Novel “Sandwich” Strategy Shows Promise in Relapsed/Refractory B-ALL: Sequential CAR T-cell Therapy & ASCT
B-cell acute lymphoblastic leukemia (B-ALL), while frequently enough treatable, can be particularly challenging in cases of relapse or refractoriness to initial therapies. A recent Phase 2 trial, published in Cancer and detailed on ClinicalTrials.gov (NCT05470777), investigated a novel ”sandwich” approach combining sequential CD22/CD19 chimeric antigen receptor (CAR) T-cell therapy with autologous hematopoietic stem cell transplantation (ASCT). The results offer a promising new consolidation strategy for patients facing a arduous prognosis. Here’s a detailed look at the study design, patient characteristics, safety profile, and potential implications for the future of B-ALL treatment.
Understanding the Challenge & the “Sandwich” Approach
Traditional treatment for relapsed/refractory B-ALL often involves intensive chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT). Though, these options carry notable risks and aren’t always feasible for all patients. CAR T-cell therapy has revolutionized treatment for some, but resistance can develop.
This study aimed to overcome potential resistance by sequentially administering CAR T-cell therapies targeting different antigens (CD22 then CD19). The rationale is that targeting two distinct B-cell antigens may broaden the anti-leukemic response and reduce the likelihood of antigen escape. The “sandwich” strategy – CAR T-cell #1,ASCT,CAR T-cell #2 – was designed to leverage the potent anti-tumor effects of CAR T-cells while providing the durable remissions perhaps offered by ASCT.
Who Was Enrolled in the study?
The trial enrolled 37 patients with Ph-negative (89%) or Ph-like (11%) B-ALL. Key baseline characteristics included:
* Age: Median age of 28 years (range 15-60), with 35% over 35.
* Disease Burden: 16% presented with a high white blood cell count (>30 x 109/L) at diagnosis, indicating a more aggressive disease.
* Risk Stratification: 57% were classified as high-risk based on NCCN criteria, often due to genetic abnormalities like TP53 mutations, complex karyotypes, or ZNF384 rearrangements.
* Ph-like ALL: Among the 11% with Ph-like ALL, two had ABL-class fusions and two had JAK-STAT pathway abnormalities. Patients with ABL-class fusions received tyrosine kinase inhibitors (TKIs) as per protocol.
Importantly, 35 patients completed the full “sandwich” protocol, demonstrating feasibility. Two patients relapsed after the first CAR T-cell infusion and proceeded to allo-HSCT, while one patient with Ph-like ALL experienced a protocol deviation regarding TKI administration.
Navigating the Safety Landscape
The safety profile was generally manageable and consistent with what’s expected from both CAR T-cell therapy and high-intensity chemotherapy.Here’s a breakdown:
* Hematologic Toxicity: All patients experienced grade 3/4 hematologic toxicities, reflecting the intensity of the treatment regimen. Neutropenia lasted a median of 11 days, and thrombocytopenia 15 days after the second CAR T-cell infusion.
* Cytokine Release Syndrome (CRS): CRS was generally mild, with grade 1/2 CRS occurring in 22% after the first infusion and 34% after the second.Crucially, no grade 3 or higher CRS or immune effector cell-associated neurotoxicity syndrome (ICANS) were reported.
* Organ Toxicity: No patients experienced severe organ toxicity.
* Infections: Four infectious complications occurred (2 sepsis,2 pulmonary infections),all successfully managed.
* Non-relapse Mortality: Notably, no non-relapse mortality was observed, a significant finding in this high-risk population.
* B-cell Aplasia: Expectedly, all patients experienced B-cell aplasia, lasting a median of 170 days post-second infusion, confirming CAR T-cell activity.
What Does This Mean for the Future of B-ALL Treatment?
This Phase 2 trial provides encouraging evidence for the feasibility and safety of the sequential CD22
