ALBERT

Description: Abstract 979 Poster Board I-1 Smoking is the leading preventable cause of death. Smokers are approximately 1.5 times more likely to develop acute myeloid leukemia (AML) than non-smokers, but little is known about the relationship between cigarette smoking and AML outcome. We studied the effect of smoking on outcome in 282 newly diagnosed AML patients treated with high-dose cytarabine and idarubicin-containing regimens at Roswell Park Cancer Institute between 9/92 and 12/08. There were 161 males and 121 females (median age 56 years, range 18-85 years). The median follow up was 12.9 (range,

Description: Loss of function of ATM gene is associated with higher incidence of leukemia and lymphoma. ATM localized to 11q22.3-q23.1, is a tumor suppressor gene and plays an important role in cell cycle arrest, DNA repair mechanisms, and apoptosis. The incidence of deletion of ATM in MM remains unknown. Using a new commercially available fluorescently labeled DNA probe, we investigated the incidence of homozygous and heterozygous deletions of the ATM gene locus to explore its potential role in the pathogenesis of multiple myeloma (MM). Fifty-three MM pts were evaluated by fluorescence in situ hybridization (FISH) using the Vysis, Inc. LSI ATM (11q22.3) probe to assess the status of the ATM gene. LSI ATM (11q22.3) is a ~500 kb probe that hybridizes to the 11q22.3 region of chromosome 11 and spans the entire ~184 kb ataxia telangiectasia mutated (ATM) gene and several others. Probe copy number was assessed in each patient after analyzing at least 200 interphase nuclei. Only pts with〉 10% bone marrow involvements with malignant plasma cells were analyzed. Heterozygous ATM deletion was noted in 2/53 (3.7%) patients. These patients had 82% and 20% involvement of bone marrow (BM) with malignant plasma cells. Twenty-eight of 53 (%) patients showed an extra signal suggestive of trisomy 11, while no abnormality (2 signals) was noted in 23/53 (%) pts. There was no significant difference in the stage, B2M or extent of marrow involvement among patient with or without aberration of ATM gene. Up to 15–20% of the pts with B-cell lymphoproliferative disorders (CLL, mantle cell and other NHL) are reported to have ATM deletion suggesting a possible role of ATM protein in the pathogenesis of at least a subset of these disorders. Even though MM is a B-cell disorder, in our observation the prevalence of ATM deletion in these pts is uncommon and thus unlikely to be a major factor in the pathogenesis of MM.

Description: Smoking is associated with AML and lung cancer, suggesting a common carcinogenic origin and raising the question of how to treat patients with concomitant cancer presentations. The Roswell Park Cancer Institute Tumor Registry was searched for patients with both diagnoses, followed by medical record review. Among 775 AML cases and 5225 lung cancer cases presented to Roswell Park Cancer Institute between January 1992 and May 2008 we identified twelve patients with both AML and lung cancer (1.5% of AML cases; 0.2% of lung cancer cases). Of these, seven cases had metachronous and five cases had synchronous presentation. Eleven of the twelve (92%) patients had a known smoking history; five (42%) of them were males. The median age at the respective diagnoses was 65 (range 58–85) years for AML and 66 (range 53–79) years for lung cancer. Five of the twelve (42%) patients had a complex karyotype. Metachronous group: Lung cancer preceded AML in six patients by a median interval of eight (range five-14) years, while AML preceded the diagnosis of lung cancer in one patient by three years. For their lung cancer, five patients had surgical resection. Two had definitive chemoradiation, one patient had adjuvant chemotherapy and one patient had adjuvant radiation suggesting that their subsequent AML was secondary. Two patients had preceding MDS even though they underwent only surgical resection for their lung cancer. For their AML, five of the seven patients were treated with cytarabine and anthracycline-containing regimens; two achieved complete remission, two had primary refractory disease and one patient died during induction. One patient with primary refractory disease underwent sibling matched allogeneic transplantation and is still alive in remission. The median survival for lung cancer was 65 (range 22–120) months. The median survival since AML diagnosis was less than one (range

Description: Background: Minimal residual disease (MRD) status is an independent prognostic marker for response duration in patients with mantle cell lymphoma (MCL). Rituximab-based therapy led to a molecular remission (MR) in 48% young MCL patients treated with intense chemo-immunotherapy. More recently, 4 courses of R-DHAP were reported to yield a 66% MRD negativity rate prior to high dose chemotherapy and autologous stem cell transplant (HDC-ASCT). Ofatumumab is a humanized type 1 anti-CD20 mAb that binds to a unique, more membrane-proximal epitope on the CD20 antigen. Pre-clinical studies have demonstrated that ofatumumab (O) is more active than rituximab in eliciting complement-mediated cytotoxicity (CMC) in MCL cell lines, primary tumor cells and murine lymphoma xenograft models. Hence, we evaluated the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL (NCT01527149). Study design: This was a single-arm, open-label, multi-center (2 centers), prospective, phase 2 clinical trial. Thirty-seven transplant-eligible patients with newly diagnosed MCL were enrolled. Ofatumumab (1000mg) was given every 3 weeks on day 1, followed by standard doses of alternating HyperCVAD and MA starting on day 3. A total of 6 cycles were given at 3-week intervals followed by HDC-ASCT. Maintenance rituximab 375 mg/m2 every 2 months for 3 years post-ASCT was added after protocol amendment following publication of the LyMa study. Primary objectives were to determine the overall response rate (ORR) and CR rate (CRR) at the end of therapy. Secondary objectives included MRD negativity, progression free survival (PFS), overall survival (OS), feasibility of successful mobilization of autologous stem cells and safety assessment. MRD assessment was performed in peripheral blood (PB) and bone marrow (BM) using high sensitivity multiparametric flowcytometry at baseline, after 2 cycles, after 4 cycles, pre-ASCT, post-ASCT and 6 months post-ASCT. Exploratory endpoints included correlation of MRD with survival, correlation of surface CD20 levels with response and to compare differences in ORR according to Cheson and modified Cheson (MC) criteria. Results: Median age was 60yrs; 73% of patients were male, 92% had an ECOG PS 0-1, majority (81%) had stage 4 disease with 86% having bone marrow involvement; 22% had low risk, 43% had intermediate risk and 35% had high risk MIPI score; 11% had blastoid and 11% had pleiomorphic variants of MCL; 25% harbored p53 deletion. MRD was assessed in 28 of 37 patients; 9 patients from partner site were excluded due to time lag in sample delivery for flowcytometry. MRD positivity was noted in 75% patients in PB and 71.4% patients in BM at baseline. Subsequent samples showed an MRD negativity rate of 82.1% and 64.3% after 2 cycles and 76% and 96% pre-ASCT in PB and BM respectively. Post-ASCT, MRD in BM and PB was found negative in 58% and 90%, respectively. Attainment of early MRD negativity (after 2 cycles) was associated with improved PFS (p=0.04) and OS (p=0.03). Since majority of patients were MRD negative pre-ASCT, we could not demonstrate correlation between pre-ASCT MRD and survival outcomes. The ORR and CRR were 95% and 62% by Cheson and 97% and 84% respectively by modified Cheson criteria. At the end of induction therapy, ORR was 86% and CRR was 62% by Cheson criteria. 73% pts underwent HDC-ASCT. Only one patient failed stem cell collection. The median PFS and OS were 45.5 months and 56 months respectively. There were 3 deaths while on therapy- 2 from sepsis and one from acute myeloid leukemia. Grade 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients, most of them were hematological AEs related to the chemotherapy regimen. Correlation of surface CD20 expression using mean fluorescent intensity (MFI) and response rates is currently under analysis and will be reported at the meeting. Conclusion: The addition of ofatumumab to HyperCVAD/MA led to high rates of MRD negativity by flowcytometry in patients with newly diagnosed MCL. Early MRD negativity (after 2 cycles) was associated with better PFS and OS. Despite higher ORR, CR and MRD negativity rates, survival outcomes were similar to historical cohorts using rituximab-HypeCVAD/MA. This may be in part due to increased number of patients with high-risk disease in our study. Disclosures Reddy: KITE Pharma: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding. Sait:Celgene: Consultancy. OffLabel Disclosure: Ofatumumab was investigated in combination with chemotherapy in newly diagnosed mantle cell lymphoma in this clinical trial.

Description: Abstract 4129 Several immunophenotypic subgroups within AML are associated with specific disease characteristics, e.g., CD19-positive AML is associated with t(8;21)(q22;q22) and CD56 expression is associated with adverse outcome. CD33 is a sialic acid-binding immunoglobulin-like lectin (Siglec) located on chromosome 19q13.3. It is highly expressed on early multilineage hematopoietic progenitors but absent from the pluripotent hematopoietic stem cells. It contains two tyrosine phosphorylation motifs whose phosphorylation depends on Src and is the target of gemtuzumab ozogamicin. We asked if lack of CD33 expression (

Description: Abstract 414 The ELN standardized system for reporting cytogenetic and select molecular findings was created to enable comparisons of studies correlating treatment outcome with genetic data in AML (Döhner et al. Blood 2010;115:453). The ELN classification is based on published reports on prognostic import of cytogenetic and molecular alterations, but has not been tested in large cohorts of similarly treated AML pts, except for 1 study comprising ∼20% secondary AML pts (Röllig et al. JCO 2011;29:2758). Thus our goal was to assess the prognostic utility of the ELN classification in a relatively large cohort lacking the confounding effects of AML type (de novo v secondary) or different therapies [chemotherapy v allogeneic stem cell transplant (SCT)]. We analyzed 1,550 de novo AML pts (excluding AML M3, which is not part of the ELN classification) treated with cytarabine-daunorubicin-based chemotherapy on Cancer and Leukemia Group B frontline protocols; no pt received SCT in 1st complete remission (CR). Since consolidation therapy of younger [

Description: The t(12;21)(p13;q22) translocation, fusing the ETV6 andAML1 genes, is the most frequent chromosomal translocation associated with pediatric B-cell precursor acute lymphoblastic leukemia. Although the genomic organization of the ETV6 gene and a breakpoint cluster region (bcr) in ETV6 intron 5 has been described, mapping of AML1 breakpoints has been hampered because of the large, hitherto unknown size of AML1 intron 1. Here, we report the mapping of the AML1 gene between exons 1 and 3, cloning of ETV6-AML1 breakpoints from different patients, and localization of the AML1 breakpoints withinAML1 intron 1. In contrast to the tightly clustered ETV6breakpoints, the AML1 breakpoints were found to be dispersed throughout AML1 intron 1. Although nucleotide sequence analysis of the breakpoint junctions showed several 5/7 matches for the V(D)J consensus heptamer recognition sequence, these matches were present only on the ETV6 alleles and not on the AML1 alleles, making it unlikely that the translocations were mediated by a simple V(D)J recombination mistake. Interestingly, several breakpoints as well as a stable insertion polymorphism mapped close to a polymorphic, alternating purine-pyrimidine tract in the ETV6 gene, suggesting that this region may be prone to DNA recombination events such as insertions or translocations. Finally, the presence of an insertional polymorphism within the ETV6 bcr must be recognized to avoid incorrect genotype designation based on Southern blot analysis.

Description: Abstract 3113 Poster Board III-50 Blastic transformation of myeloproliferative neoplasms (MPN) is still poorly understood. Mutations of JAK2V617F were described in the majority of MPN patients but only about half of those undergoing blastic transformation continue to harbor that mutation. We describe a cohort of 23 patients from Roswell Park Cancer Institute (RPCI) and discuss 90 additional cases from the English literature for whom biologic features were described. We also screened our cases for JAK2V617F, JAK2T875N and MPL515L/K. We initially compared our 23 patients to the 90 cases from the literature. Our population had significantly less patients with prior history of polycythemia vera (22% vs. 53%; P

Description: The t(12;21)(p13;q22) translocation, fusing the ETV6 andAML1 genes, is the most frequent chromosomal translocation associated with pediatric B-cell precursor acute lymphoblastic leukemia. Although the genomic organization of the ETV6 gene and a breakpoint cluster region (bcr) in ETV6 intron 5 has been described, mapping of AML1 breakpoints has been hampered because of the large, hitherto unknown size of AML1 intron 1. Here, we report the mapping of the AML1 gene between exons 1 and 3, cloning of ETV6-AML1 breakpoints from different patients, and localization of the AML1 breakpoints withinAML1 intron 1. In contrast to the tightly clustered ETV6breakpoints, the AML1 breakpoints were found to be dispersed throughout AML1 intron 1. Although nucleotide sequence analysis of the breakpoint junctions showed several 5/7 matches for the V(D)J consensus heptamer recognition sequence, these matches were present only on the ETV6 alleles and not on the AML1 alleles, making it unlikely that the translocations were mediated by a simple V(D)J recombination mistake. Interestingly, several breakpoints as well as a stable insertion polymorphism mapped close to a polymorphic, alternating purine-pyrimidine tract in the ETV6 gene, suggesting that this region may be prone to DNA recombination events such as insertions or translocations. Finally, the presence of an insertional polymorphism within the ETV6 bcr must be recognized to avoid incorrect genotype designation based on Southern blot analysis.

Description: Inherited genetic polymorphisms in ARID5B, GATA3, and IKZF1 have been reported to be associated with ALL and vary by cytogenetic subgroups. For example, ARID5B variants are associated with hyperdiploid B-ALL in pediatric patients, which occurs in approximately 30% of ALL patients and is a marker of good prognosis. In contrast, a variant in GATA3 (rs3824662) has been consistently associated with ALL regardless of cytogenetics. While associations by subtype and across age have been explored in ALL patients, the effect of sex on the association of germline variants with ALL has not been tested, despite the higher incidence and worse prognosis of ALL in males than females. We tested the association of previously reported ALL variants in a high-risk ALL population of URD-BMT recipients, assessing the association of these variants with different cytogenetic subgroups and for heterogeneity of effect by sex. Genotyping was performed using the Illumina Omni-Express BeadChip containing approximately 730,000 single nucleotide polymorphisms (SNPs). After quality control, cohort 1 (C1) and cohort 2 (C2) included 364 (C1) and 82 (C2) B-ALL cases of continental European ancestry and 2,229 (C1) and 809 (C2) controls (unrelated healthy donors). The sample size of non-European cases was not adequate for genetic analyses. Cases were a subset of the genome wide association study (GWAS) named Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT (DISCOVeRY-BMT) a parent GWAS study in collaboration with the Center for International Blood and Marrow Transplant Research. We tested SNPs within GATA3, IKZF1 and ARID5B for associations with disease status using logistic regression assuming an additive model adjusted for age. Analyses were done separately for the following B-ALL subgroups: hyperdiploid negative ALL, Ph-negative ALL, Abnormal cytogenetics and Normal cytogenetics. P-values for each cohort were combined using METAL software with weights proportional to the square root of the sample size(Pmeta). Sex-stratified analyses were performed using all B-ALL cases and by subgroup. Tests for heterogeneity using Cochran's Q method and I² statistic were used to calculate the percentage of variation across sex and cytogenetic group, abnormal versus normal). The study population consisted mostly of non-hyperdiploid and Ph negative B-ALL. The GATA3 variant conferred a 78% (P=2.9x10-10) and 82% (P=0.001) increased odds of B-ALL in C1 and C2, respectively, Pmeta=1.7x10-12 (Table 1). The GATA3 SNP was significantly associated, Pmeta 〈 5x10-8, with all subgroups except abnormal cytogenetics ALL. The SNP in IKZF1 wasassociated (Pmeta 〈 5x10-8) with B-ALL overall, Ph negative and normal cytogenetics ALL, with some evidence of heterogeneity in odds ratios (ORs) between normal and abnormal cytogenetics B-ALL in both cohorts. The ARID5B variant, previously shown to be strongly associated with pediatric ALL, showed weak or no evidence of association (Table 1). IKZF1 (rs11980379) associations were stronger across all associated subgroups in males (Table 2). When comparing ORs calculated for males and females in there was evidence of significant heterogeneity (Table 2) for B-ALL overall (P=0.02), non-hyperdiploid (P =0.02) and normal cytogenetics (P=0.004). GATA3 showed consistent association, with replication, across the cytogenetic subgroups analyzed. IKZF1 variant demonstrated differences by sex, with significant associations between this SNP and B-ALL, observed primarily in males, regardless of cytogenetics. Thus, sex-specific associations were not an artifact of underlying cytogenetic distributions between males and females. The variation between males and females indicates the IKZF1 variant may impact ALL risk differently in males and females, potentially explaining both the overall greater risk of ALL in males and the risk of ALL with worse outcomes. ARID5B associations have previously been associated with hyperdiploid ALL, however the majority of our high-risk study population is non-hyperdiploid, so ARID5B may be a marker of good risk ALL which is rarely treated with URD-BMT. Disclosures Hahn: Novartis: Equity Ownership; NIH/NHLBI: Research Funding. McCarthy:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sucheston-Campbell:NIH/NHLBI: Research Funding.