CAR-T Therapy in Pediatric Leukemia: Past, Present, and Future

The researchers said BMNGS-MRD status is currently the best biomarker for determining relapse risk in the first year after a patient receives tisagenlecleucel, but B-cell aplasia assessment also has a place in assessing relapse risk. Patients who maintain B-cell aplasia during the first year after infusion may be more likely to achieve long-term response. Those who lose B-cell aplasia prior to 6 months have a higher probability of relapse.

The researchers found multiparameter flow cytometry MRD assessment to be of limited benefit in this study. It detected disease much later than BMNGS-MRD assessment, which impacted the amount of time available to plan and initiate therapy to prevent relapse and resulted in poor outcomes.

The researchers concluded that clinicians should consider allogeneic HCT or other cell or immune therapy for patients who lose B-cell aplasia in the first 6 months after infusion or those who have BMNGS-MRD greater than 0. However, the researchers also noted limitations of the study and said further evaluation is warranted.

Based on the data from this study, Dr Shah and colleagues will be leading the CAR-CURE trial. The trial, which is under review by an institutional review board, is intended to systematically evaluate NGS-MRD testing in the marrow and blood along with monitoring B-cell aplasia.²

The researchers’ hypothesis is that a biomarker-informed, risk-based strategy is feasible for monitoring pediatric and young adult patients with B-cell ALL after CD19 CAR-T therapy. The theory is that this will lead to timely referral to preemptive allogeneic HCT in high-risk patients and result in low rates of overall relapse. The researchers also aim to identify the intervals of testing needed to be able to identify those high-risk patients who would benefit from HCT.

In addition to research to guide treatment decisions after CAR-T therapy, work is also underway to better understand which patients will achieve a response to the treatment. Specifically, researchers have wondered about CAR-T efficacy in patients who have previously received the CD19/CD3 bispecific immunotherapy blinatumomab.

Data on the use of blinatumomab prior to CD19 CAR-T therapy is limited in part because patients who received prior blinatumomab were excluded from the ELIANA trial.

However, researchers evaluated patients who received prior blinatumomab in a study published in the Journal of Clinical Oncology this year.⁵ The study included 420 patients who had received a CD19 CAR-T therapy.

At a median follow-up of 30.1 months, there was no significant difference in event-free survival (EFS) after CAR-T therapy between patients who had not received blinatumomab and patients who had received blinatumomab and achieved a CR (P =.59).

However, patients who did not achieve a CR with blinatumomab had significantly worse EFS than patients who achieved a CR with blinatumomab (P =.01) or patients who had not received blinatumomab (P =.0001). In addition, the researchers found that high disease burden was independently associated with inferior EFS.

Dr Shah explained that blinatumomab nonresponse and high disease burden could independently serve as a proxy to understand which patients are extremely high-risk for inferior long-term outcomes after CD19 CAR-T therapy.²

Looking beyond CD19 CAR-T therapies for B-cell ALL, researchers are studying other targets or dual targeting, such a CD22 CAR-T or a CD19/CD22 CAR-T, and other indications like acute myeloid leukemia (AML).

Dr Shah noted that, as different antigens are targeted, the same rules may not apply when it comes to toxicity. For example, when studying a CD22 CAR-T therapy, researchers found no grade 3-4 cytokine release syndrome or neurotoxicity, both of which are well-known side effects of CD19 CAR-T therapies.⁶  

AML has proven to be more challenging to treat with CAR-T therapy because the antigen expression in AML is more heterogeneous than in B-cell ALL. However, clinical trials are underway.

Dr Shah and Richard Aplenc, MD, PhD, from the Children’s Hospital of Philadelphia in Pennsylvania, are leading a phase 1/2 CD33 CAR-T trial exclusively for children and young adults with relapsed/refractory AML (ClinicalTrials.gov Identifier: NCT03971799).

The phase 1 portion of the trial is designed to determine the maximum tolerated dose of CD33 CAR-T cells, while phase 2 is designed to evaluate the percentage of patients who achieve remission at day 28 after CD33 CAR-T infusion. Those who achieve remission will proceed to allogeneic HCT or another therapy as clinically applicable.

The Center for International Blood and Marrow Transplant Research (CIBMTR) is sponsoring the trial in collaboration with the National Marrow Donor Program (NMDP)/Be The Match. The trial is open at 6 centers across the United States.

As research in B-cell ALL has shown, CAR T-cell therapies can change the treatment paradigm for children and young adults. Although questions remain, the answers gained will continue to inform the field going forward and bring new treatments to more patients.

Disclosures: Heather Stefanski, MD, PhD, is the vice president of medical services at the NMDP/Be The Match. Please refer to the original references for a full list of author disclosures.

References

1. Pasquini MC, Hu Z-H, Curran K, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4(21):5414-5424. doi:10.1182/bloodadvances.2020003092
2. Shah, NM. The role of CAR T-cell therapy in pediatric patients. Presented at: The ONE Forum 2022; November 2022; Minneapolis, MN.
3. Qayed M, Bleakley M, Shah NN. Role of chimeric antigen receptor T-cell therapy: bridge to transplantation or stand-alone therapy in pediatric acute lymphoblastic leukemia. Curr Opin Hematol. 2021;28(6):373-379. doi:10.1097/MOH.0000000000000685
4. Pulsipher MA, Han X, Maude SL, et al. Next-generation sequencing of minimal residual disease for predicting relapse after tisagenlecleucel in children and young adults with acute lymphoblastic leukemia. Blood Cancer Discov. 2022;3(1):66-81. doi:10.1158/2643-3230.BCD-21-0095
5. Myers RM, Taraseviciute A, Steinberg SM, et al. Blinatumomab nonresponse and high-disease burden are associated with inferior outcomes after CD19-CAR for B-ALL. J Clin Oncol. 2022;40(9):932-944. doi:10.1200/JCO.21.01405
6. Fry TJ, Shah NN, Orentas RJ, et al. CD22-CAR T cells induce remissions in CD19-CAR naïve and resistant B-ALL. Nat Med. 2018;24(1):20-28. doi:10.1038/nm.4441

This article originally appeared on Hematology Advisor