CAR T before transplant yields durable remission in B-cell malignancies

BY KARI OAKES in Oncology on March 14th, 2018


SALT LAKE CITY (FRONTLINE MEDICAL NEWS) – Chimeric antigen receptor (CAR) T-cell therapy may be an effective bridge to hematopoietic cell transplant (HCT) for high-risk B-cell malignancies, according to a systematic analysis of patient data from the National Cancer Institute.

Additionally, patients who have received CAR T-cell therapy are likely to enter HCT with a minimal residual disease (MRD)–negative complete response, which raises the possibility of a significantly less intense conditioning regimen that could omit total body irradiation (TBI), Haneen Shalabi, DO , said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

“Patients who underwent HCT post–CAR T therapy did not have increased transplant-related morbidity or mortality,” said Dr. Shalabi, a pediatric oncologist in the hematologic diseases division of the National Cancer Institute’s pediatric oncology branch.

The combined approach also overcomes the frequent relapses seen after CAR T-cell therapy in this population. Of the 45 patients who received CAR T-cell therapy and achieved MRD-negative complete response as measured by flow cytometry, 20 did not go on to receive HCT. Of the 20 who didn’t receive HCT, 16 (80%) relapsed; 19 of the 20 (95%) had received prior HCT, said Dr. Shalabi.

However, of the 25 patients who proceeded on to receive HCT, 15 (60%) were in ongoing remission, with a median duration of 35 months (range, 11-55 months). Six patients (24%) experienced transplant-related mortality; four of these patients had no prior HCT. Ten patients (40%) experienced acute graft-versus-host disease (GVHD); two of these patients experienced grade 4 GVHD, and one experienced grade 3 GVHD.

Of the 25 patients who went on to HCT, 19 were receiving their first transplant, with a median time to transplant after CAR T-cell therapy of 57 days. Five patients (20%) had primary refractory disease. Most patients (n = 18; 72%) had TBI-based conditioning prior to their post–CAR T-cell therapy HCT. The median patient age was 15 (range, 5-30) years.

The systematic review included patients from two phase 1 studies; one was of CD19-28z CAR T-cell therapy for children and young adults with B-cell leukemia or lymphoma, and the other was of CD22-41BB CAR T-cell therapy for children and young adults with recurrent or refractory B-cell malignancies expressing CD22.

To weigh the benefit of the combined CAR T-cell therapy/HCT approach, Dr. Shalabi and her colleagues used a competing risk analysis to determine the risk of relapse post-HCT versus the risk of transplant-related mortality. Among patients undergoing their first HCT, the researchers found a 12-month cumulative incidence of relapse of 5.3% with the combined CAR T-cell therapy/HCT approach (95% confidence interval, 0.3%-22.1%). The 24-month cumulative incidence of relapse was 11.3% (95% CI, 1.7%-31.1%).

The analysis also showed the value of next-generation sequencing (NGS). “As we think about utilizing CAR T therapy as a bridge to transplant, we wanted to study the depth of CAR T–induced remission by next-gen sequencing,” Dr. Shalabi said.

Eight patients on the CD22 CAR trial had MRD analyses based on both flow cytometry and NGS. According to flow cytometry, all eight were MRD negative by 1 month; however, according to NGS, two did have detectable disease, which decreased with time. “Next-gen sequencing can identify earlier time points for relapse or ongoing remission” than flow cytometry can, she said.

An additional finding was that two-thirds of the patients who received the CD19/CD28z CAR T cells had no detectable CAR T cells when the pre-HCT conditioning regimen was initiated, said Dr. Shalabi. “CAR persistence – or lack thereof – didn’t impact post-HCT outcomes,” she said, adding that shorter-acting CAR T cells may actually be preferable when HCT is readily available as an option.

“The impact of CAR persistence peritransplant requires further analysis,” Dr. Shalabi said. It’s possible, though, that “consolidative HCT following CAR may synergistically improve event-free and overall survival for this high-risk population.”

Looking forward, Dr. Shalabi and her team are asking bigger questions: “For future directions – and this is a very big question that those in the room would probably like to know – by inducing NGS-negativity, can CAR T therapy allow for HCT conditioning deintensification, potentially reducing the risk of TRM [transplant-related mortality] and long term comorbidities?”

A future trial will explore outcomes for a conditioning regimen that omits TBI for patients who are MRD-negative by NGS, said Dr. Shalabi.

Another direction for her team’s research is to see whether introducing CAR T-cell therapy earlier in a very-high-risk population may improve outcomes; the current study population was heavily pretreated, Dr. Shalabi said.

Dr. Shalabi is employed by the National Cancer Institute. She reported no conflicts of interest.

SOURCE: Shalabi H et al. 2018 BMT Tandem Meetings, Abstract 6 .


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