is not desired and a transplant option is readily available,” noted Shalabi.

One of the most important questions generated by these results, and one that will be addressed in a future trial, explained Shalabi, is whether patients with ALL who are NGS MRD-negative prior to transplant can receive a conditioning regimen without TBI. Such a regimen might reduce the risk for TRM and long-term comorbidities by allowing for a reduction in intensity of HCT conditioning.

Reference

Shalabi H, Delbrook C, Stetler-Stevenson M, et al. Chimeric antigen receptor t-cell (CAR-T) therapy can render patients with ALL into PCR-negative remission and can be an effective bridge to transplant (HCT). Presented at: the 2018 ASPHO Conference; May 2-5, 2018; Pittsburgh, PA. Poster 1017.