BLOG: ALL relapse prevention with HSCT after CD19 CAR T-cell therapy remission
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Allogeneic hematopoietic stem cell transplantation after CD19 chimeric antigen receptor T-cell therapy is thought to improve leukemia-free survival.
This is particularly true for CD19 CAR T cells, which incorporate the CD28 costimulatory domain due to its known short persistence.
However, it is clear that a small subset of patients achieve a long-term cure after 4-1BB-containing CD19 CAR T-cell therapy without HSCT.
Work is desperately needed to identify which patients following therapy with 4-1BB-containing CD19 CAR T cells can safely avoid HSCT.
HSCT is associated with short- and long-term morbidity and mortality. The pediatric population is particularly susceptible given developmental/growth needs. Thus, HSCT avoidance without impacting leukemia-free survival would be highly beneficial for patients.
Researchers at Seattle Children’s Hospital retrospectively analyzed patients with ALL who received a CD19 4-1BB CAR T-cell product as part of a clinical trial.
Results showed patients in remission who were HSCT naive and/or had short B-cell aplasia derived a leukemia-free survival benefit from HSCT. Patients with prior HSCT only appeared to derive a leukemia-free survival benefit when they experienced short B-cell aplasia.
Additional groups have worked to identify high-risk patients who likely would benefit from HSCT.
Jiang and colleagues identified bone marrow disease burden of 5% or greater, as well as high-risk cytogenetics (eg, MLL, BCR-ABL1, TP53 and E2A-PBX1) as deriving an EFS benefit with HSCT after CD19 4-1BB CAR T-cell remission.
Molina and colleagues retrospectively evaluated patients who received CD19/CD28 CAR, CD22 4-1BB CAR or a bispecific product with both CAR constructs.
Within this heterogeneous population, they found patients who had received five or more lines of therapy, those who received prior blinatumomab (Blincyto, Amgen) and/or inotuzumab ozogamicin (Besponsa, Pfizer), or those who had high disease burden ( 5% ALL in the bone marrow) continued to have worse outcomes even with incorporation of HSCT. Results also showed HSCT-naive individuals with primary refractory ALL achieved improved EFS with HSCT consolidation compared with those who had relapsed disease.
Pulsipher and colleagues retrospectively evaluated patients with next-generation sequencing testing after CD19 4-1BB tisagenlecleucel (Kymriah, Novartis) and found that early next-generation sequencing positivity predicts impending relapse.
Work is underway to identify the use of post-CD19 4-1BB CAR biomarker monitoring for future relapse risk in pediatric and adolescent/young adult patients.
This clinical trial will monitor peripheral blood B-cell counts every 2 weeks until 6 months, and bone marrow evaluations monthly following CAR therapy through month 3 and then every 3 months through 1 year.
Additionally, investigators will obtain peripheral blood next-generation sequencing data to understand how this could be used as a less invasive monitoring method to identify patients at high risk for relapse.
Prospective studies are desperately needed to guide clinicians on which patients would clearly benefit from consolidative HSCT following CD19 4-1BB CAR T-cell therapy and which patients can undergo close monitoring without negatively impacting leukemia-free survival.
References:
- Jiang H, et al. Am J Hematol. 2019;doi: 10.1002/ajh.25582.
- Molina JC, et al. Transplant Cell Ther. 2022;doi:10.1016/j.jtct.2021.10.011.
- Pulsipher MA, et al. Blood Cancer Discov. 2022;doi:10.1158/2643-3230.BCD-21-0095.
- Summers C, et al. Blood. 2021;doi:10.1182/blood-2021-147928.
For more information:
Corinne Summers, MD, is interim co-chief medical officer of Seattle Children’s Therapeutics, as well as assistant professor in the department of pediatrics at University of Washington School of Medicine.
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