ALBERT

Description: Biochemistry DOI: 10.1021/bi301657w

Description: Background: In their seminal paper SWOG described the expected EMR for patients by age enrolled on clinical trials in AML (Appelbaum et al Blood 2006; 107: 3481-5). We sought to contrast these to population based outcomes. Methods: Using case listing session of SEER 18 (1973-2010) we identified patients (pt) 18 years of age and older diagnosed (dx) from 1990-2005 with AML (Site recode ICD-O-3/WHO 2008 Acute Myeloid Leukemia which includes ICD-0-3 9861/3, 9873/3, 9920/3, 9910/3, 9840/3, 9891/3, 9867/3, and 9895/3 and includes all FAB and WHO subtypes except M3 ). This was done in order to match the accrual periods of the SWOG studies. We then examined the EMR of pt with non-M3 AML and compared them to those reported by SWOG. EMR in SEER was defined as death within 0 to 1 month from dx; EMR in the SWOG studies was defined as death within 30 days of initiation of induction chemotherapy. Analyses were conducted with SEER*Stat 8.1.2, Microsoft Excel 2007 and GraphPad Prism 6. All p-values were 2-sided. Results: 26,272 pt were identified within SEER and 955 pt were in the SWOG EMR cohort. 54% of patients were male in SEER and 55% were male in SWOG; 85% of patients were white in SEER and 89% were white in SWOG. The EMR was 38.6% (10,130) in the SEER cohort; EMR was 12.2% (116) in the SWOG cohort (chi-squared with Yates correction p

Description: Despite advances in supportive care and post-remission therapy, the outcome of elderly and relapsed/refractory AML patients (pts) remains poor. These pts commonly present with high risk features including antecedent myelodysplastic syndrome and unfavorable cytogenetics. In addition, such pts are often unable to tolerate standard induction chemotherapy (IC) or myelotoxic salvage chemotherapy (SC), limiting clinical options. Between 1/2007 and 5/2008, we treated 24 pts with two cladribine based regiments designed to limit hematologic and non-hematologic toxicities, while maintaining cytotoxic activity. Treatment consisted of Cladribine (5 mg/m2 d1–5) and Cytarabine (2 g/m2 d1–5) in combination with G-CSF (300mcg sc d0–5) (CLAG) or mitoxantrone (10mg/m2 d1–3) (CLAM). IC pts had a median age of 63 (range 23–80). SC pts had a median age of 56 (range 25–68). No pt had favorable cytogenetics. 40% (IC) and 56% (SC) of patients had unfavorable cytogenetics. Prior anthracycline/topoisomerase inhibitor therapy, myelodysplastic syndrome or other antecedent hematologic disorder was common (53% IC and 11% SC) and prior remission had been brief among SC pts (median 165 days). Complete response occurred in 53% of IC and 44% of SC patients lasting a median of 73 days (IC) and 222 days (SC). The median duration of neutropenia and thrombocytopenia in IC pts (CLAG/CLAM) was 22 and 24 days, respectively. The median duration of neutropenia and thrombocytopenia in SC pts (CLAG/CLAM) was 25 days and 21 days, respectively. Neutropenia and thrombocytopenia contributed to significant rates of documented infection (53% IC and 78% SC) and severe bleeding (33% IC and 11% SC). Significant cardiac, hepatic or renal toxicities were not noted in any group. Examining subgroups, those that received IC CLAG were elderly (median age 70) and fared poorly (14%CR, 43%PD, 43%TRM). In contrast the younger IC CLAM cohort did well with 7/8 pts achieving CR with a median duration of 126 days despite poor risk features (38% high-risk cytogenetics/63% AHD). This is the first report of front-line CLAM in AML. Both CLAG and CLAM performed similar to other salvage regimens reported in the literature though in a less favorable population than has been previously reported with CLAG and CLAM (median age 45 and 17–25% unfavorable cytogenetics in the Polish experience compared to median age 56 and 56% unfavorable cytogenetics in this report) (Wierzbowska A et al. Eur J Haematol2007; 80: 115–26, Wrzesien-Kus A et al. Eur J Haematol2003; 71: 155–62). CLAM warrants further study, especially in the context of other agents as both induction and salvage therapy for high-risk AML. New Diagnosis Relapsed (xx/xx)=data from CLAG and CLAM, respectively. Patients (CLAG/CLAM) 15 (7/8) 9 (5/4) Median Age 63 (range 23–80) (70/56) 56 (range 25–68) (56/53) Median WBC count 18,000 (1000–157,600) 15,400 (200–83,000) Favorable cytogenetics 0% 0% High risk cytogenetics or FLT3-ITD positive 40% (43%/38%) 56% (60%/50%) Prior tAML, MDS or AHD 53% (43%/63%) 11% (20%/10%) Duration of first remission NA 165 days (30–263) CR 53% (14%/88%) 44% (40%/50%$) PD 27% (43%/12%) 56% (60%/50%) Death during aplasia 20% (43%/0%) 0% CLAG/CLAM Duration of CR (days) 73 (range 73)/126# (range 96–∞) 222 (range 219–224)/164 (range 61@-267) % of CR going on to receive allogeneic transplant 13% (0%/14%) 11% (20%/0%) Median duration of neutropenia

Description: Background Follicular lymphoma (FL) is the most common form of indolent lymphoma, however Grade 3 FL (FL3) has more aggressive behavior and its response to therapy is controversial. Several studies have reported improved clinical outcomes in patients with FL3 treated with rituximab (R), approved in early 2006, as a first line therapy for diffuse large B-cell lymphoma. The aim of this population based study is to compare the overall survival and disease specific survival in patients diagnosed with FL3 prior to and after 2006. Materials and methods We used the Surveillance, Epidemiology, and End Results 18 database to identify cases diagnosed with FL3 between 1983 and 2013, limiting the selection to patients aged more than 15 years with single primary malignancy. The data was split into two cohorts - Cohort 1 comprised of cases diagnosed between 1983 and 2005, with a study cutoff of December 2005, and Cohort 2 comprised of cases diagnosed between 2006 and 2013. The Overall Survival (OS) and Disease Specific Survival (DSS) for the two cohorts were calculated using the Kaplan-Meier method and the results were compared using the Log Rank test. The Cox proportional hazards regression model was used to identify factors other than time of diagnosis, which had a significant impact on survival times. Results Cohort 1 included 3,959 cases with death occurring in 1,319 cases during the study period (1,013 deaths due to disease specific factors) and Cohort 2 included 3,050 cases with death occurring in 509 cases (374 deaths due to disease specific factors) (table 1). The 5-year OS and DSS survivals for Cohort 1 were 59.3% and 67.7%, and for Cohort 2 were 78.3% and 84% respectively (figure 1). The differences in both OS and DSS survival rates were confirmed to be significant using the Log Rank test (p

Description: Background: Limited data exists regarding the characteristics and outcomes of adolescents and young adults (AYAs) with acute myeloid leukemia (AML) which are largely under-represented in both pediatric and adult trials. We sought to compare the characteristics and outcomes of AYAs with AML using a large population based registry in the United States. Methods: We utilized Surveillance Epidemiology and End Results (SEER)-18 registry to identify all pediatric (0-18 years) and AYA (age 19-30 years) patients diagnosed with AML using appropriate histology codes based on the International Classification of Diseases for Oncology, 3rd version. Patients with acute promyelocytic leukemia (APL) were excluded from all analysis. Survival statistics were computed for each group using actuarial (Kaplan-Meier method) and compared using Z test for comparison of population proportions. Early mortality, defined as mortality within 1 month of diagnosis, was used as a surrogate for treatment related mortality. Kaplan Meier survival curves were plotted and compared using log-rank test. Multivariate analysis was done using logistic regression and Cox proportional hazard regression model. All p values were two sided and the level of significance was chosen at 0.05. Results: A total of 6343 eligible patients were identified, which comprised 2836 (44.7%) AYAs. A total of 52% (n=3346) were males, whereas 76%(n=4825) were whites. Histologically, majority of patients (56%; n=3545) were categorized as AML, not otherwise specified, followed by acute monocytic leukemia (9.9%, n=630). Majority (55%; n-3509) of the patients were diagnosed between 2001-2012. The early mortality rate was lower in the pediatric AML patients (pAML) as compared to AYAs (6.2% vs 9.2%; p

Description: Introduction: Previous research has shown that weekend hospital admissions are associated with an increased mortality in comparison to weekday admissions for a number of emergent conditions including myocardial infarction [Relative Risk (RR) 1.048; 95% confidence interval [CI], 1.022 to 1.076; P value

Description: Introduction: Acute Megakaryocytic Leukemia (AMegL) is a rare subtype of Acute Myeloid Leukemia (AML) resulting from uncontrolled proliferation of megakaryoblasts. Due to its rarity it is unclear if AMegL morphology is independently associated with outcomes in AML. Methods: We used the Surveillance, Epidemiology and End Results (SEER) 18 database to identify adult patients with AML diagnosed between 1991-2011 using the appropriate International Classification of Disease (ICD-O-3) histology codes. Cases of APL (M3) were excluded. Kaplan Meier Survival curves were generated to compare survival statistics between AMegL subtype and the rest of AML types. Multivariate analysis was done using Cox Linear Proportional Hazard Regression model. Statistical analysis was done using Statistical Package of Social Sciences (SPSS) version 21.0 (IBM Corporation, Armonk, NY). Results: Of 45,564 cases of AML identified, 304 (0.7%) belonged to the AMegL subtype. The median ages were 69 (range 18-111), and 67.5 (range 18-92) years, respectively (p value 0.08); the proportion of males were 54.3% and 59.2% respectively (p value 0.09), the median year of diagnosis was 2004 in AMegL versus 2002 in other AML. Whites comprised 82.6% and 84.7% respectively. The 5 year overall survival rates were 17.5% and 10.6% respectively. Kaplan Meier Survival curves showed significantly inferior survival for AMegL relative to other AML cases (p value of log rank test 0.01). On multivariate analysis AMegL was as an independent predictor of increased mortality (adjusted RR 1.23, 95% CI 1.09-1.38, p value

Description: Introduction: 9p24 contains genes that are critical for immune evasion and propagating cell division. The loci for PD-L1, PD-L2, JAK2, and the histone demethylases KDM4C/JMJD2C are linked on 9p24 (Van Roosbroeck et al. Genes, Chromosomes and Cancer 2016). Amplification or rearrangements of this region have been described in the pathogenesis of classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (Ansell et al. New England Journal of Medicine 2015). Additionally, JAK2 amplification up-regulates PD-L1 and L2, which leads to increased T-cell inactivation and suggests synergy between these drug targets. The recent success of PD-1 blockade in numerous malignancies has led to the development and approval of PD-1 inhibitors in cHL as well as other cancers. Targeted therapies are approved for JAK2 inhibition, such as ruxolitinib, and are in development for histone demethylases, which illustrates the utility of identifying the 9p24 amplicon in hematologic malignancies (HM) (Van Roosbroeck et al. Genes, Chromsomes and Cancer 2016). The goal of this analysis is to better understand the distribution of 9p24 abnormalities across a broader range of leukemias and lymphomas in order to facilitate future studies of targeted therapy. Methods: The National Cancer Institute's Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer was queried for 9p24 breakpoint abnormalities within HM. Incidence of additions and rearrangements in chromosome 9p24 for all subtypes of HM listed in the Mitelman Database were calculated. Individual references were manually reviewed and pathologic data was extracted as available from the primary sources. Diffuse large B-cell lymphoma (DLBCL) cases were further assessed for co-incident rearrangement of MYC (8q24), BCL2 (18q21) and BCL6 (3q27) with 9p24. All subtypes with greater than 2% incidence of additions and/or rearrangements in chromosome 9p24 were reported. Results: 48,761 patients (pts) with HM across 74 lymphoid and myeloid subtypes were identified. 361 (

Description: Abstract 1102 Poster Board I-124 Background Therapy-related acute myeloid leukemia (t-AML) is a lethal iatrogenic complication of radiation therapy and chemotherapy. It is unclear whether t-AML represents a truly stochastic event, or if individuals have different degrees of susceptibility. It has been shown that women diagnosed with breast cancer younger than 50 are at the highest risk of developing subsequent AML compared to age-matched controls (RR 4.14). This may either reflect more aggressive therapy given to younger women or differences in their ability to tolerate chemotherapy, perhaps through germline polymorphisms in DNA repair or drug metabolism genes. BRCA1 and BRCA2 genes are involved in DNA repair and germline variants confer an increased risk of breast cancer at a young age (median age at diagnosis 40 and 41, respectively) as well as an increased risk of ovarian cancer. The age-dependent risk of t-AML in breast cancer survivors mirrored the risk of a subsequent diagnosis of ovarian cancer, suggesting a common genetic factor may be responsible. Therefore, we hypothesized that young women with breast cancer that develop t-AML would have an increased prevalence of BRCA1 or BRCA2 mutations compared to the predicted prevalence of mutations based on age, personal and family history. Methods We identified 13 women under the age of 50 that were treated at our institution for t-AML following a diagnosis of breast cancer (median age = 43.5). Each chart was reviewed for family and personal history of breast cancer and ovarian cancer. The predicted prevalence of mutations in BRCA1 and BRCA2 were calculated from tables developed by Myriad Genetic Laboratories and the number of expected cases was calculated with a weighted sum. Normal DNA obtained from a skin biopsy was sequenced for BRCA1 and BRCA2 in 11 women and bone marrow DNA was sequenced in 1 woman in whom a skin sample was unavailable. One woman had a known deleterious mutation in BRCA2 and only the exon containing the mutation was resequenced. Total exonic sequencing, including splice sites, was performed (excluding BRCA2 exon 12, and partial coverage of BRCA2 exon 20 that failed primer design). There are no described deleterious mutations in exon 12 in the On-line Breast Cancer Mutation Data Base (BIC) (http://research.nhgri.nih.gov/ projects/bic/). Statistical differences between the observed versus expected frequencies of nucleotide variants were compared using the Chi-square goodness-of-fit test. Functional significance of nucleotide variants were determined using BIC, SIFT (http://blocks.fhcrc.org/sift/SIFT.html), FastSNP (http://fastsnp.ibms.sinica.edu.tw/pages/-input_CandidateGeneSearch.jsp) and PolyPhen (http://genetics.bwh.harvard.edu/pph/) computational algorithms. Results The expected number of patients harboring mutant BRCA1 or BRCA2 alleles was 1.46 in these 13 patients (11%). We identified 4 patients with sequence variants predicted to alter function in the 13 patients (31%), which represents a statistically significant increase over the expected frequency (p=0.026). Of the 4 mutations, two (BRCA2 - S1760X and BRCA2 – F1182X) are known to be deleterious in BIC, and one (BRCA1 - Q356R, found in 2 patients) is of uncertain significance in BIC, and is computationally predicted to disrupt protein function by SIFT, FastSNP, and PolyPhen algorithms. The functional consequence of each nucleotide change is being tested using DNA repair activity assays in isogenic cell lines expressing either the wild-type or mutant allele. Discussion In this study, we observed an increased prevalence of mutations in BRCA1 and BRCA2 in young women with breast cancer treated with chemotherapy and/or radiotherapy that developed t-AML, suggesting that alterations in DNA repair genes may be important for the development of t-AML. A case-control study is being performed to validate this finding in a larger group of uniformly treated breast cancer patients. Disclosures No relevant conflicts of interest to declare.