Consolidation with CAR T-cell therapy may abrogate the need for allogeneic stem cell transplant in patients with relapsed B-cell acute lymphoblastic leukemia after receiving dose-dense mini-hyper-CVD with inotuzumab ozogamicin and blinatumomab Free

The historical outcomes for patients with relapsed and/or refractory (R/R) B-cell acute lymphoblastic leukemia (B-cell ALL) are poor. Here, we present the 2-year follow-up results of the phase 2 trial of adults with R/R B-cell ALL who received mini-hyper-CVD in combination with inotuzumab ozogamicin (InO) and blinatumomab (blina) in a dose-dense fashion, with an analysis focused on outcomes stratified by consolidative treatment received.

Methods Pts>18 years old with R/R Philadelphia (Ph) positive (+) or Ph-negative (-) B-cell ALL were eligible for this trial. Pts received mini-hyper-CVD in combination with InO and blina in a dose-dense fashion: cycles 1, 3, 5 consisted of mini-hyper-CVD (cyclophosphamide 150 mg/m² D1-3, vincristine 2mg D4, dexamethasone 20 mg D1-4, InO 0.6 mg/m² D2 and 0.3 mg/m² D8 [of C1], InO 0.3 mg/m² D2 and 0.3 mg/m² D8 [of C3], blina 9ug D4-5 and 28 ug D6-21 [of C1] and blina 28 ug D4-21 [of C3 and C5); cycles 2, 4, 6 consisted of mini-MTX and ara-C (MTX 250 mg/m2 D1, cytarabine 500 mg/m² q12 hours D2-3, InO 0.3 mg/m² D2 and 0.3 mg/m² D8 [of C2 and C4], blina 28 mg D4-21), with Peg-G-CSF administered after each course. Pts received 12 IT chemotherapy administrations and rituximab if CD20 positive. All pts received ursodiol. Pts with Ph+ ALL received a concomitant BCR::ABL1 tyrosine kinase inhibitor.

Results Between September 2021-June 2025, 25 pts were enrolled: median age was 39 years (range, 19-62); 3 pts (12)% >60 years and 16 pts (64%) were male. Three pts (12%) had Ph+ ALL; the remaining pts (88%) had Ph- ALL, of which 8 pts (36%) had Ph-like disease. Four pts (16%) had adverse risk cytogenetics including 1 pt with KTMT2Ar. Six pts (24%) had a mutation in TP53. Twenty-two pts (88%) were in salvage 1, of which 7 (32%) had primary refractory disease and 3 (14%) pts had a duration of prior remission of <12 months. Three pts (12%) had previously undergone allogeneic stem cell transplantation (ASCT) and 8 pts (32%) had previously received blina.

All patients achieved a CR/complete remission with incomplete count recovery (CRi), of which 19 (79%) achieved CR. Twenty-one pts (95%) achieved measurable residual disease (MRD)-negativity by flow cytometry (FC) overall, with 16 (73%) achieving after 1 cycle. Eighteen pts (95%) achieved MRD-negativity by next generation sequencing (NGS) overall, with 6 (38%) achieving after 1 cycle.

The median follow-up time was 25 months. Five out of 25 pts (20%) proceeded to ASCT consolidation, of which 3 pts (60%) relapsed (1 died); 2 pts (40%) are alive in CR after ASCT. Ten (40%) proceeded to CAR T consolidation (8 [80%) were in salvage 1, 2 [20%] were in salvage 2), of which 9 pts (90%) are alive in remission; only 1 of these pts relapsed and died. At the time of CAR T infusion, 6/9 pts (67%) were NGS MRD-negative, 3 (33%) were NGS-MRD positive. The peak CAR T expansion was 3 cells/uL (range, 0-20). Of the 3 pts with NGS-MRD positivity pre-CAR T, 2 (67%) became MRD-negative and 1 (33%) is below LOD post CAR T at last follow-up.

Five out of the remaining 10 pts (50%) are in continuous remission with no further consolidative treatment. Three pts (30%) relapsed without further consolidative treatment, of which 2 have died. Two pts (20%) died in CR (sepsis and klebsiella pneumonia).

The median EFS and OS are 41 months and not reached, respectively. The 1- and 2-year OS rates are 87% and 77%, respectively. The 1- and 2-year EFS rates are 77% and 69%, respectively. The 2-year EFS and OS rates in patients who received CAR T consolidation vs. ASCT consolidation vs. no further consolidation were 89%, 80%, and 44%, and 89%, 100%, and 52% (p=0.18), respectively. The 2-year cumulative incidence of relapse with CAR T vs. ASCT vs no consolidation was 11% vs 20% vs. 33% (p=0.4) and the 2-year cumulative incidence of death without relapse was 0%, 0%, and 22% (p=0.2).

Conclusion For adult patients with R/R B-cell ALL, the dose-dense mini-CVD regimen in combination with InO and blina leads to 100% response rates, 95% NGS MRD-negativity, and 2-year OS and EFS rates of 77% and 69%, respectively. Proceeding with CAR T consolidation leads to impressive outcomes with a 2-year EFS and OS rates of close to 90%. Such strategy is being evaluated in the frontline setting.