Abstract: Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1− B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%] , ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%] , PAX5 P80R [4.1%], high-hyperdiploid [6.9%] ); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%] , low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%] ); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%] , MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non–risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.

Abstract: Leukemia cells accumulate DNA damage but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/one-carbon cycle metabolism contributed to accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases [OTKs: FLT3(ITD), JAK2(V617F), BCR/ABL1]. To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLq) by ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLq and its proteasomal degradation. Overexpression of POLq in OTK-positive cells resulted in efficient repair of DPC-containing DNA double-strand breaks (DSBs) by POLq-mediated end-joining (TMEJ). Transforming activity of OTKs and other leukemia-inducing oncogenes, especially of those causing inhibition of BRCA1/2 -mediated homologous recombination (HR) with and without concomitant inhibition of DNA-PK -dependent non-homologous end-joining (D-NHEJ), was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POLq polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitor or DPC-inducing drug etoposide enhanced anti-leukemia effect of POLq inhibitor (POLqi) in vitro and in vivo. In conclusion, we demonstrated that POLq plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde and that it can be targeted to achieve therapeutic effect.

Abstract: Introduction: Allogeneic stem cell transplantation (alloSCT) is the most effective post remission anti-leukemia strategy. However, the associated toxicity is a barrier for its routine adoption as standard of care in older adults. Studies of AML patients who underwent alloSCT are mainly retrospective as randomized controlled trials comparing transplantation to non-transplantation are very difficult to conduct. We herein present prospective data from a randomized controlled phase III study, E2906, designed to compare two intensive chemotherapy arms. Patients who achieved remission and had a donor were to proceed to alloSCT after induction or first consolidation, at investigator discretion. Non-transplanted patients received 2 cycles of consolidation and then underwent a second randomization between observation and decitabine maintenance. Herein are reported all patients who received alloSCT either on protocol during first remission (CR1) or at other post induction time-points. Patients and Methods: Enrolled to E2906 study were 727 AML patients age 60 years and over. AlloSCT was performed in 166 patients, of whom 71 received alloSCT as part of the study and 95 received alloSCT off protocol. 105 patients (66/71 on protocol, 39/95 off protocol) received alloSCT at CR1/CRi1/LFS1 (CR: 92, CRi: 9 LFS: 4). Patients were followed for a median of 33.6 months from diagnosis and 29.1 months from transplant. No patients received decitabine maintenance prior to alloSCT. Overall survival (OS) is defined as the time from allo transplant to death from any cause, with follow-up censored at the date of last contact. Disease free survival (DFS) is defined as the time from alloSCT transplant to relapse or death of any cause. The censored follow-up time for patients without relapse or death information is the date of last contact. Kaplan-Meier estimates were used to estimate OS and DFS. DFS and OS were compared between subgroups using log rank tests. A cumulative incidence analysis, with death without prior relapse as competing events, was performed to evaluate the subgroup effect on time to relapse after transplant. Results: Patient characteristics of those who received alloSCT at CR1/CRi1/LFS1 are similar to the general distribution of AML patients eligible for intensive chemotherapy. Median age was 66 years, 52% were male and 88% with ECOG PS of 0-1. Cytogenetic data were available for 85 patients of whom 26% presented with unfavorable cytogenetics. Minimal residual disease (MRD) status prior to alloSCT was available for 44 patients of whom 19 (43%) achieved a MRD negative state. Long-term OS and DFS rates for all 105 patients who underwent alloSCT at CR1/CRi1/LFS1 are encouraging (Figure 1). OS and DFS at two years were 56.4% and 53.6% and 49.4%, 45.6% and 42.9%, 39% at 3 and 4 years, respectively. Age above or below 65 years, gender, induction regimen (3+7 or clofarabine) and MRD status prior to transplantation had no impact on outcome. Survival curves by intermediate or adverse cytogenetic risk are not significantly different. The numbers of patients with CRi1 or LFS1 are too small to compare with patients in CR1. Nevertheless, 36/38 patients that were alive and remain in first remission at the time of data cutoff, are patients who achieved CR1 and only 2/38 are patients transplanted at CRi1 or LFS1. Notably, the non-relapse mortality (NRM) was not significantly different for patients less or over 65 years. NRM at 6 months and 2 years for patients over and under 65 years of age were 4.4%, 8.4% and 15.6%, 24.0% respectively. Relapse during the first year post alloSCT is the main barrier for longer survival, particularly in patients with adverse cytogenetics and MRD positivity prior to transplantation (Figure 2). Conclusions: Fit older patients, including those over age 65, who undergo an alloSCT in CR1, can expect a 4-year survival of 43% with an acceptable NRM rate. The NRM was, surprisingly, not higher than for a typically younger cohort of AML. Relapse within one year after transplant is the major limitation to prolonged survival and this finding reflects the biology of the leukemia in these patients. In this patient population, novel post remission strategies should either be complimentary to alloSCT or competitive with updated outcome of alloSCT. Figure 1 Figure 1. Disclosures Ofran: Medison Israel: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Astellas: Consultancy; AbbVie: Consultancy. Claxton: Astellas: Other: Clinical Trial; Novartis: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding. Tallman: Syros: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; NYU Grand Rounds: Honoraria; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Melnick: Constellation: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Research Funding; Sanofi: Research Funding; Janssen Pharmaceuticals: Research Funding; KDAC Pharma: Membership on an entity's Board of Directors or advisory committees. Levine: Prelude: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Lilly: Honoraria; Morphosys: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Astellas: Consultancy; Imago: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Research Funding; Roche: Honoraria, Research Funding; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Foran: gamida: Honoraria; aptose: Research Funding; syros: Honoraria; boehringer ingelheim: Research Funding; kura: Research Funding; takeda: Research Funding; abbvie: Research Funding; trillium: Research Funding; revolution medicine: Honoraria; certara: Honoraria; actinium: Research Funding; OncLive: Honoraria; pfizer: Honoraria; servier: Honoraria; bms: Honoraria; novartis: Honoraria; taiho: Honoraria; sanofi aventis: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: Jazz: Other: Advisory Board; AbbVie: Research Funding; Omeros: Other: Advisory Board; Amgen: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Pluristem: Research Funding; Biosight: Other: Data monitoring committee.