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

The US Food and Drug Administration’s (FDA) approval of tisagenlecleucel for the treatment of children and young adults with B-cell acute lymphoblastic leukemia (ALL) changed the treatment paradigm for this disease.

Before the introduction of chimeric antigen receptor (CAR) T-cell therapy, this patient population had limited treatment options for ALL that is refractory or in a second or later relapse. To have the best outcomes, patients with relapsed or chemotherapy-resistant disease had to achieve remission and minimal residual disease (MRD) negativity and then receive an allogeneic hematopoietic cell transplant (HCT).

CD19-targeted CAR-T therapy has produced high complete response (CR) rates in pediatric patients with relapsed or refractory ALL.¹ However, not every patient achieves long-term remission. Some patients who relapse are negative for CD19. Those patients may benefit from allogeneic HCT or a CAR-T therapy with a different construct. Therefore, additional research on different CAR-T constructs and patient risk stratification are necessary.

Nirali N. Shah, MD, head of the Hematologic Malignancies Section of the Pediatric Oncology Branch at the National Cancer Institute’s Center for Cancer Research in Bethesda, Maryland, discussed current CAR-T therapy uses and challenges, CAR-T research, and future CAR-T targets during The ONE Forum 2022, which took place in Minneapolis, Minnesota, in November.²

Dr Shah described a challenge that many hematologists/oncologists face when a patient has relapsed/refractory B-cell ALL. The clinician must determine whether CD19 CAR-T therapy should be used as a bridge to an allogeneic transplant or whether a “watchful waiting” approach would be more beneficial.

There are pros and cons to each approach. Watchful waiting means the patient can avoid the short- and long-term toxicities associated with HCT. However, as Dr Shah noted, outcomes after CAR-T therapy relapse are dismal. Additionally, a patient may be unable to proceed to transplant if their disease comes back after CAR-T therapy.

Dr Shah suggested that alignment on risk-stratification is urgently needed so clinicians can identify those patients at high risk for post-CAR-T relapse and develop the patient’s treatment plan accordingly. In addition, prospective studies are needed to define the role for post-CAR-T consolidative allogeneic HCT.³

Some of this work is already underway. Dr Shah pointed to a study, published in Blood Cancer Discovery in 2022, in which researchers aimed to define biomarkers predictive of relapse after tisagenlecleucel.⁴

The researchers analyzed blood and marrow samples from patients enrolled in the ELIANA (ClinicalTrials.gov Identifier: NCT02435849) and ENSIGN (ClinicalTrials.gov Identifier: NCT02228096) trials. The samples were drawn at specific time points after CAR-T infusion.

The researchers hypothesized that measuring MRD at various time points after a patient achieved remission with tisagenlecleucel could reveal patients at high or low risk of relapse. The team also assessed the role of B-cell aplasia.

The researchers found that detectable disease by bone marrow next generation sequencing (BMNGS)-MRD was “highly predictive” of relapse, in the presence or absence of B-cell aplasia.

This article originally appeared on Hematology Advisor