Abstract: Background: The prognosis of children with relapsed/refractory B-cell (CD20+) non-Hodgkin lymphoma (B-NHL), including Burkitt lymphoma (BL), is dismal due to chemo-radiotherapy resistance (Cairo et al, JCO, 2012, Cairo et al, BJH, 2018). Rituximab has been widely used in frontline treatment of B-NHL, however, some patients retreated with rituximab will relapse which limits patient treatment options (Goldman/Cairo, Leukemia, 2013). Several strategies for overcoming rituximab-resistance are currently being evaluated, including engineering of NK cells with chimeric antigen receptors (Chu/Cairo et al, Can Imm Res 2015), as well as second-generation engineered anti-CD20 antibodies (Tiwari/Cairo et al BJH 2015). To enhance NK based therapy, our group has successfully expanded the functionally activated peripheral blood NK cells (exPBNK) with irradiated feeder cells (Chu/Cairo, et al, Can Imm Res 2015). To enhance NK cell-based targeted therapy, we had successfully engineered expanded NK cells with chimeric antigen receptors (Chu/Cairo, et al, Can Imm Res 2015) and combined expanded NK with an anti-CD20 targeted IL-15 fusion protein N-820 (2B8T2M) targeting rituximab-sensitive and -resistant BL (Chu/Cairo, et al, ASH 2017). N-820 was generated by fusing ALT-803 to four single-chain antibody domains of rituximab (Liu/Wong, et al, JBC, 2016). ALT-803 is a superagonist of an IL-15 variant bound to an IL-15RαSu-Fc fusion with enhanced IL-15 biological activity (Zhu et al. 2009 J Immunol), longer half-life and increased potency (Han, et al. Cytokine. 2011). N-820 displayed tri-specific binding activity through its recognition of CD20 on tumor cells, activated NK cells to enhance antibody-dependent cellular cytotoxicity (ADCC), and induced apoptosis of B-lymphoma cells (Liu/Wong, et al, JBC, 2016). Objective: To investigate how N-820 modulates the crosstalk between BL tumor cells and expanded NK cells by monitoring cytokines, chemokines and growth factors released and the anti-tumor effects of N-820 on NK cells in BL xenografts. Method: PBMCs were expanded with lethally irradiated K562-mbIL21-41BBL cells and isolated as we have previously described with K562-mbIL15-41BBL (Chu/Cairo, et al, Can Imm Res 2015). ALT-803 and N-820 were generously provided by Altor Bioscience. Equal doses of N-820, Rituximab (R), ALT-803, R+ALT-803, obinutuzumab (obinu, generously provided by Christian Klein, PhDfrom Roche) were used for comparison. IgG was used as control. Rituximab-sensitive Raji and -resistant BL cells Raji-2R and Raji-4RH were used as target cells. NK cells were sorted by Beckman Coulter MoFlo XDP high-speed sorter and NK purity was confirmed by flow cytometry. Cytokines, chemokines and growth factors mRNA levels in NK cells were monitored by real-time PCR. Secreted cytokines, chemokines and growth factors were examined by standard ELISAs. Raji-2R-Luc cells were injected into NSG mice. ExPBNK+N-820 and controls were injected to the xenografted NSG mice. The tumor burden was measured with the IVIS-200 system. Results: We found that ALT-803 and N-820 at equal doses significantly enhanced the expression of NK activating receptors such as NKG2D, NKp30, NKp44, and CD16 on exPBNK compared to IgG controls. Additionally, N-820 significantly enhanced exPBNK cytotoxicity against Raji, Raji-2R and Raji-4RH cells compared to the controls IgG, R, ALT-803, R+ALT-803, or obinu (p 〈 0.001). We further examined 84 genes of cytokines, chemokines and growth factors by real time PCR. Among these 84 genes, N-820 up-regulated 26 genes and down-regulated 22 genes in exPBNK when co-cultured with Raji-2R compared to exPBNK alone. Using ELISAs, we confirmed that N-820 significantly enhanced IFN-g, granzyme B, and GM-CSF (Fig.1A) release from exPBNK against Raji-2R and Raji-4RH compared to IgG and R+ALT-803 (p 〈 0.001). We also found that N-820 significantly reduced MDC (CCL22) (Fig.1B) release from Raji-2R cells compared to IgG (p 〈 0.01) and R+ALT-803 (p 〈 0.05). In NSG mice bearing Raji-2R tumor xenografts, we found that N-820 added to exPBNK significantly reduced tumor burden (p 〈 0.05) and expanded mice survival (Fig.1C) (p 〈 0.05) compared to control groups. Conclusions: N-820 significantly enhanced exPBNK cytotoxicity, IFN-g, granzyme B, GM-CSF release from exPBNK in-vitro, inhibited MDC release from BL and increased anti-tumor activity against BL xenografts in NSG mice. Disclosures Jeng: Altor: Employment. Alter:NANTCell / Altor Bioscience: Employment. Rhode:NANTCell / Altor Bioscience: Employment, Patents & Royalties: Altor Bioscience. Lee:NantKwest: Employment. Lee:Merck, Sharp, and Dohme: Consultancy; Courier Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; CytoSen Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wong:Altor: Employment, Equity Ownership, Patents & Royalties: Altor Bioscience. Cairo:Janssen: Research Funding.

Abstract: Abstract 163 Background: Despite progress in Ph+ leukemia therapy, patients who experience failure of tyrosine kinase inhibitors (TKIs) and those with the T315I BCR-ABL mutation have limited treatment options. Ponatinib is an oral TKI developed using computational and structure-based design with optimal binding to the BCR-ABL active site. At clinically achievable concentrations, ponatinib demonstrated potent in vitro activity against native BCR-ABL and all BCR-ABL mutants tested, including T315I. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with Ph+ leukemia were evaluated in a phase 2, international, open-label clinical trial. Methods: 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled and assigned to 1 of 6 cohorts: chronic phase (CP)-CML R/I (N=203), CP-CML T315I (N=64), accelerated phase (AP)-CML R/I (N=65), AP-CML T315I (N=18), blast phase (BP)-CML/Ph+ALL R/I (N=48), BP-CML/Ph+ALL T315I (N=46). Five patients (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months for CP-CML and major hematologic response (MaHR) at any time within 6 months for advanced Ph+ leukemia. The trial is ongoing. Data as of 23 July 2012 are reported: median follow-up 11 (0.1 to 21) months; minimum follow-up 9 months. Results: Median age was 59 (18–94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3–28) yrs. Patients were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib; median number of prior TKIs was 3, with 53% exposed to all 3 approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, and 23% MaHR or better in advanced Ph+ leukemia. Frequent BCR-ABL mutations confirmed at entry were: 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44%. The primary endpoint response rates (see Table) in each cohort exceeded the prespecified statistical criteria for success. In CP-CML and AP-CML R/I (the 3 largest cohorts), 95% CIs exceeded the prespecified response rate. Median time to response (for responders) was 84 days in CP-CML, 112 days in AP-CML, 55 days in BP-CML/Ph+ALL. Responses were durable; the estimated (Kaplan-Meier) probability of responders maintaining the primary endpoint at 1 yr was 91% in CP-CML, 42% in AP-CML, 35% in BP-CML/Ph+ALL. In CP-CML, 46% had complete cytogenetic response and molecular response rates were 32% MMR, 20% MR4, and 12% MR4.5. Response rates were higher in patients exposed to fewer prior TKIs and those with shorter disease duration. Similar response rates were observed in patients with and without BCR-ABL mutations. In CP-CML, response rates were higher in those with T315I; however, a post hoc analysis found that presence of T315I was not a predictor of response. Instead, the difference in response rate was explained by T315I patients' younger age, shorter duration of leukemia, and exposure to less prior therapy. At the time of analysis, 52% of patients remained on therapy (66% CP-CML). The most frequent reasons for discontinuation were progression (18%) and AEs (12%). The most common drug-related AEs were thrombocytopenia (36%), rash (33%), and dry skin (31%). Pancreatitis was the most common drug-related SAE (5%); however, it occurred early and was managed with dose modification (1 patient discontinued due to pancreatitis). Conclusions: Ponatinib has substantial activity and is generally well tolerated in these heavily pretreated Ph+ leukemia patients who have limited available treatment options. Data with a minimum follow-up of 12 months will be presented. Disclosures: Cortes: Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kim:Novartis, BMS, Pfizer, ARIAD, Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Deciphera: Research Funding; ARIAD: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers Squibb, Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, BMS, Pfizer, MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Briston-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

Abstract: Abstract 3749 Background: Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the uniformly TKI-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with CP-CML were evaluated in a pivotal phase 2, international, open-label clinical trial. Objectives: This prospectively defined analysis was performed to evaluate the impact that previous exposure to approved TKIs had on the efficacy and safety of ponatinib treatment among patients with CP-CML. Methods: The PACE trial enrolled 449 patients, including 270 patients with CP-CML. Enrolled patients were required to be resistant or intolerant (R/I) to dasatinib or nilotinib, or they had to have the T315I mutation at baseline. Patients with CP-CML were assigned to 1 of 2 cohorts: R/I (N=203) or T315I (N=64). Three patients were post-imatinib and did not have T315I at baseline; they were treated but not assigned to a cohort. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 months (median 12 [0.1 to 19] months). The efficacy and safety of ponatinib according to prior approved TKI therapy (imatinib, dasatinib, nilotinib) is presented for the total CP-CML (N=270) population. Results: The median age of CP-CML patients was 60 (18 to 94) years. Median time from initial diagnosis to start of ponatinib was 7 (0.5 to 27) years. Patients were heavily pretreated: 97% had received prior imatinib, 80% dasatinib, 68% nilotinib; 7% of patients had received 1 prior approved TKI, 40% 2 prior approved TKIs, 53% all 3 prior approved TKIs; 60% had received ≥3 prior approved/investigational TKIs. In patients previously treated with dasatinib or nilotinib (N=256), 84% had a history of resistance and 16% were purely intolerant to dasatinib or nilotinib. At the time of analysis, 66% of patients remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%) and progressive disease (7%). Response rates according to the number of prior approved TKIs are shown in the table below. Patients receiving fewer prior approved TKIs had higher response rates. The difference in MCyR rate was statistically significant for patients previously treated with 1 vs. 3 approved TKIs (p=0.003) and for patients previously treated with 2 vs. 3 approved TKIs (p=0.011). Differences in MMR rates were not statistically significant. Of patients achieving MCyR, 98% of patients receiving 2 prior approved TKIs and 83% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MCyR at 1 year. Of patients achieving MMR, 86% of patients receiving 2 prior approved TKIs and 80% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MMR at 1 year. Kaplan-Meier estimates were not calculable for patients receiving 1 prior TKI. The most common treatment-related AEs according to number of prior approved TKIs (1, 2, 3, respectively) were thrombocytopenia (32%, 38%, 44%), rash (37%, 37%, 39%), dry skin (37%, 36%, 39%), abdominal pain (21%, 26%, 28%), and headache (26%, 28%, 19%). Rash, dry skin, abdominal pain, and headache were generally grade 1 or 2 in severity. Thrombocytopenia was typically reported early in treatment and was manageable with or without dose reductions and/or dose interruptions. Conclusions: Ponatinib has substantial activity in patients with CP-CML, with higher response rates and improved tolerability observed in patients receiving fewer prior approved TKIs. Data with a minimum follow-up of 12 months will be presented. Disclosures: Kim: Novartis, BMS, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Pfizer: Research Funding; BMS: Research Funding; Novartis: Consultancy, Research Funding; ARIAD: Research Funding.

Abstract: Abstract 3763 Background: Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the TKI resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML), or Ph+ acute lymphoblastic leukemia (Ph+ ALL) were evaluated in a pivotal phase 2, international, open-label clinical trial (PACE). Objective: To evaluate the patterns of molecular response in patients treated with ponatinib in the PACE trial. Methods: The PACE trial enrolled 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I BCR-ABL mutation. Patients were assigned to 1 of 6 cohorts according to disease phase (CP-CML, AP-CML, or BP-CML/Ph+ ALL), R/I to dasatinib or nilotinib, and presence of T315I. Mutation and molecular response analyses were performed at a single central laboratory. Molecular responses are reported on the International Scale (BCR-ABLIS; b2a2/b3a2 [p210] transcript only): major molecular response (MMR), ≤0.1%; MR4, ≤0.01%; MR4.5, ≤0.0032%. The trial is ongoing. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 months (median 12 [0.1 to 21] months). Results: The median age was 59 (18 to 94) years. The median time from initial diagnosis to start of ponatinib was 6 (0.3 to 28) years. 96% had received prior imatinib, 84% dasatinib, 65% nilotinib; 8% received 1, 39% received 2, and 53% received all 3 prior approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. BCR-ABL mutations were detected in 55% of all patients at baseline: 22.9% T315I only, 26.5% mutations other than T315I, 5.8% mutations in addition to T315I. The most common mutations were T315I (29%), F317L (8%), E255K (4%), F359V (4%), and G250E (3%). Baseline BCR-ABL transcript levels were 〉 10% in 74% (74% in CP-CML) and 〉 1% to ≤10% in 14% (20% in CP-CML). No patients entered the study in MMR. The best response to the most recent dasatinib or nilotinib containing regimen was MMR or better in 4% (3% in CP-CML). Molecular response rates by cohort are shown below for CP-CML and AP-CML. Deep molecular responses, including MR4.5, were observed in both disease phases. Of 16 BP-CML and 3 Ph+ ALL patients with the b2a2/b3a2 transcript and baseline and post-baseline bone marrow assessments, 5 BP-CML and 0 Ph+ ALL patients achieved MMR. In CP-CML, MMR rates for the most frequent mutations other than T315I were 41% F317L, 50% E255K, 31% F359V, 38% G250E. Subgroup analyses in CP-CML indicated significant differences in the MMR rate for patients with T315I only (56%; p 〈 0.001) and mutations in addition to T315I (50%; p=0.0216) vs. no mutation (21%), and for T315I only vs. mutations other than T315I (34%; p=0.0237). These differences are likely due to younger age (median 51 vs. 61 years) and exposure to fewer prior TKIs (median 2 vs. 3) in CP-CML patients with T315I vs. those without T315I. In CP-CML, 53% maintained or achieved BCR-ABLIS ≤10% by 3 months, with a trend towards higher rates in patients receiving fewer prior approved TKIs (1: 81%; 2: 61%; 3: 45%). The MMR rate (cumulative) in CP-CML improved over time: 13% by 3 months, 24% by 6 months, 28% by 9 months. The median time to MMR for CP-CML patients achieving MMR was 6 (2 to 17) months. CP-CML patients with MMR had an estimated probability of remaining in MMR at 6 months and 1 year of 87% and 84%, respectively (Kaplan-Meier). Ponatinib was generally well-tolerated. Data with a minimum follow-up of 12 months will be presented. Conclusions: Ponatinib treatment led to significant and deep molecular responses in this heavily pretreated population. In CP-CML, the MMR rate was ∼10-fold higher than that reported with the most recent dasatinib or nilotinib treatment. Disclosures: Hochhaus: ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kim:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, NOVARTIS PHARMA, BRISTOL MYERS SQUIBB, PFIZER: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy; Pfizer: Research Funding; ARIAD: Research Funding; BMS: Research Funding; Novartis: Research Funding. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding.

Abstract: Abstract 3747 Introduction: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally QD) were evaluated in a phase 2, international, open-label clinical trial (PACE). These multivariate analyses explored the impact of dose intensity and several prognostic and predictive factors on clinical responses, adverse events (AEs), and laboratory changes. Methods: Enrolled patients were resistant or intolerant (R/I) to dasatinib or nilotinib, or had the T315I BCR-ABL mutation at baseline. A total of 267 chronic phase (CP), 83 accelerated phase (AP), and 94 blast phase (BP) CML/Ph+ ALL patients were assigned to 1 of 6 cohorts according to disease phase (CP-, AP-, or BP-CML/Ph+ ALL), R/I to dasatinib or nilotinib, and presence of T315I. Three CP-CML and 2 AP-CML patients were treated, but not assigned to a cohort (post-imatinib, did not have T315I at baseline); these patients were excluded from efficacy analyses and included in safety analyses. For the purposes of the efficacy multivariate analyses, AP-CML, BP-CML, and Ph+ ALL patients were combined. The baseline covariates analyzed were age, time since diagnosis, number of prior TKIs, presence or absence of the T315I mutation, neutrophil and platelet counts, and weight. The primary efficacy outcome analyzed was major cytogenetic response (MCyR) in CP-CML and major hematologic response (MaHR) for all other patients. The safety outcomes analyzed were the following AEs: pancreatitis, elevated lipase, alanine aminotransferase (ALT) increase, aspartate aminotransferase (AST) increase, rash, neutropenia, thrombocytopenia, arthralgia, and hypertriglyceridemia. The impact on neutrophils, platelets, bilirubin, ALT, AST, creatinine, lipase, and triglycerides was also examined. Binary event outcomes were analyzed using logistic regression models. Data values over time were analyzed using linear mixed effects models. Laboratory values were log-transformed. Data as of 27 April 2012 were used in these analyses. Results: Median baseline characteristics of the CP-CML R/I and T315I cohorts, respectively, were: 61 vs 51 yrs of age, 8 vs 5 yrs since initial diagnosis, 3 vs 2 prior TKIs. The median dose intensity for the CP-CML R/I and T315I cohorts was 30 and 39 mg/day, respectively. In general, other baseline characteristics were balanced between these 2 cohorts. Multivariate analysis found statistically significant associations between MCyR and increasing dose intensity (mg/day) (p 〈 0.0001) and decreasing age (p=0.046) in CP-CML. Despite the finding that CP-CML patients with the T315I mutation had a higher response rate than those without the T315I mutation (MCyR 70% vs 49%), presence of T315I was not a significant prognostic factor for response after adjusting for other covariates (p 〉 0.2). This was likely because patients with T315I received a greater dose intensity, were younger, and were previously treated with fewer TKIs. The probability of achieving MaHR in patients with AP-CML, BP-CML, and Ph+ ALL increased with increasing dose intensity (p 〈 0.001) and with higher numbers of baseline platelets (p=0.0046). As in CP-CML, similar trends in baseline characteristics were observed, and the presence of the T315I mutation was not a significant prognostic factor for MaHR. In all patients, the probability of AEs (pancreatitis, lipase increase, ALT and AST increase, thrombocytopenia, neutropenia, arthralgia, and rash) increased with increasing dose intensity. Hypertriglyceridemia was trend level associated with dose intensity (p=0.054). Presence of T315I was associated with a lower risk of thrombocytopenia (p 〈 0.0001) and neutropenia (p=0.005) after adjustment for dose intensity and the other factors. In general, younger age, less time since diagnosis, and fewer prior TKIs were associated with a lower probability of AEs. Conclusion: These findings suggest that dose intensity and factors related to extent of disease and prior treatment were most predictive of effectiveness and tolerance of ponatinib. T315I was not a significant prognostic factor for efficacy or safety after adjustment for other factors, with the exception of thrombocytopenia and neutropenia; patients with T315I had lower predicted rates of these AEs after adjustment for dose intensity and other factors in the reduced models. Disclosures: Off Label Use: Ponatinib - non FDA approved (experimental) compound. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kim:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis : Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Bristol Myers-Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Dorer:ARIAD: Employment, Equity Ownership. Knickerbocker:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:Novartis: Consultancy; Bristol Myers-Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding. Kantarjian:Pfizer: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding.

Abstract: Abstract 915 Background: Many patients (pts) with advanced Ph+ leukemias experience failure of all currently available tyrosine kinase inhibitors (TKIs) targeting BCR-ABL and have limited treatment options. Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the TKI resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in pts with AP-CML, BP-CML, or Ph+ ALL were evaluated in a phase 2, international, open-label clinical trial. Methods: The PACE trial enrolled 449 pts, including 85 AP-CML, 62 BP-CML, and 32 Ph+ ALL. Pts were resistant or intolerant (R/I) to dasatinib or nilotinib, or had the T315I mutation at baseline. AP-CML, BP-CML, and Ph+ ALL pts were assigned to 1 of 4 cohorts: AP-CML R/I, AP-CML T315I, BP-CML/Ph+ ALL R/I, BP-CML/Ph+ ALL T315I. Two AP-CML pts were not assigned to a cohort (post-imatinib, did not have T315I at baseline) and were excluded from efficacy analyses and included in safety analyses. The primary endpoint was major hematologic response (MaHR) at any time within 6 mos after treatment initiation. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 mos (median 13 [4 to 21] , 6 [0.1 to 18], and 6 [0.1 to 16] mos for AP-CML, BP-CML, and Ph+ ALL, respectively). Results: The median age for AP-CML, BP-CML, and Ph+ ALL pts was 60, 53, and 62 yrs, respectively. Median time from initial disease diagnosis to start of ponatinib was 7, 4, and 1.5 yrs, respectively. Pts were heavily pretreated: 94% received prior imatinib, 88% dasatinib, 61% nilotinib; 8% received 1 prior approved TKI, 39% received 2, and 53% received 3. Sixteen percent had undergone prior stem cell transplant. In pts previously treated with dasatinib or nilotinib (N=171), 94% had a history of resistance to dasatinib or nilotinib, 6% were purely intolerant. Reported MaHR rates with the most recent dasatinib or nilotinib therapy were 35% AP-CML, 16% BP-CML, 43% Ph+ ALL. At the time of analysis, 59% of AP-CML, 8% of BP-CML, and 9% of Ph+ ALL pts remained on study. Overall, the most common reasons for discontinuation were progressive disease (19%, 50%, and 53%, respectively) and adverse events (AEs; 11%, 16%, and 6%, respectively). Hematologic and cytogenetic response rates are shown in the table; MaHR and MCyR were observed across cohorts. MMR was achieved by 14% of AP-CML pts (14% R/I, 17% T315I). There was a trend for higher response rates among pts who received fewer prior approved TKIs. In AP-CML pts, the differences in MaHR rates by number of prior approved TKIs (1: 3/4 [75%]; 2: 20/33 [61%] ; 3: 24/46 [52%]) were not significant (Fisher's Exact); differences in MCyR rates (1: 4/4 [100%] ); 2: 13/33 [39%]; 3: 15/46 [33%] ) were significant for pts treated with 1 vs 2 (p=0.0360) and 1 vs 3 prior approved TKIs (p=0.0168). Of pts achieving MaHR, 42% of AP-CML and 35% of BP-CML/Ph+ ALL pts were projected (Kaplan-Meier) to remain in MaHR at 1 yr. In AP-CML, the median progression-free survival (PFS) was estimated (Kaplan-Meier) as 80 (range 6 to 88) wks; the probability of maintaining PFS at 6 mos and 1 yr was estimated as 80% and 57%, respectively. Median overall survival (OS) had not yet been reached; the probability of OS at 6 mos and 1 yr was estimated (Kaplan-Meier) as 96% and 85%, respectively. In BP-CML/Ph+ ALL, median PFS was estimated as 18 (range 0.1 to 74) wks; the probability of maintaining PFS at 6 mos and 1 yr was estimated as 34% and 20%, respectively. Median OS was estimated as 30 (range 0.4 to 77) wks; the probability of OS at 6 mos and 1 yr was estimated as 54% and 34%, respectively. Ponatinib was generally well-tolerated; the most common treatment-related AEs were thrombocytopenia (29%), rash (25%), and neutropenia (22%). The most common serious treatment-related AEs were thrombocytopenia (3%) and pancreatitis (3%). Rash was generally grade 1 or 2 in severity. Thrombocytopenia, neutropenia, and pancreatitis were typically reported early in treatment and were manageable with dose modification. Conclusions: Ponatinib was generally well-tolerated and had substantial activity in pts with AP-CML, BP-CML, or Ph+ ALL, regardless of mutation status or prior therapy. Data with a minimum follow-up of 12 mos will be presented Disclosures: Kantarjian: Novartis: Consultancy; Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding; ARIAD: Research Funding. Off Label Use: ponatinib. Kim:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers Squibb, Amgen: Honoraria. Shah:ARIAD Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding.

Abstract: The lymphatic system plays an important physiological role in vascular and immune homeostasis. Lymphatic vessel function is implicated in a number of pathological conditions including tumor metastasis and impaired wound healing. The identity and origin of lymphatic endothelial precursors is poorly understood. Previously we have shown that adult bone marrow-derived, hematopoietic stem cells (HSCs, c-kit+, Sca-1+, lineage−) can differentiate into functional blood vascular endothelial cells. Given the close relationship between the blood and lymphatic vascular systems, we have investigated whether HSCs also give rise to lymphatic endothelial cells (LEC). GFP+ HSCs were transplanted into lethally irradiated (1200 cGy) recipient mice. Donor-derived LEC expressing lymphatic endothelial markers including LYVE-1 and VEGFR3 were clearly distinguished from hematopoietic cells by the absence of CD45 and F4/80 expression. Deconvolution microscopy confirmed the co-localization of donor and LEC marker expression in individual cells. Transplanted HSCs gave rise to LEC in the liver, gut, gastric and kidney. Donor-derived LEC were detected in 2.4% of liver lymphatic vessels at 4 weeks and persisted for at least 12 months (mean of 3.4%). The self-renewal capacity of HSC-derived lymphatic progenitor cells was demonstrated by serial transplantation. The contribution of these progenitors to tumor lymphatics was evaluated. Transplantation of HSCs into young Min−/− mice resulted in the incorporation of donor-derived LEC into the lymphatics of intestinal adenomas that spontaneously develop in these mice. In addition, CD45+F4/80+ leukocytes were detected in the vessel lumens indicating that these are functional tumor lymphatic vessels. Finally, to determine if LEC progenitors contribute to lymphatic vessels in the absence of radiation injury or tumorigenesis, a parabiosis model was evaluated. Donor-derived LEC were detected in parabiotic mice at a frequency similar to that observed for donor-derived blood vascular endothelial cells. This finding suggests that circulating progenitor cells contribute to lymphangiogenesis during steady-state conditions. Our results indicate that hematopoietic stem cells have the potential to contribute to lymphatic endothelium and therefore HSC-derived progenitors may be potential therapeutic targets for hematopoietic and lymphatic disease.

Abstract: Introduction: Burkitt lymphoma (BL) accounts for approximately 50% of all pediatric non-Hodgkin lymphomas compared to 1-2% in adults. Adult BL (aBL) remains a poorly understood entity and its relationship to pediatric BL (pBL) and to DLBCL has not been fully elucidated. The variable treatment outcomes between these entities necessitate a more thorough understanding of the genetic and molecular features underlying their biology to enable better prognostication and more effective treatments. We sought to comprehensively determine genetic features shared with DLBCL and those that are unique to BL, to further delineate genetic subgroupings within each entity. Methods: Samples for this study were collected through the Burkitt Lymphoma Genome Sequencing Project (BLGSP). We sequenced the tumor genomes of 139 pBL and 92 aBL, consisting of both EBV-positive (EBV+) and EBV-negative (EBV-) BLs, and compared these to the genomes of 252 DLBCL patients. All cases were analyzed for simple somatic mutations (SSM), recurrent copy number variations (CNV), structural variations (SV), aberrant somatic hypermutation (aSHM), and SSM hotspots. Mutations were used as features for the identification of genetic subgroups using non-negative matrix factorization (NMF) clustering. Results: Clustering of BL and DLBCL revealed six distinct genetic subgroups (Figure 1) with three primarily representing DLBCLs (DLBCL-1, DLBCL-2, and DLBCL-3) and three predominantly comprising BLs (M53-BL, IC-BL, and DGG-BL). The DLBCL-predominant subgroups partially overlapped with those previously described and resembled features of EZB and ST2-like subgroups. The frequency of aBLs within these subgroups was higher than that of pBL patients (p=0.0005). The new cluster M53-BL consists of both pBL (9/27) and aBL (13/27) samples and is characterized by the highest prevalence of mutations in TP53 accompanied by the paucity of other driver mutations but without the aneuploidy associated with the A53 subgroup described in DLBCL. Enrichment of EBV- samples in this cluster further corroborate our previous findings of TP53 mutations being associated with EBV- BL. IC-BL is characterized by mutations in ID3, CCND3, and SMARCA4. In contrast, DGG-BL, where 65% of the cluster consisted of EBV+ BL samples, had mutations in DDX3X, GNA13, and GNAI2. Using a linear model, we compared the rates of aSHM in BL genomes from all clusters and identified the DLBCL-3 cluster to harbor the highest aSHM rates at common sites while the M53-BL cluster harbored the lowest rates. To further establish the biological basis of unique clusters within BL, we conducted differential gene expression analyses between the two major BL genetic subgroups, DGG-BL and IC-BL. We identified a total of 86 differentially expressed genes between the two clusters (p.adj & lt; 0.01 and |log2foldChange| & gt; 1). Among the genes with the strongest differential expression were IRF4, SERPINA9, and TNFRSF13B. Each of these are notable as their expression is a component of the DLBCL cell-of-origin and double-hit signature classifiers. Further, we found IRF4 expression to be one of the strongest predictors of cluster membership, with high IRF4 expression associated with IC-BL membership. Using TP53 and ID3 mutations as a proxy for M53-BL and IC-BL clusters in aBL, we found mutations in TP53 to be associated with significantly inferior progression free survival (PFS) at 2 year follow up, while mutations in ID3 were associated with overall better PFS at 2 year follow up. Conclusion: This work identifies novel genetic subgroups within BL with characteristic genetic and gene expression differences and some bearing relationship to DLBCL subgroups. The three subgroups with predominantly BL samples (DGG-BL, IC-BL, and M53-BL) each comprised a mixture of aBL and pBL samples, confirming similar molecular features in these entities. The IC-BL cluster is associated with mutations in ID3 and CCND3, high IRF4 expression, and ID3 mutated cases exhibited significantly better outcomes. M53-BL is associated with TP53 mutations and inferior PFS in aBL, representing a subset of patients to be considered for novel treatment approaches. These findings highlight shared pathogenesis between aBL and pBL and establish genetic subtypes within BL that delineate cases with distinct molecular and clinical features. This provides a new framework for new diagnostic and therapeutic strategies. Figure 1 Figure 1. Disclosures Abramson: Seagen Inc.: Research Funding; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Kymera: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Bluebird Bio: Consultancy; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Bartlett: Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Casper: EUSA Pharma: Consultancy. Gerrie: Roche: Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Astrazeneca: Honoraria, Research Funding; Sandoz: Honoraria. Grande: Sage Bionetworks: Current Employment. Mullighan: Illumina: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; AbbVie: Research Funding; Amgen: Current equity holder in publicly-traded company. Noy: Epizyme: Consultancy; Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria. Scott: NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; AstraZeneca: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Research Funding; Rich/Genentech: Research Funding; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. . Morin: Foundation for Burkitt Lymphoma Research: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Epizyme: Patents & Royalties.

Abstract: Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.

Abstract: The ERG stem cell enhancer is active in acute myeloid leukemia and is regulated by a heptad of transcription factors. Expression signatures derived from ERG promoter–enhancer activity and heptad expression are associated with clinical outcome.