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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.

MRD assessment is used for risk stratification, prognosis, and treatment decisions (eg, hematopoietic stem cell transplant (HSCT) recommendation) in adult and childhood ALL. In Ph+ ALL, three distinct assay methods may be used to detect MRD: polymerase chain reaction (PCR) for clonal immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements, quantitative RT-PCR (RQ-PCR) measurement of BCR-ABL1 transcripts, and flow cytometry (Flow). If results vary by assay method, different treatment decisions might be made. To assess this possibility, we examined the concordance of MRD levels and corresponding HSCT recommendations across the three methods for measuring MRD in patients (pts) enrolled to CA180372, a phase 2 study of dasatinib added to standard of care chemotherapy in pediatric pts with newly diagnosed Ph+ ALL. CA180372 (Children's Oncology Group (COG) AALL1122) was a collaboration between the COG, EsPhALL (European Intergroup Study on Post Induction Treatment of Ph+ ALL), and Bristol-Myers Squibb. Prior to study initiation, validation and proficiency testing were completed for standardization of methods used to detect MRD and for interpretation of IG/TR and BCR-ABL1 in accordance with guidelines developed by the EuroMRD consortium. All Flow analyses were performed at Johns Hopkins University. All pts received continuous treatment with dasatinib (60 mg/m2/d starting at day 15 of induction therapy) added to successive blocks of the EsPhALL multiagent chemotherapy regimen for a maximum of 2 y. MRD was analyzed 4 times during therapy (induction IA/baseline, end induction IA, start high risk block 1 (HR1), and end HR block 3 (HR3)). Pts were recommended for HSCT if: · Start of HR1 ≥0.05% by IG/TR PCR (or by Flow), less than 3-log reduction in MRD as measured by RQ-PCR for BCR-ABL1 OR · Start of HR1 0.005-0.05% by IG/TR PCR (or by Flow) or any positivity by BCR-ABL1 AND MRD remains positive at any detectable level (providing the assay limit is at least 0.1%) at the end of HR3 Clinical decisions were based on a single MRDmethodology, with the hierarchy of IG/TR > BCR-ABL1 > Flow. In this report we evaluated the concordance in HSCT recommendation among all three MRD methods. A total of 106 pts >1 y and These data were used to conduct inter-assay HSCT recommendation comparisons (Table). Rates of concordance in HSCT recommendations varied from 79.5-89.7% across methods. Among the discordant HSCT recommendations observed between each pair-wise comparison, 6/9 (IG/TR vs Flow), 2/4 (IG/TR vs BCR-ABL1), and 4/8 (BCR-ABL1 vs Flow) numerical MRD results were within 1-log, but fell on opposite sides of the assay cutoff point; assay-specific protocol criteria resulted in discordant HSCT recommendation in those cases. All pts enrolled to CA180372 were followed by at least one MRD method. HSCT recommendations could be made for most (98%) pts by Flow, while HSCT recommendation by IG/TR could be made for 84% of pts. Only 39% of pts could be recommended for HSCT based on BCR-ABL1 results. The main reason that BCR-ABL1 results were available for fewer pts was the requirement for at least 10,000 copies at baseline in order to assess if a 3-log reduction was achieved. Re-evaluation of assay-specific requirements is warranted. The overall concordance in HSCT recommendation was approx 80-90% across all three MRD methods. Overall, HSCT recommendation would have differed in 14 pts. Discordance between assays may be attributable (in part) to protocol-specific criteria, assay-specific threshold cut points, and/or differences in MRD results over different marrow pulls. Outcome data are not mature enough at this time to know whether pts recommended against HSCT by one method have increased risk for relapse when found to be eligible for HSCT by another method. Figure 1. HSCT Recommendation Concordance, by MRD Method Figure 1. HSCT Recommendation Concordance, by MRD Method Disclosures Borowitz: Becton Dickinson Biosciences, Medimmune: Research Funding. Geese:BMS: Employment. Healey:Bristol-Myers Squibb: Employment. Gastier-Foster:Bristol-Myers Squibb: Research Funding. Hunger:Bristol-Myers Squibb: Employment; Jazz Pharmaceuticals; Sigma Tau Pharmaceuticals; Erytech: Honoraria.

Background: Dasatinib is a potent BCR-ABL tyrosine kinase inhibitor (TKI) currently approved at 100 mg once daily (QD) as a first-line therapy in CML-CP pts and a second-line therapy in pts with CML resistant/intolerant to prior therapy. CA180-034 (NCT00123474), a prospective, randomized phase 3 study, was designed to compare the dose and schedule of dasatinib therapy for the optimal benefit/risk ratio among pts with imatinib-resistant or -intolerant CML-CP. Results from this study have previously demonstrated significant efficacy of dasatinib in this pt population. Here, we report the final 7-yr analysis of efficacy and safety outcomes of CA180-034, which represents the longest follow-up of any second-generation BCR-ABL TKI to date. Methods: The CA180-034 2 X 2 factorial study design has previously been described (Shah 2010, J Clin Oncol). Pts (n=670) were randomized to dasatinib: 100 mg QD (n=167), 50 mg twice daily (BID; n=168), 140 mg QD (n=167), or 70 mg BID (n=168). To manage inadequate response or adverse events (AEs), dose escalation (up to a total daily dose [TDD] of 180 mg) and dose interruption or reduction (down to a TDD of 20 mg) were allowed. After 2 yrs, the protocol was amended to allow switching to a QD regimen with the same TDD after at least one dose reduction for recurrent anemia, thrombocytopenia, neutropenia, pleural effusion, or any other fluid retention during study progress or at the investigator’s discretion (Shah 2014, Blood). Results: Approximately 55% (50 mg BID) and 51% (70 mg BID) of pts treated after the protocol amendment switched to QD dosing by the last recorded dose. The overall median duration of therapy was longer for the 100 mg QD group (37.4 months [mos]) compared with the 50 mg BID, 140 mg QD, and 70 mg BID groups (28.1 mos, 26.6 mos, and 28.9 mos, respectively).At 7 yrs of follow-up, progression-free survival (PFS) andoverall survival (OS) rates were similar for all doses, as were the proportions of pts with a best on-study molecular response of MMR (Table 1). In an exploratory landmark analysis, pts in the 100 mg QD arm with BCR-ABL ≤10% (on the International Scale) at 3 mos had improved PFS and OS rates at 7 yrs relative to pts with BCR-ABL>10% (Table 2). BCR-ABL mutations were assessed in pts prior to the start of dasatinib (baseline), at the time of disease progression, or at end of treatment. Three mutations persisted or developed in pts who discontinued dasatinib due to loss of response on 100 mg QD: V299L (n=3), T315I (n=6), and F317L (n=7). For 100 mg QD, most nonhematologic and hematologic AEs (all grades) typically first occurred within the first 24 mos of treatment. Rates of nonhematologic AEs (all grades) over 7 yrs for 100 mg QD compared with other treatment arms included fluid retention (51% vs 54%), diarrhea (42% vs 47%), nausea/vomiting (27% vs 43%), myalgias/arthralgias (38% vs 33%), fatigue (37% vs 34%), and rash (33% vs 36%). Within yr 7 of the study, new cases of pleural effusion occurred in 5% (2/42) of pts at risk treated with dasatinib 100 mg QD compared with 8% (7/88) in other treatment arms. Severe (grade 3–4) AEs (any relationship) occurred less frequently in the 100 mg QD group (98/165, 59%) relative to other treatment arms (341/497, 69%). Three pts died due to study drug toxicity (1 due to sepsis; 1 due to pulmonary edema, congestive heart failure, neck pain, and pleural effusion; 1 due to necrosis of the colon). Conclusions: Long-term follow-up of dasatinib continues to demonstrate durable efficacy and benefit for pts with CML-CP following imatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 mos. Dasatinib is well-tolerated amongst pts, with most AEs occurring early on during the course of treatment; however, pleural effusion did occur through 7 yrs of treatment. No new safety signals were detected. Table 1 Efficacy results Patients 100 mg QD (n=167) 50 mg BID (n=168) 140 mg QD (n=167) 70 mg BID (n=168) MMR in assessed treated patients, n (%) 73 (46) 70 (44) 68 (44) 69 (46) PFS at 7 yrs, % (95% CI) 42 (33–51) 44 (35–53) 38 (30–47) 44 (35–52) OS at 7 yrs, % (95% CI) 65 (56–72) 70 (62–77) 73 (65–80) 68 (60–75) Table 2 Landmark analysis: Efficacy rates at 7 yrs Patients 100 mg QD (n=165) BCR-ABL ≤ 10% at 3 mos BCR-ABL > 10% at 3 mos PFS, % (95% CI) 56 (43–67) 21 (10–34) OS, % (95% CI) 72 (60–81) 56 (42–68) Transformation-free,a% (95% CI) 93 (84–97) 88 (67–96) a Limited to events during the study therapy as reason for progression not collected in follow-up. Disclosures Shah: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding. Rousselot:Bristol-Myers Squibb: Consultancy, Research Funding. Schiffer:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: DSMB Other. Rea:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Ariad: Honoraria. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Milone:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mohamed:BMS: Employment. Healey:Bristol-Myers Squibb: Employment. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; MSD: Research Funding. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other.