Interim Results of a Phase II Study Investigating Dasatinib and Inotuzumab Ozogamicin-Based Induction for Newly-Diagnosed Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Introduction:

Ph+ ALL is ~50% of B-cell ALL cases in patients (pts) > 50 years old. Tyrosine kinase inhibitor (TKI)-based therapy is the standard of care, and achieving a major or complete molecular response (MMR; CMR) is associated with excellent survival (Short et al. Blood 2016). Recently, TKI + blinatumomab regimens have shown high CMR rates (Foa et al. NEJM 2020; Advani et al. Blood Adv 2023; Jabbour et al. Lancet Haematol 2023). The anti-CD22 antibody drug conjugate inotuzumab ozogamicin (InO) has efficacy in relapsed/refractory Ph+ ALL and is an alternative immune targeting method. We hypothesized that induction with dasatinib (DAS) + InO for newly-diagnosed (ND) Ph+ ALL would achieve high rates of MMR or better while minimizing cytotoxic chemotherapy.

Methods:

This investigator-initiated, Phase 2 study has a primary endpoint of MMR rate after 2 courses. Molecular response is measured by BCR::ABL1 qRT-PCR and defined per Short et al. Eligibility criteria includes ND Ph+ ALL, age ≥ 18, ECOG ≤2, CD22+ on ≥20% blasts, and no central nervous system (CNS) disease.

For Schema 1, Course (C) 1 (28 days) was DAS 140mg daily, dexamethasone (dex) 10mg/m² D1-7 & D15-21, and InO 0.8mg/m² D8, 0.5mg/m² D15 and D22. C2 (28d) was DAS 140mg daily + InO 0.5mg/m² on D1, D8, D15. C3 was TKI + POMP (84d); C4 was TKI + InO (28d), and C5-7 (84d each) were 3 cycles of TKI + POMP. The TKI was switched from DAS to ponatinib (PON) if a CMR was not achieved prior to C3. Dose limiting toxicity (DLT) was assessed in C1. While there were no DLTs, a planned interim analysis after 7 pts led to an amended schema (#2) due to the occurrence of veno-occlusive disease (VOD) outside of the DLT assessment period.

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 CMR); C5-7 (84d each) TKI + POMP. DLT window was C1 + C2 along with continuous VOD monitoring. CNS prophylaxis was 15 doses of intrathecal chemotherapy. Pt could exit the study to receive allogeneic transplant (allo-HCT). Interim analysis performed after 5 pts treated on Schema 2 met the efficacy threshold (≥3 pts with MMR or deeper) to enroll 9 additional pts.

Results:

Eighteen pts provided consent and enrolled on study (7 Schema 1; 11 Schema 2). Median age was 61 (range 21-79) and 50% were female. Nine pts were non-Hispanic (NH) White, 5 were NH Black, 2 were Hispanic, and 2 did not report race/ethnicity. Twelve pts had p190 transcript, 5 had p210, and 1 had an atypical transcript. Eight pts had IKZF1 aberrations (IZKF1aber) (7 loss, 1 mutation) and 3 pts had IKZF1^plus as defined by Foa et al.

Among all 18 pts, the end of C2 CMR rate was 61% and MMR rate was 22%; 3 pts had complete hematologic remission without MMR. Pts (n=7) who did not achieve CMR at end of C2 switched TKI to PON. The end of C3 CMR rate was 89% (n=16). For the 8 pts with IZKF1aber, CMR rate was 63% at end of C2 and 100% at end of C3. For the 3 pts with IKZF1^plus, CMR rate was 67% at end of C2 and 100% at end of C3. For the 11 pts treated on Schema 2, the end of C2 CMR rate was 55% and MMR rate was 18%; the end of C3 CMR rate was 91%.

Measurable residual disease (MRD) was also tracked with next-generation-sequencing (NGS) (sensitivity 10^-6); MRD negative (MRD-) rate was 67% after C2 and 89% after C3. By the end of C3, all 18 pts achieved either a CMR by qRT-PCR or MRD- disease by NGS; 14 pts had CMR and were MRD- by NGS, 2 had CMR but were MRD+ by NGS, and 2 had less than CMR but were MRD- by NGS.

Median follow-up is 343 days (range, 171-1043) and there have been no relapses. No pts have received allo-HCT. One pt died in remission while on protocol (respiratory failure during C5) and 3 pts died in remission after going off study (2 sepsis, 1 gastrointestinal (GI) bleed).

Two of the first 7 pts on Schema 1 developed non-fatal VOD. These cases occurred 9 days after C1 and 24 days after C2. No VOD or DLTs have occurred on Schema 2. Grade 3-4 adverse events with incidence ≥10% were COVID19 (22%), dyspnea (22%), anemia (17%), fatigue (17%), anorexia (11%), bacteremia (11%), constipation (11%), elevated liver enzymes (11%), GI bleeding (11%), kidney injury (11%), vomiting (11%), and neutropenic fever (11%).

Conclusion:

DAS + InO induction has an MMR+CMR rate of 83% within 2 courses thus far; 100% of pts achieved CMR and/or MRD negativity by NGS within 3 courses. No cases of VOD were seen after decoupling DAS and InO in Schema 2. There have been no relapses thus far. Enrollment is ongoing; updated results will be presented at the meeting.