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2839 Phase II Study of Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy As Consolidation and Maintenance Therapy for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Following Chemotherapy-Sparing Induction

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Poster III
Hematology Disease Topics & Pathways:
Leukemia, ALL, Biological, Adult, Diseases, Therapies, Combinations, immunotherapy, Lymphoid Malignancies, Study Population, Clinically relevant, TKI
Monday, December 7, 2020, 7:00 AM-3:30 PM

Mark B. Geyer, MD1,2, Amber C. King, PharmD, BCOP3, Justin C. O'Brien1* and Jae H. Park, MD2,4

1Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
2Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
3Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY
4Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY

Background: Combining oral ABL-targeted tyrosine kinase inhibitors (TKIs) with (w/) multi-agent chemotherapy has improved the long-term disease-free survival of adults w/ Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, Ph+ ALL occurs more commonly in older adults, and toxicities of multi-agent chemotherapy, including sequelae of prolonged myelosuppression, are amplified in this population. Others have previously reported rates of morphologic complete response (mCR) approaching 100% among adults w/ Ph+ ALL treated w/ corticosteroids (CS) and dasatinib (DAS) alone as induction therapy, but w/ low rates of minimal residual disease (MRD) negativity by flow cytometry (FACS) and BCR-ABL1 PCR (complete molecular response, CMR) and high rates of relapse in the absence of further consolidation.

The bispecific T-cell engager blinatumomab (BLIN) has considerable efficacy in clearing MRD in patients (pts) w/ Ph- B-cell ALL. We have previously reported our institutional experience combining ABL TKIs w/ BLIN in pts w/ Ph+ ALL and MRD, including encouraging safety data and high rates of MRD eradication (King/Geyer et al., Leuk Res, 2019). The ongoing D-ALBA study (GIMEMA LAL2116) is also investigating BLIN + DAS consolidation following 12 weeks of induction (prednisone + DAS followed by DAS), w/out protocol-specified maintenance, and has demonstrated preliminary evidence of efficacy (Chiaretti et al., ASH Meeting, 2019). As such, we designed a phase II study of BLIN as part of a chemotherapy sparing strategy in pts w/ Ph+ ALL (BLISSPHALL), introducing BLIN as early as 6 weeks into treatment for pts in morphologic CR, w/ aim of enhancing early MRD negativity and suppressing resistant clones early in disease course.

Study design and methods: Our institution is leading a phase II trial of TKI + BLIN consolidation and maintenance in adults w/ newly-diagnosed Ph+ ALL, w/ potential multicenter expansion (NCT04329325). Pts are eligible if they are ≥18 years-old w/ Ph+ ALL confirmed by cytogenetic or molecular studies, ECOG performance status 0-2, w/out prior therapy for ALL beyond CS, hydroxyurea, or intrathecal chemotherapy, w/out known active extramedullary disease and/or CNS-3 disease, and w/ appropriate organ function.

See Figure 1: pts will receive a CS pre-phase (days [d] -6 – 0) followed by modified GIMEMA LAL1205 induction (dexamethasone [DEX] 10 mg/m2 [max 24 mg/d], d1-24, tapered off d25-32) + DAS 140 mg/d (dose adjustments or TKI change permitted per protocol) w/ intrathecal methotrexate (IT MTX) d22, 43 and bone marrow (BM) assessments including FACS and BCR-ABL1 PCR. Pts in mCR on d43 (or optional reassessment ≤ 3 weeks later) will be eligible to proceed to consolidation w/ 3 cycles (C) BLIN 28 mcg/d IVCI, d1-28, concurrent w/ TKI, w/ 14d off BLIN between cycles and BM MRD assessment/IT MTX after each cycle. C1 BLIN + TKI is required to begin inpatient x72 hours. TKI is given continuously including between BLIN cycles. Pts in CMR after consolidation may proceed to maintenance (C4-7 BLIN + TKI, 28d off between cycles). Pts may come off study to proceed to hematopoietic cell transplant (HCT) at any point, though it is recommended such pts receive ≥2C of BLIN + TKI.

The primary objective is to determine the proportion of evaluable pts achieving CMR by the end of consolidation (≤ 3C BLIN + TKI). Secondary objectives include safety/toxicity of BLIN + DAS, duration of CMR, incidence of relapse, event-free/overall survival. Exploratory objectives include safety/toxicity of non-DAS TKIs + BLIN, defining patterns/mechanisms of resistance to BLIN+TKI (including ABL kinase mutations), and outcomes among pts not undergoing HCT.

The trial utilizes a Simon’s minimax two-stage design; 20% CMR rate is considered not promising, a 50% CMR rate is considered promising, and probabilities of type I/II error are set at 0.10/0.10. If ≥ 3 of the first 10 pts achieve CMR we will continue enrollment to max 17 pts. If ≥ 6 pts achieve CMR, then BLIN + TKI will be considered promising for further investigation.

The investigators are hopeful this study will add to the currently limited prospective data supporting TKI + BLIN consolidation/maintenance for pts w/ Ph+ ALL and efforts to develop chemotherapy-sparing and immunotherapeutic strategies for older pts w/ ALL.

Disclosures: Geyer: Amgen: Research Funding. King: Abbvie: Other: advisory board. Park: Allogene: Consultancy; Artiva: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Research Funding; Juno Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; AstraZeneca: Consultancy; GSK: Consultancy; Autolus: Consultancy, Research Funding; Novartis: Consultancy; Intellia: Consultancy; Minverva: Consultancy; Genentech/Roche: Research Funding; Fate Therapeutics: Research Funding; Servier: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Kite: Consultancy, Research Funding.

OffLabel Disclosure: Blinatumomab is not approved to be given in combination with ABL tyrosine kinase inhibitors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

*signifies non-member of ASH