Acute leukemias, particularly acute lymphoblastic leukemia (ALL) and, to a lesser extent, acute myeloid leukemia (AML), remain among the most challenging hematologic malignancies due to high mortality rates and limited treatment options. In this context, Chimeric Antigen Receptor T (CAR-T) cell therapy has emerged as a promising approach for patients with refractory or relapsed disease.

CAR-T cells are generated by genetically engineering the patient's T cells to express synthetic receptors targeting specific tumor-associated antigens. In ALL, CD19-targeted CAR-T cell therapies have demonstrated complete remission (CR) rates of 70–90%. For AML, ongoing research is exploring alternative targets.

Clinical Studies and Outcomes

ELIANA Trial

The ELIANA trial, the largest global multicenter study of CD19-targeted CAR-T therapy, focused on pediatric and young adult ALL patients Tisagenlecleucel was infused into 75 ALL patients and evaluated for efficacy. The overall remission rate at 3 months was 81%, and all patients who responded to treatment were found to be negative for minimal residual disease by flow cytometry. Event-free survival and overall survival rates were 73% and 90% at 6 months and 50% and 76% at 12 months, respectively. Median duration of remission was not achieved. Tisagenlecleucel persisted in the blood for up to 20 months. Grade 3 or 4 adverse events thought to be related to tisagenlecleucel occurred in 73% of patients. Cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurological events occurred in 40% of patients and were managed with supportive care, and no brain edema was reported.

ZUMA-3 Trial

The ZUMA-3 an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 CAR-T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. KTE-X19 was administered to 55 (77%) patients. At a median follow-up of 16.4 months (13.8-19.6), 39 patients (71%; 95% CI 57-82, p<0.0001) had CR or CRi and 31 (56%) achieved CR. Median duration of remission was 12.8 months (95% CI 8.7 - not estimable), median relapse-free survival was 11.6 months (2.7-15.5) and median overall survival was 18.2 months (15.9 - not estimable). Among responders, median overall survival was not reached and 38 (97%) patients had MRD negativity. Ten (18%) patients received allo-SCT consolidation after KTE-X19 infusion. The most common adverse events of grade 3 or higher were anemia (27 [49%] patients) and pyrexia (20 [36%] patients). 14 (25%) patients had grade 3 or higher infections. Two grade 5 KTE-X19-related events occurred (cerebral herniation and septic shock). Grade 3 or higher cytokine release syndrome occurred in 13 (24%) patients, and grade 3 or higher neurologic events occurred in 14 (25%) patients.

AML Target Studies

AML poses unique challenges due to its heterogeneous cell populations. Early-phase studies of CD33-targeted CAR-T cells have shown promising tumor burden reductions in specific patient cohorts. However, these studies are still in the clinical validation phase.

Future Perspectives

Next-generation CAR-T cell designs aim to enhance target specificity and minimize adverse effects, improving the therapy's safety and efficacy profile. Allogeneic CAR-T platforms and universal CAR-T cell technologies are also under development, potentially increasing accessibility for a broader range of patients.

In conclusion, CAR-T cell therapy represents a transformative step in personalized treatment strategies for acute leukemias. Continued advancements in clinical trials and translational research will further unlock the potential of this innovative approach in hematology.