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98 CA180-372: An International Collaborative Phase 2 Trial of Dasatinib and Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)Clinically Relevant Abstract

Acute Lymphoblastic Leukemia: Clinical Studies
Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Advances in the Treatment of ALL
Saturday, December 9, 2017: 9:45 AM
Bldg C, Lvl 2, C211-C213 (Georgia World Congress Center)

Stephen P. Hunger, MD1, Vaskar Saha, MD, PhD2*, Meenakshi Devidas3*, Maria Grazia Valsecchi4*, Julie Gastier Foster5*, Gianni Cazzaniga, PhD6, Shalini C. Reshmi, PhD7, Michael Borowitz, MD, PhD8, Anthony Moorman9*, Nyla A. Heerema, PhD10, Andrew J. Carroll III, PhD11*, Phillip Barnette12*, M. Monica Monica Gramatges, MD13, Kelly Maloney, MD14*, Weili Sun, MD, PhD15, Rene Swanink16*, Amanda Termuhlen17*, Mignon L. Loh, MD18, Elizabeth A. Raetz, MD19, Lewis B. Silverman, MD20,21, Martin Schrappe, MD, PhD22, Kirk R. Schultz23*, William Slayton, MD24*, Diane Healey16* and Andrea Biondi, MD25

1Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
2University of Manchester, Manchester, United Kingdom
3Department of Biostatistics, College of Medicine, University of Florida, Gainesville, FL
4University of Milano Bicocca, Monza, Italy
5The Ohio State University College of Medicine, Columbus, OH
6Fondazione Tettamanti ONLUS, Monza, Italy
7Institute for Genomic Medicine, /The Ohio State University, Columbus, OH
8Johns Hopkins Medical Institutions, Baltimore, MD
9Newcastle University, Newcastle upon Tyne, United Kingdom
10Department of Pathology, College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH
11University of Alabama at Birmingham, Birmingham, AL
12Primary Children's Hospital, Salt Lake City, UT
13Texas Children's Cancer and Hematology Services, Baylor College of Medicine, Houston, TX
14Center for Cancer and Blood Disorders, Department of Pediatrics, Children's Hospital Colorado and the University of Colorado School of Medicine, Aurora, CO
15City of Hope National Medical Center, Duarte, CA
16Bristol-Myers Squibb, Princeton, NJ
17Children’s Hospital Los Angeles, Los Angeles, CA
18Department of Pediatrics, Benioff Children’s Hospital and the Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA
19Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT
20Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
21Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA
22Christian-Albrechts University; University Medical Center, Kiel, Germany
23Department of Pediatrics, British Columbia Children's Hospital, Vancouver, BC, Canada
24University of Florida, Gainesville, FL
25University of North Carolina, Chapel Hill, NC

Introduction: Ph+ ALL comprises ~5% of childhood and adolescent ALL. Prior to development of tyrosine kinase inhibitor (TKI) therapy, survival rates were poor. Less than half of patients (pts) survived despite treatment with intensive chemotherapy and frequent use of allogeneic hematopoietic stem cell transplant (HSCT) in first remission (CR1). The Children’s Oncology Group (COG) AALL0031 trial (Schultz, JCO 2009) and the EsPhALL trial (Biondi, Lancet Oncology 2012) showed adding imatinib to different intensive chemotherapy backbones improved event-free (EFS) and overall survival (OS) in pediatric Ph+ ALL. Dasatinib is attractive to study in Ph+ ALL because it is a dual ABL/SRC TKI that is 300 times more potent than imatinib in vitro, is active against most ABL1 TKI domain mutations that cause imatinib resistance, and accumulates in the central nervous system (CNS), a sanctuary site for ALL where imatinib penetration is poor.

Methods: We conducted a phase 2 trial of dasatinib added to the EsPhALL chemotherapy backbone in pediatric (>1-17.99 years (yrs) of age) Ph+ ALL pts at COG sites in North America and Australia and EsPhALL sites in Italy and the United Kingdom. Protocol therapy added continuous daily dasatinib (60 mg/m2) at day 15 of induction chemotherapy. The study measured minimal residual disease (MRD) by Ig/TCR PCR, flow cytometry, and BCR-ABL1 RT-PCR, with clinical actions based upon a single method, in this hierarchical order. Pts with MRD ≥ 0.05% at the end of block Ib (day 78) and those with MRD 0.005-0.05% at end of Ib who remained MRD positive at any detectable level after three additional high-risk (HR) chemotherapy blocks underwent HSCT in CR1. Dasatinib treatment post HSCT was optional. The remaining pts received chemotherapy plus daily dasatinib for 2 yrs, with cranial irradiation limited to CNS3 pts. The primary study endpoint was 3-year EFS assessed when all patients completed 3 years of follow-up.

Results: From April 2012 to May 2014, 109 pts enrolled; 3 did not meet inclusion criteria and received no trial therapy. The median age was 9.0 yrs (range 1-17), 54% were males, and 80% were Caucasian. 71% had CNS1 status at baseline, 24% CNS2, and 5% CNS3. Safety analysis included all treated pts (N=106) and efficacy analysis included all treated Ph+ ALL pts (N=104; 2 pts were retrospectively diagnosed with blast crisis CML). The database lock date was 8/17/16; at this time all pts had completed therapy and 75% had ≥3 yrs of follow-up. Two pts discontinued dasatinib for toxicity (1 allergy and 1 prolonged myelosuppression post HSCT). Nineteen pts met study criteria for HSCT, and 15 received HSCT in CR1 (14.2% of pts). The remaining 91 pts (85.8%) received EsPhALL chemotherapy plus dasatinib without HSCT. Patients tolerated dasatinib combined with chemotherapy well. The primary toxicity was febrile neutropenia and infection: Grade 3+ febrile neutropenia occurred in 75.5% of pts, Grade 3+ sepsis in 18.9%; and Grade 3+ bacteremia in 13.2%. Elevated ALT (21.7%) and AST (10.4%) were the only non-hematologic, non-infectious Grade 3+ adverse events attributed to dasatinib reported in >10% of pts. Relevant Grade 3+ non-hematologic, non-infectious toxicities attributed to dasatinib included pleural effusion (3.8%), edema (3.8%), hemorrhage (2.8%), and cardiac failure (0.8%). No cases of pulmonary hypertension or pulmonary arterial hypertension were reported. All 104 treated Ph+ ALL pts achieved CR. As of the database lock date, 33 events had occurred including 5 deaths (3 in HR3 and 2 in reinduction) due to proven or suspected infection in the 91 patients receiving chemotherapy plus dasatinib, 2 deaths from infection post-HSCT in the 15 HSCT pts, and 26 relapses (chemotherapy 22/86; HSCT 4/12). Sites of relapse included isolated bone marrow (BM; 14), CNS (4), BM+CNS (3), BM+other (2), and other (3). At the time of the interim analysis the 3-yr EFS is 66.0% (95% CI, 54.8-75.0) and the 3-yr OS is 92.3% (95% CI, 85.2-96.1); updated results with all patients having at least 3 years of follow-up will be presented.

Conclusions: Addition of dasatinib to the EsPhALL chemotherapy regimen is safe and effective in pediatric Ph+ ALL pts. With only 14% of pts undergoing SCT in CR1, as compared to 80% in the EsPhALL imatinib trial, this trial demonstrates similar outcomes with 3-yr EFS/OS 66.0%/92.3% in this trial vs. published 4-yr EFS/OS 61.9%/72.1% in the EsPhALL imatinib trial.

Disclosures: Hunger: Novartis: Consultancy; Jazz Pharmaceuticals: Honoraria; Erytech Pharmaceuticals: Consultancy; Amgen: Consultancy, Equity Ownership. Saha: Shire: Research Funding. Gastier Foster: Bristol-Myers Squibb: Research Funding. Cazzaniga: Italian Association for Cancer Research: Research Funding; Fondazione Tettamanti onlus: Employment. Borowitz: Beckman Coulter: Honoraria; Becton-Dickinson Biosciences: Research Funding; HTG Molecular: Honoraria. Gramatges: Bristol Meyer Squibb: Research Funding. Sun: Baxalta: Consultancy. Swanink: Bristol-Myers Squibb: Employment. Schrappe: Baxalta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; JAZZ Pharma: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Medac: Consultancy, Research Funding. Healey: Bristol-Myers Squibb: Employment, Equity Ownership; Pfizer: Equity Ownership.

*signifies non-member of ASH