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.

Disclosures

Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Short:Novartis: Honoraria; BeiGene: Honoraria; Autolus: Honoraria; Sanofi: Honoraria; Adaptive Biotechnologies: Honoraria; Takeda Oncology: Honoraria, Research Funding; Xencor: Research Funding; Astellas Pharma, Inc.: Honoraria, Research Funding; Amgen: Honoraria; Stemline Therapeutics: Research Funding; NextCure: Research Funding; Pfizer Inc.: Honoraria; GSK: Consultancy, Research Funding. Jain:Servier: Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Support; CareDx: Consultancy, Honoraria, Other: Travel Support; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; Medisix: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; Ipsen: Consultancy, Honoraria, Other: Travel Support; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Aprea Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; NovalGen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; ADC Therapeutics: Research Funding; Fate Therapeutics: Research Funding; TransThera Sciences: Research Funding; Pfizer: Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; Dialectic Therapeutics: Research Funding; Incyte: Research Funding; Loxo Oncology: Research Funding; MingSight: Honoraria, Research Funding; Newave: Research Funding; Takeda: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding. Chien:AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Garcia-Manero:AbbVie: Research Funding; Aprea: Research Funding; Helsinn: Other: Personal fees; Forty Seven: Research Funding; Astex: Research Funding; Helsinn: Research Funding; Astex: Other: Personal fees; Janssen: Research Funding; Genentech: Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Curis: Research Funding; Genentech: Other: Personal fees; Amphivena: Research Funding. Kadia:Rigel: Honoraria; BMS: Consultancy, Research Funding; Pfizer: Research Funding; Amgen: Research Funding; DrenBio: Consultancy, Research Funding; JAZZ: Research Funding; Servier: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Incyte: Research Funding; ASTEX: Research Funding; AstraZeneca: Research Funding; Cellenkos: Research Funding; Novartis: Honoraria; Ascentage: Research Funding; Regeneron: Research Funding; Sellas: Consultancy, Research Funding. Daver:KITE: Research Funding; Novartis: Consultancy; Celgene: Consultancy; Menarini Group: Consultancy; Trovagene: Research Funding; Astellas: Consultancy, Research Funding; Jazz: Consultancy; Trillium: Consultancy, Research Funding; Syndax: Consultancy; Agios: Consultancy; FATE Therapeutics: Other: Consulting Fees, Research Funding; Glycomimetics: Research Funding; Arog: Consultancy; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Shattuck Labs: Consultancy; Novimmune: Research Funding; Gilead: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding. DiNardo:Genetech: Honoraria; Astex: Research Funding; Foghorn: Research Funding; Astellas: Consultancy, Honoraria; Rigel: Research Funding; Gilead: Consultancy; Loxo: Research Funding; ImmuneOnc: Research Funding; Jazz: Consultancy, Honoraria; Schrodinger: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Riegel: Honoraria; Immunogen: Honoraria; AstraZeneca: Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; GSK: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy; Notable Labs: Honoraria; Cleave: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Stemline: Consultancy. Sasaki:Daiichi-Sankyo: Consultancy; Chugai: Other: Lecture fees; Enliven: Research Funding; Otsuka: Other: Lecture fees; Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Ravandi:Syros: Consultancy, Honoraria, Research Funding; Astyex/Taiho: Research Funding; BMS: Consultancy, Honoraria; Amgen: Research Funding; Prelude: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Xencor: Research Funding. Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding; AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy.

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2024
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