Blinatumomab before CAR-T associated with shorter RFS, EFS in pediatric advanced ALL
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Young patients with B-cell acute lymphoblastic leukemia had shorter RFS and EFS if they received blinatumomab before chimeric antigen receptor T-cell therapy, according to results presented at the virtual ASH Annual Meeting and Exposition.
Use of blinatumomab (Blincyto, Amgen) — a CD3-CD19 bispecific T-cell engager —also appeared associated with a higher risk for not responding to therapy with CD19-directed CAR T cells.
CD19-directed therapies have proved effective for pediatric B-cell ALL, according to Nirali N. Shah, MD, head of the hematologic malignancies section of the pediatric oncology branch at the NCI.
Shah said patients can be given both blinatumomab and tisagenlecleucel (Kymriah, Novartis) — a autologous CD19-directed CAR T-cell therapy — sequentially for relapsed or refractory ALL.
“We anticipate increased utilization of both these agents as they are incorporated into front-line studies,” she said during a presentation.
Shah said antigen modulation represents a mechanism of resistance to CD19 targeting. Further, both blinatumomab and CD19 CAR T cells are associated with lineage switch, CD19 loss and CD19 antigen downregulation, which promote resistance.
“There are limited data on the impact of one treatment on the outcomes of the other,” including response, treatment durability and disease relapse rates, Shah said.
“Because there are limited data on the use of blinatumomab before the use of CD19 CAR constructs, there is a concern that prior CD19 targeting may adversely impact CD19 CAR outcomes,” Shah said.
Shah and colleagues conducted a multicenter, retrospective study to evaluate the impact of blinatumomab before CD19 CAR T-cell therapy among patients with relapsed or refractory ALL who were aged 25 years or younger at diagnosis.
The study included 420 patients who received one of three CD19 CAR T-cell constructs across seven centers in the United States from 2012 to 2019. Median age of patients at CAR T-cell infusion was 12.4 years (interquartile range [IQR], 7-17.1). Seventy-five patients (17.9%) received blinatumomab before CD19 CAR T-cell therapy. The response rate to blinatumomab in this group was 57.3%, and 43 patients had a complete response to therapy.
Median time from therapy with blinatumomab to CAR T-cell infusion was 129 days (IQR, 79-304).
RFS and EFS rates at 6 months after CD19 CAR T-cell infusion served as the study’s primary objectives. Secondary objectives included RFS and EFS rates 1 year after infusion and an assessment of CD19 antigen modulation.
Median follow-up was 2.3 years (IQR, 1.6-3.3).
Results showed a 91% complete response rate to CD19 CAR T cells among 412 patients evaluable for response, with a minimal residual disease-negative remission rate of 88%.
A total of 164 of those patients (39.8%) experienced disease relapse and 234 (56.8%) remained alive and in remission as of the data cutoff date.
Further analysis revealed that patients who received blinatumomab were significantly more likely to have residual disease after CD19 CAR T-cell therapy (18.3% vs 7%; P = .0052). They also had lower 6-month RFS (63.4% vs 81.1%; P = .027) and EFS (49.7% vs 72.1%; P = 0034) rates, as well as shorter median RFS (20.3 months vs. 44.9 months) and median EFS (5.8 months vs. 22.6 months).
“Blinatumomab utilization prior to CD19 CAR was associated with worse outcomes,” Shah said. “Understanding the reasons for worse outcomes in patients who receive blinatumomab is needed for optimal planning of patient care.”
Shah said further study should focus on whether patients who relapse after or do not respond to blinatumomab are inherently higher-risk patients or part of a CD19-reistant population. This would require a more in-depth analysis of CD19 expression before and after receiving blinatumomab and CD19 CAR T cells, she added.
Perspective
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E. Anders Kolb, MD
This is an important retrospective analysis of more than 400 patients treated at seven centers. Blinatumomab and CAR T cells are exciting new immunotherapies for children with ALL.
The investigators reported that use of blinatumomab prior to CAR T cells increased the risk for relapse. The authors speculated the sequential immunotherapies targeting the same molecule on the leukemia cells may foster or select cells resistant to these therapies.
The challenge clinically is that both blinatumomab and CAR T cells are highly effective therapies for children with relapsed ALL. Neither may be expendable, but clinicians need to be selective in how these therapies are used sequentially. Future studies may focus on the use of conventional transplant after T-cell therapy to mitigate the impact of prior blinatumomab in patients when use of both is unavoidable.
Nemours Children's Health System
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