Updated Results of the Combination of Mini-Hyper-CVD with Inotuzumab Ozogamicin and Blinatumomab in Patients with Relapsed/Refractory B-Cell ALL

Background: The sequential combination of mini-Hyper-CVD (mini-HCVD) with inotuzumab ozogamicin (INO) and blinatumomab (Blina) improved the outcome of patients (pts) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) with a tolerable safety profile. Here, we report updated results from a phase II trial including the “dose-dense” (D-D) administration of INO and Blina in combination with chemotherapy with longer follow-up. Methods: Pts ≥18 years with R/R B-ALL were eligible for this phase II trial. All pts received mini-HCVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x4 doses) and INO. In Cohort 1, pts were treated with mini-HCVD for 8 cycles and INO at 1.3-1.8 mg/m2 on Day (D)3 of Cycle 1, and 0.8-1.3 mg/m2 during Cycles 2-4. Maintenance consisted of POMP for 36 months (mo). Following a protocol amendment starting pt #68 (Cohort 2), INO was given at a fractionated dose of 0.6 mg/m2 on D2 and 0.3 mg/m2 on D8 of Cycle 1, then 0.3 mg/m2 on D1 and D8 in Cycles 2-4 for a cumulative dose of 2.7mg/m2; Blina consolidation was added for 4 cycles. Maintenance was 18 mo of POMP alternating with Blina every 3 mo. Starting pt #111, Blina was introduced earlier in a D-D fashion (D-D cohort). In addition to mini-HCVD and INO, pts received Blina from D4 to D21 of each 28-day cycle for up to 6 cycles. CD20+ pts received rituximab on D2 and D8 of the first 4 cycles. All pts received Ursodiol for the prevention of hepatic sinusoidal obstruction syndrome (SOS). Results: From February 2013 to February 2024, 133 pts were treated with a median age of 37 years (range,17-87); 66 (50%) were males. 67 pts were treated in Cohort 1, 44 in Cohort 2, and 22 in the D-D cohort. 41 pts (31%) had high-risk cytogenetics. CRLF2 rearrangement was found in 16/87 pts (18%) and TP53 mutation in 24/79 pts (30%). 25 pts (19%) had prior ASCT. 98 pts (74%) were treated in Salvage (S)1, 19 pts (14%) in S2, and 16 pts (12%) in S3+. Among 132 evaluable pts, the overall response rate (ORR) was 86% (CR, 65%). The ORR was 76% in Cohort 1 (CR, 60%), 93% in Cohort 2 (CR, 66%), and 100% in the D-D cohort (CR, 81%). 7 pts (5%) died within 4 weeks of therapy, all in Cohort 1. The rate of measurable residual disease (MRD) negativity by flow cytometry was 53% after Cycle 1 and 85% overall. These rates were 51% and 82% in Cohort 1, 46% and 85% in Cohort 2, and 74% and 95% in the D-D cohort, respectively. In the D-D cohort, 16 of 17 pts (94%) who had NGS MRD testing achieved negative MRD status. Fifty-seven pts (43%) underwent ASCT and 12 pts (9%) received CAR T-cell therapy. After a median follow-up of 40 mo (range, 3-136) for the entire cohort, the 3-year OS rate was 45% and the relapse-free survival rate was 44%. Pts treated in S1 had better OS compared to pts treated in S2+ (3-year OS, 54% vs 20%; P=0.0001). In a 4-month landmark analysis, the 3- year OS was 60% in patients who underwent transplant and 56% in those who did not (P=0.61). Outcomes appear superior with the D-D regimen. The 1-year OS rate was 51% in Cohort 1, 66% in Cohort 2, and 90% in the D-D cohort (P=0.006). Among patients in S1, these rates were 63%, 66%, and 94%, respectively (P=0.08). SOS was observed in 10 pts: 9 (13%) with the initial trial design and 1 (2%) after the first amendment with fractionated INO dosing (P=0.02). Conclusion: The combination of mini-HCVD, INO and Blina is safe and effective in R/R B-ALL. Introducing Blina and fractionating INO seem to improve the safety and efficacy of this combination. Using a D-D approach resulted in high rates of deep and early MRD responses and promising survival outcomes, which may be better than the sequential use of these agents.