Primary efficacy analysis of phase II study investigating tyrosine kinase inhibitor (TKI) and inotuzumab ozogamicin-based therapy for newly diagnosed Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) Free

Introduction: Amongst patients (pts) ≥ 50 years old diagnosed with B-ALL, half have Ph+ ALL. Achieving a BCR::ABL1 qRT-PCR of <0.1% (MR3) or <0.01% (MR4) with TKI-based therapy correlates with excellent long-term survival in Ph+ ALL (Short et al. Blood 2016). Tyrosine kinase inhibitor (TKI) + blinatumomab regimens have demonstrated high MR4 rates and favorable overall survival (OS); however, these regimens include up to 5 courses of blinatumomab which is a continuous 28-day infusion (Kantarjian et al, JCO 2024; Foa et al, JCO 2024). The anti-CD22 antibody drug conjugate inotuzumab ozogamicin (InO) has efficacy in both relapsed/refractory Ph+ ALL and newly diagnosed B-ALL (Stock et al, Cancer 2021; Wieduwilt et al, JCO 2023). We hypothesized that TKI + InO-based therapy for newly diagnosed Ph+ ALL would achieve high rates of MR3 or better (MR3+) while minimizing cytotoxic chemotherapy, prolonged antibody-based treatment, and inpatient administration of treatment.

Methods: The primary endpoint of this investigator-initiated, Phase 2 study was MR3+ rate after 2 courses. Eligibility criteria includes newly diagnosed Ph+ ALL, age ≥ 18, ECOG ≤2, CD22+ on ≥20% blasts, and no central nervous system (CNS) disease.

Schema 1 was as follows; Course (C) 1 was (28 days) dasatinib (DAS) 140mg daily, dexamethasone (dex) 10mg/m² D1-7 & D15-21, and InO 0.8mg/m² D8, 0.5mg/m² D15 and D22. C2 was (28d) DAS 140mg daily + InO 0.5mg/m² on D1, D8, D15. C3 was TKI + POMP (84d), C4 was TKI + InO (28d), and C5-7 were (84d each) 3 cycles of TKI + POMP. If MR4 was not achieved by end of C2 (EOC2), DAS was switched to ponatinib (PON). Dose limiting toxicity (DLT) window was C1. There were no DLTs, however, a planned interim analysis after 7 pts led to an amended schema (#2) due to the occurrence of veno-occlusive disease (VOD) after the DLT period in 2 pts.

Schema 2 is the following: C1 (28d) DAS 140mg daily, dex 10mg/m² D1-7 & D15-21; C2 (28d) InO 0.5mg/m² on D1, D8, D15; C3 (84d) TKI + POMP; C4 (28d) TKI (InO added if no MR4); C5-7 (84d each) TKI + POMP. DLT window was C1 + C2 along with continuous VOD monitoring. CNS prophylaxis was 15 doses of intrathecal chemotherapy. Fourteen pts were treated on Schema 2. MR3+ rate of ≥ 64% by EOC2 would meet the efficacy endpoint.

Results: Twenty-one pts were enrolled. Median age was 60 (range 21-79) and 57% were female. Race/ethnicity distribution was 53% non-Hispanic (NH) White, 24% NH Black, 14% Hispanic, and 10% not reported. Fourteen pts had p190 transcript, 6 had p210, and 1 had an atypical transcript. Three pts had IKZF1^plus.

Among all 21 pts, the EOC2 MR4 rate was 62% and another 19% achieved MR3; 4 pts had complete remission without MR3+. Pts (n=8) who did not achieve MR4 at EOC2 switched TKI to PON. The end of C3 (EOC3) MR4 rate was 90%. For the 3 pts with IKZF1^plus, MR4 rate was 67% at EOC2 and 100% at EOC3. One pt had a WBC ≥70 at diagnosis and achieved MR4 by EOC2. For Schema 2 (n=14), the EOC2 MR4 rate was 57% and MR3 rate was 14%; the EOC3 MR4 rate was 93%.

Measurable residual disease (MRD) was also assessed with next-generation-sequencing (NGS) (sensitivity 10^-6); MRD negative (MRD-) rate was 62% by EOC2 and 90% by EOC3. By EOC3, all pts achieved either a MR4 or MRD- disease by NGS.

Median follow-up was 1.66 years (range, 0.19-3.85). Estimated 2-year OS was 79% (95% CI, 62%-100%). No pts received allogeneic transplant and there have been no CNS relapses. One pt died in remission while on study (respiratory failure during C5), 3 pts died in remission after going off study (2 sepsis, 1 gastrointestinal (GI) bleed), and 1 pt had a CD19+/CD22- systemic relapse with acquisition of an ABL1 T315I mutation after completing protocol therapy.

Two of the first 7 pts on Schema 1 developed VOD; one pt completed protocol therapy with the omission of InO moving forward while the other came off study upon development of VOD. No VOD or DLTs have occurred on Schema 2. Grade 3-4 adverse events with incidence ≥10% were COVID-19 (19%), dyspnea (19%), anemia (14%), and fatigue (14%).

Conclusion: TKI + InO-based therapy for newly diagnosed pts with Ph+ ALL has an MR3+ rate of 81% within 2 courses and 100% of pts achieved MR4 and/or NGS MRD- disease by EOC3. No cases of VOD were seen with Schema 2. Given the excellent rates of MR3+ with limited cycles of InO, further development of this induction approach is warranted. Longer follow-up will be necessary to better understand the risk of post-protocol relapse.