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Abstract Abstract 4238 Background Duplication of the long arm of chromosome 1 (1q) is a recurrent finding in hematologic neoplasms. It is most commonly observed as an unbalanced whole arm translocation with chromosome 7, resulting in concurrent deletion of 7q (ISCN as der(1;7)(q10q10)). It is less frequently observed as an unbalanced translocation with a chromosome other than chromosome 7 or as a duplication of only a segment of 1q. The der(1;7) has been described in myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML), and is reportedly less commonly associated with myeloproliferative neoplasms (MPN). The effect of this rearrangement on prognosis is unclear, although it is classified by the International Scoring System (IPSS) as a karyotypic variant of del(7q)/-7 and is thus assigned poor risk. We have initiated a thorough review of all cases of duplication of the long arm of chromosome 1 seen at our institution. Methods After approval from the Institutional Review Board, all cases seen at Mayo Clinic over a 20 year period (1989-2009) were searched for a duplication of the long arm of chromosome 1. The sole exclusion criterion was a complex karyotype (3 or more independent chromosome abnormalities in the clone). Cytogenetic and hematopathology review was done and relevant clinical data were abstracted from the Mayo Clinic record. Survival of MDS patients and MPN patients was determined from time of cytogenetic diagnosis of der(1;7) until death or last contact with the patient, using the Kaplan-Meier method. Results Among 23,375 unique patients at Mayo Clinic with a cytogenetic study for hematologic neoplasm, 229 (0.98%) patients carried a duplication of 1q. Within this group, 99 (0.42%) had duplication of part of 1q, 123 (0.53%) carried a whole arm duplication of 1q, and 7 patients carried an isochromosome 1q (resulting in 4 copies of 1q). The most common karyotype among those with a whole arm duplication of 1q was der(1;7) (n=84), followed by similar whole arm translocations involving chromosomes 9 and 19 (n=7 each) or chromosomes 12, 13, 14, 15, 16, 17, 18, 20, 21, or 22 (n=1 to 6 each). We focused on 65 der(1;7) patients who had adequate hematopathological material that could be reviewed and sub-classified according to WHO criteria. MDS was identified in 30 patients and MPN in 20. MDS (therapy related, RARS, RAEB-1 or 2) was seen in 9 patients (14%), MDS/ refractory cytopenia with multilineage dysplasia (RCMD) in 19 (29%). MDS/Myeloproliferative neoplasm (MPN) in 2 (3%), MPN not otherwise classified in 5 (8%), and MPN / primary myelofibrosis (including 1 post-polycythemic and one post-thromobocythemic) (PMF) in 15 (23%). The bone marrow was apparently normal in 5 patients (8%), CLL was noted in 3 (5%), and 1 each exhibited features of systemic mast cell disease or myeloma. Acute myeloid leukemia (AML) was identified 5 patients (8%). The M:F ratio of the der(1;7) patients was 2.8:1. The median age at occurrence of the der(1;7) was 63 years (range: 13-87 years). All 5 AML patients have died (median survival 9 months). Of the MDS and MPN patients, the median survival was 2.2 and 2.8 years, respectively, from the time of cytogenetic diagnosis. Overall survival was not significantly different between the MDS and MPN group, and they exhibited 30% survival after 5 years (see Figure). Conclusions Duplication of 1q was observed in nearly 1% of the Mayo Clinic patients who had a bone marrow cytogenetic study for a hematologic neoplasm. Among those with a der(1;7), AML was uncommon but MDS and MPN were similar in frequency. Median survival of 2.2 to 2.8 years for the MDS and MPN group justifies assignment to a more favorable group than the current IPSS assignment. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1733 Introduction: Much remains to be elucidated regarding the etiology of myelodysplastic syndrome (MDS) and why some cases progress to acute myeloid leukemia. Further, there are few data on how accurate case classification is within state cancer registries and the impact of the 2008 WHO MDS classification modifications on clinical practice. We are conducting a large population-based prospective study of MDS to investigate risk factors for initial disease as well as disease progression. Our study includes comprehensive central review of all cases. Initial findings are reported here. Methods: We began evaluation and follow-up of all newly diagnosed MDS cases in Minnesota between the ages of 20 and 85 years from April 1, 2010 onward. Our process includes rapid case identification by the Minnesota Cancer Surveillance System (MCSS), contact of individual patients after primary physician approval, and, for interested patients, participation in an extensive questionnaire with medical history review and optional saliva sample for DNA. In concert, all cases pass through central medical review including: 1) independent pathology report +/− slide review by two hematopathologists to confirm diagnosis and subclassification; 2) independent cytogenetic review by a cytogeneticist; and 3) medical chart review by an oncologist to identify pertinent clinical history and prospectively calculate the International Prognostic Scoring System (IPSS) and WHO-based prognostic scoring system (WPSS) scores. Annual follow-up is planned to monitor for disease progression and outcome. In cases of unknown cytogenetics, IPSS calculations are not completed. In cases of unknown cytogenetics or diagnosis of MDS-U, not currently stratified in the WPSS, WPSS calculations are not completed. Results: We describe the first 67 patients enrolled on this study that have completed central review. The majority of patients were male (n=44) and the median age of the cohort at diagnosis was 71 (range 41–85). Table 1 Conclusion: Ours is the first large prospective population-based study of MDS that includes central pathology, cytogenetic, and clinical review of newly diagnosed patients with prospective calculation of IPSS and WPSS and plans for long term follow-up. This study is expected to enroll approximately 700 MDS cases over a five year period. While early in investigation, our initial review highlights the variability in distinct WHO diagnosis between initial cancer registry (i.e., MCSS) designation and designation after thorough central review of all appropriate diagnostic components. Our data suggest the robustness of the WHO RA, RARS, and RCMD classifications, the possible over-utilization of MDS-U classification, and highlight the under-representation of therapy-related MDS identification with registry designation. The impact of discordant diagnoses between MCSS and central review on therapeutic strategies is uncertain, but warrants continued evaluation and underscores the importance of complete central review in evaluation of MDS cases. Supported by NIH R01 CA142714. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 873 Each year in the United States, approximately 45,000 individuals are newly diagnosed with leukemia and 22,000 will die of the disease. Due to this poor survival, leukemia ranks fifth in person years of life lost among specific cancers. Little is known about causes, although exposure to solvents, radiation, pesticides and, to a modest extent, cigarette smoke has been implicated for some subtypes. The last comprehensive report of leukemia trends covered the period 1973–1998 [Xie Y et al, Cancer 2003]. Evaluation of recent leukemia incidence trends could provide important new etiologic insights. Using Surveillance, Epidemiology and End Results (SEER) Program data, we analyzed leukemia incidence trends in U.S. adults (≥ 20 years of age) by age, leukemia subtype (acute myeloid (AML), acute lymphoid (ALL), chronic myeloid (CML), chronic lymphoid (CLL)) sex, race, and ethnicity for the period 1987–2007. Frequencies, age-adjusted incidence rates (IR, per million), and trends were calculated along with annual percent change (APC) and corresponding 95% confidence intervals (CI). Joinpoint analyses were used to detect any significant directional changes in IRs over the period. Of 43,970 newly diagnosed cases identified, IRs increased with age and were consistently higher in males than females for all four subtypes. The highest IRs occurred for CLL (54.4), followed by AML (38.3), CML (20.6) and ALL (7.0). With regard to trends, IRs for CLL (APC -0.5; CI: -0.9, -0.1) and CML (APC -1.2; CI: -1.6, -0.8) declined over the time period; declines were observed in males and females, and by race and ethnicity. Male(M):Female(F) IR ratios remained relatively constant at approximately 2.0 and 1.7, respectively. For ALL, IRs decreased in males (APC -0.9; CI: -1.9, 0.2) but slightly increased in females (APC 0.4; CI: -1.0, 1.7), which was most notable in Hispanics (APC 4.0; CI: 1.2, 6.8). In contrast to CML and CLL, the overall M:F rate ratio for ALL decreased, although it did not reach statistical significance (p=0.08). For AML, IRs increased significantly for males (APC 1.0; CI: 0.3,1.6) and females (APC 1.7; CI: 0.7, 2.7) from 1987–2000 and 1987–2001, respectively. However, since then, AML IRs for males have been significantly decreasing by 4.2% per year (CI: -6.4, -2.1), while IRs for females have been decreasing by 1.6% per year (CI: -4.1, 0.9). Across the entire time period 1987–2007, there was a statistically significant negative trend (p=0.002) in the M:F IR ratio for AML. Decreasing IRs across many leukemias since 1987 are unlikely to reflect changes in screening or diagnostic coding practices. Instead, these observations may reflect temporal changes in etiologically relevant environmental exposures. Of note, the prevalence of cigarette smoking in the population has decreased and occupational safety practices (e.g., reducing solvent/radiation/pesticide exposure) have improved over the last several decades, which could contribute to the gradual decreases in some IRs observed. In contrast, the rapid and significant decrease noted for AML since 2000, especially following a significant increase, was striking and deserved additional scrutiny. We further consulted with our cancer registry colleagues to determine whether the introduction of myelodysplastic syndrome (MDS) as a new malignancy in SEER in 2001 could be influencing recent AML trends given the (apparently) coincidental overlap in time periods. Of note, approximately one third of MDS patients subsequently develop AML. We learned that AML following an MDS diagnosis from 2001–2009 was not reportable to SEER and therefore not counted. We are not aware that this has been documented in the literature. However, beginning for 2010 diagnoses, SEER changed this practice such that AML following MDS will be captured as a second malignancy. Based on these changes in AML surveillance, it will especially be important to monitor future trends for this malignancy. Overall, this study demonstrates the value of in-depth analyses of SEER cancer IRs and trends; analyses may reveal patterns of clinical and/or etiological importance, or, in the instance of AML, unpublished coding rule changes. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms has specifically categorized germline mutations that are associated with myeloid clonal evolution (Arber et al. Blood 2016). This group consists of myeloid neoplasms with an isolated germline predisposition (CEBPA, DDX41), myeloid neoplasms associated with congenital thrombocytopenia (ETV6, RUNX1, ANKRD26) and germline myeloid neoplasms with multi-organ dysfunction (GATA2, chromosomal breakage disorders, telomere biology disorders etc). We carried out this study to describe the clinical spectrum of germline disorders with predisposition to myeloid neoplasms as categorized by the 2016 WHO classification revision. Methods: After Institutional Review Board (IRB) approval, the adult and pediatric bone marrow failure syndrome database (1990-2016) and the electronic medical record were queried for germline disorders involving GATA2, CEBPA, DDX41, ETV6, RUNX1, ANKRD26, Down syndrome and Noonan syndrome. Chromosomal breakage assays (Diepoxybutane/Mitomycin-C), flow-fluorescent in-situ hybridization (FISH) for telomere length assessment, Fanconi anemia complementation assays and Sanger/Next Generation sequencing (NGS) for the aforementioned germline disorders with myeloid predisposition were carried out in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. These disorders were then classified based on the 2016 WHO classification revision. Results : 54 individuals (37 families) were included in the study. Eleven (20%) patients belonging to 5 families were identified as having germline mutations with a preexisting platelet disorder: ETV6 (n=1), ANKRD26 (n=5), RUNX1 (n=5). Forty-three (79%) patients (32 families) had inherited syndromes with multi-organ dysfunction: GATA2 (n=11, 26%), bone marrow failure syndromes (n=14, 33%) and telomere biology disorder (n=14, 33%). There was one patient with neurofibromatosis with a germline PTPN11 mutation who developed juvenile myelomonocytic leukemia, while there were three patients with Down syndrome; 2 with transient abnormal myelopoiesis and one who developed acute megakaryocytic leukemia. The clinical phenotype, prevalence and characteristics of myeloid clonal evolution and outcomes are presented in Table 1. No patients with germline CEBPA or DDX41 mutations were identified. Patients with germline platelet disorders did not have any prominent non-hematological manifestations. Erythrocytosis (20%) with long-standing thrombocytopenia (100%) was a unique feature associated with ANKRD26 mutations. Non-hematologic clues such as human papillomavirus (HPV)-driven warts, primary lymphedema (Emberger syndrome) and frequent atypical infections with monocytopenia were seen in patients with germline GATA2 mutations, and preceded myeloid clonal evolution (morphologic, cytogenetic and molecular). Notably, the age at presentation and penetrance of myeloid transformation was variable, with individuals from the same family developing symptoms during the first decade of life and others remaining asymptomatic to date (fifth decade). Somatic ASXL1 mutations were detected in all 3 (100%) patients with GATA2 mutations and in one patient with ANKRD26 mutation that developed myeloid clonal evolution. In our study myeloid clonal evolution was seen in 40% with RUNX1 mutations, 27% with GATA2 mutations, and 20% with ANKRD26 mutations. We could not calculate the same for bone marrow failure syndromes as the total number of cases seen are still being assessed. Outcomes with allogeneic stem cell transplantation were favorable in appropriately selected patients (Table 1). Conclusion : The 2016 WHO revision to the classification of myeloid neoplasms highlights the importance of recognition and molecular characterization of germline mutations (syndromic and non-syndromic) with risk for myeloid clonal evolution. While some of these disorders (GATA2, Fanconi anemia, telomere biology disorders) may have important non-hematological clues, many present with isolated thrombocytopenia (RUNX1, ETV6). The age and frequency of myeloid evolution is highly variable. Acquisition of somatic ASXL1 mutations at the time of clonal myeloid transformation highlights the role of epigenetic dysregulation in disease evolution. Disclosures Kenderian: Novartis: Patents & Royalties, Research Funding.

Abstract Abstract 4767 Previous studies have demonstrated that heme-oxygenase-1 (HO-1), the rate limiting enzyme in the catabolism of heme, is a regulator of the balance between hematopoiesis and stem cell preservation under stress. HO-1 produces three by-products, carbon monoxide, biliverdin/bilirubin, and iron/ferritin, all of which have demonstrated antioxidant and anti-apoptotic properties. HO-1-/- mice display oxidative stress, anemia, and leukocytosis with chronic inflammation. We hypothesize that therapy with inhaled carbon monoxide (CO) may reduce stress hematopoiesis in HO-1-/- mice, restoring them to normal hematopoiesis. We have previously reported that treatment with 250 ppm CO for 1 h raises mouse carboxyhemoglobin to 14–20% which returns to baseline within 24 hours. Therefore, in order to test this hypothesis we treated 25 week old HO-1-/- mice and HO-1+/+ mice (n=7/strain) with 250 ppm inhaled CO for 1 h/day, 3 days/week for eight weeks and compared them to an equal number of untreated HO-1-/- and HO-1+/+ mice. We demonstrate that after four weeks, CO-treated HO-1-/- mice have a total white blood cell count of 11.9 ± 3.2 K/μ L compared to 22.6 ± 3.2 K/μ L in untreated HO-1-/- mice (p<0.05), with HO-1+/+ mice having no treatment effect. After 8-weeks of treatment the mice were sacrificed and methylcellulose colony-forming unit assays and flow cytometry were performed on bone marrow to assess their hematopoietic potential. Total methylcellulose colony-forming units were similar in both HO-1-/- and HO-1+/+ mice with CO-treatments significantly (p<0.05) increasing the total number of colonies per animal. Of note, in both the CO-treated HO-1-/- and HO-1+/+ mice the CFU-GM were not significantly affected. Cell cycle analysis of the bone marrow using propidium iodide demonstrates that untreated HO-1-/- mice have a significantly decreased percent of cells in S-phase compared to untreated HO-1+/+ mice. Treatment with CO significantly (p<0.05) increases the percent of cells in S-phase in HO-1-/- mice but not HO-1+/+ mice. Similarly, untreated HO-1-/- mice have a lower frequency of cells in sub-G1 phase compared to untreated HO-1+/+ mice, however CO-treatments significantly (p<0.01) increase this frequency in HO-1-/- mice to levels comparable with untreated and CO-treated HO-1+/+ mice. Reactive oxygen species (ROS) production in lineage-, c-kit+, Sca-1+ (KLS) cell population was assessed using 5-(and 6-)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate dye. HO-1-/- mice have a significantly (p<0.001) increased proportion of ROS positive KLS cells compared with HO-1+/+ mice. Interestingly, the CO-treated HO-1-/- mice had a significantly higher proportion of KLS cells staining positive for ROS, but the mean fluorescent intensity of this population was significantly (p<0.05) decreased compared to untreated HO-1-/- mice. This indicates that there is an overall decrease in ROS in the KLS cells of CO-treated HO-1-/- mice compared to untreated HO-1-/- mice. Analysis of long-term, short-term, and multipotent progenitor cell populations was conducted and reveals significant changes at the level of the short-term hematopoietic progenitor population (ST-HSC). Specifically, untreated HO-1-/- mice have a significantly increased percent of ST-HSC cells compared to untreated HO-1+/+ mice. Treatment with CO significantly (p<0.05) decreases the percent of ST-HSC cells in HO-1-/- mice but not HO-1+/+ mice. Combined this data indicates that CO therapy is able to modify the hematopoietic potential of HO-1-/- mice. We propose a model in which CO-mediated signaling initiates a homeostatic conditioning program in stem cells to balance hematopoiesis and stem cell preservation. Disclosures: Belcher: Sangart: Research Funding. Vercellotti:Sangart: Consultancy, Research Funding.

Abstract Background Polymorphisms in mitochondrial DNA can be used to group individuals into haplogroups that reflect human global migration. These mitochondrial variants are associated with differences in mitochondrial function and have been associated with multiple diseases, including cancer. In this analysis, we evaluated the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Methods Cases were identified by rapid case ascertainment through the population-based Minnesota Cancer Surveillance System (MCSS). Participants were recruited to the MDS study if they were diagnosed with MDS between April 1, 2010 and October 31, 2014. Eligibility criteria included residence in Minnesota, age at diagnosis between 20 and 85 years, and ability to understand English or Spanish. Centralized pathology and cytogenetics review were conducted to confirm diagnosis and classify by subtypes. Controls were identified through the Minnesota State driver's license/identification card list. Genomic DNA from cases and controls was collected using Oragene DNA collection kits (DNA Genotek, Ontario, Canada) and extracted via Autopure LS Instrument according to manufacturer's instructions (Qiagen). We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation (Mitchell et al Hum Genet 2014; Raby et al J Allergy Clin Immunol 2007) on the Sequenom iPLEX Gold MassArray platform (Sequenom, Inc., San Diego, CA) in the University of Minnesota Genomics Core. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non-Hispanic white cases and controls. All statistical analyses were conducted using SAS v.9.3 (SAS Institute, Cary, NC). Odds ratios (OR) and 95% confidence intervals (CI) were calculated. We also evaluated associations by MDS subtype and IPSS-R risk category. Results We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. The distribution of haplogroups in our control sample was similar to the distribution reported in a previous sample of non-Hispanic white individuals from the United States (Mitchell et al Hum Genet 2014), with the highest number in the H haplogroup (42%). Due to small sample sizes in some subgroups, we combined mt haplogroups into larger bins based on the haplogroup evolutionary tree, including HV (H+V), JT (J+T), IWX (I+W+X), UK (U+K), and Z (van Oven & Kayser Hum Mut 2009) for comparisons of cases and controls. Using haplogroup HV as the reference group, we found a statistically significant association between haplogroup JT and MDS (OR=0.57, 95% CI 0.36, 0.90, p=0.02). No other significant associations were observed in a comparison of cases and controls (Figure). In the analysis stratified by MDS subtype, the association with haplogroup JT reached statistical significance only in MDS cases with the RCMD subtype (OR=0.42, 95% CI 0.18, 0.97), although the association was similar in magnitude for RARS and the p-value for heterogeneity was non-significant (0.76). Similarly, the associations between haplogroup JT and MDS were similar in the analysis stratified by IPSS-R risk category (p-value for heterogeneity = 0.71). Conclusions In this population-based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. Previous studies using cybrid cells have reported functional differences by mtDNA haplogroup and provide biological plausibility for the observed association, including higher capacity to cope with oxidative stress in haplogroup T (Meuller et al PLoS One 2012) and lower levels of ATP and reactive oxygen species production in haplogroup J (Kenney et al PLoS One 2013). Further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes. Figure 1. Association between mtDNA haplogroup and MDS Figure 1. Association between mtDNA haplogroup and MDS Disclosures No relevant conflicts of interest to declare.

Abstract Background MDS is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective hematopoiesis and an increased risk for developing acute myeloid leukemia (AML). The majority of MDS cases are sporadic, but rare familial cases have been described and are often ascertained through clinic-based referrals. To our knowledge, no population based study of MDS has examined the frequency of family history of hematologic malignancies and disorders in patients, nor associations with disease characteristics and outcomes. Methods Newly diagnosed MDS cases are being identified by rapid case ascertainment by the Minnesota Cancer Surveillance System (MCSS), a population-based cancer registry in Minnesota. Eligibility criteria include all newly diagnosed cases of MDS during the period April 1, 2010-October 31, 2014, between 20-85 years, Minnesota resident, and ability to understand English or Spanish. Proxy interviews are not being conducted. Medical records and biologic samples are obtained and questionnaires are filled out by participants. Centralized pathology and cytogenetics review confirm diagnosis and classify by subtype and risk score including the Revised International Prognostic Scoring System (IPSS-R). Since 2010, information on family history has been obtained through questionnaire responses and/or medical record review on 353 MDS patients. Cases were considered to have a positive family history if they reported a first degree relative with MDS, leukemia, lymphoma or other hematologic condition (multiple myeloma [n=4], Waldenstrom’s macroglobulinemia [n=1] and idiopathic thrombocytopenic purpura [n=1]). Treatment related MDS cases were excluded leaving 330 MDS patients for analysis. Unconditional logistic regression was used to calculate crude odds ratios (ORs) and 95% confidence intervals (CI) overall and by sex. Results A total of 61/330 (18.5%) cases reported a family history of a hematologic condition. The mean age at diagnosis was 71.3 years in those with a family history compared to 72.2 years in those without a family history (p=0.53). There was no difference in the sex distribution between the two groups. Though not statistically significant, the odds of having abnormal cytogenetics or an IPSS-R of High/Very High was lower for those having a positive family history (OR 0.57 [CI 0.25-1.33, p=0.19 and 0.67 [CI 0.24-1.84, p=0.29], respectively). The odds of survival at one year after diagnosis was significantly higher in those with a family history (OR 2.79 [CI 1.04-7.51, p=0.04]) compared to those without (Table). Further stratification by sex revealed that this association was strongest for males (OR=4.23, [CI 0.94-19.0, p=0.06] compared to females (OR=1.84 [CI=0.47-7.19, p=0.38]). Discussion In this population based study of adults with MDS, the prevalence of MDS cases having a positive family history was higher than previous reports. Additionally, cases reporting a family history of hematologic malignancies and disorders appear to experience lower risk disease and have significantly improved overall survival, especially males. It is possible that patients with a family history of hematologic conditions are diagnosed earlier in the course of their disease secondary to increased awareness about blood disorders and/or more active screening within the family. Our analysis is limited by relatively small numbers, but enrollment is ongoing so subsequent analyses with larger numbers of subjects may be more revealing. Additionally, a prospective study to examine these families further, including detailed medical histories and collection of biospecimens (saliva, blood, skin) for genetic analyses is underway in order to identify potential mechanisms and mutations involved in the development of MDS and progression to AML. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction Much remains unknown regarding the etiology of MDS and why some cases progress to acute myeloid leukemia (AML). With MDS reportable as a distinct myeloid malignancy for the first time only in 2001, there are few data on state cancer registry case identification and classification accuracy. To grasp the true incidence and the scope of this heterogeneous clonal hematopoietic malignancy, the accuracy of such information is essential. In our third year of a large population-based prospective study of MDS to investigate risk factors for initial diagnosis and disease progression, we report our experience with MDS case identification and classification according to both our state cancer registry and our comprehensive central review process Methods We began our identification and follow-up of all newly diagnosed adult MDS cases in Minnesota in April 2010. Our process includes rapid case identification by the Minnesota Cancer Surveillance System (MCSS), contact of individual patients, and their participation in an extensive questionnaire and medical history review. In concert, all cases pass through central medical review including: 1) independent pathology review by two hematopathologists; 2) independent cytogenetic review by a cytogeneticist; 3) integrated central pathology-cytogenetic review; and 4) medical chart review by an oncologist to identify pertinent clinical history and treatments and prospectively calculate risk stratification scores (International Prognostic Scoring System (IPSS)). Annual follow-up monitors for disease progression and outcome. Results We describe the first 161 patients enrolled who have completed central review. Our data highlight the excellent concordance between MCSS and central review for the MDS subtypes RAEB (n=40/50, 80%), RARS (n=20/23, 87%), and RCMD (n=19/25, 76%). However, we noted poor concordance for the MDS subtypes RA (n=1/7 (14%) with 5 cases re-classified as RCMD) and MDS-U (n=3/24(13%) with 21 cases re-classified into other MDS subtypes). Notably, our integrated central review process identified and reclassified 12 additional cases of t-MDS when all data were considered. Our central review process noted an additional 30 cases classified as MDS by MCSS that we deemed ineligible after central review due to insufficient morphology (n=20) or reclassification to chronic myelomonocytic leukemia (CMML) (n=5), MDS/MPD (n=3), or AML (n=4). Conclusion Ours is the first large prospective population-based study of MDS that includes central pathology, cytogenetic, and clinical review of newly diagnosed patients with prospective risk stratification calculation and long term follow-up. Our review highlights the variability in the diagnosis and subclassification of MDS between our state cancer registry and after integrated central review, with as many as 80% of cases in certain MDS subtypes being re-classified, and an approximately 20% ineligibility rate. The high proportion of cases submitted in MCSS as MDS-U that were re-classifiable into specific MDS subtypes following central review suggests a possible misapplication of this MDS category in a way not intended by the 2008 WHO guidelines. The additional classification of t-MDS by our central review process suggests that this subtype is likely underestimated by cancer registries. Assessment of therapeutic implications will be important to determine if these variabilities are consequential. Disclosures: No relevant conflicts of interest to declare.

Abstract Despite improvements in front-line therapy for acute lymphoblastic leukemia (ALL), treatment after relapse remains a critical challenge. Examination of outcome after relapse in a large, recently treated, and unselected population provides a useful benchmark for evaluating new approaches. Survival after relapse was tracked on Children’s Cancer Group (CCG) ALL trials. Relapses were categorized by site (isolated or combined bone marrow relapse (MR); isolated central nervous system relapse (CNSR); isolated testicular relapse (TR)), and time from diagnosis to relapse (early < 18 months; intermediate between 18 and 36 months; late > 36 months). We examined the impact of age, sex, ethnicity, initial risk assignment (standard risk (SR) or higher risk (HR)), immunophenotype, length of first remission (CR1), and site of relapse on outcome in multivariate analyses. A total of 9,585 infants, children, and adolescents with newly diagnosed acute lymphoblastic leukemia were enrolled on CCG trials conducted between 1988 and 2002. We examined survival after relapse for 1,874 children with MR, CNSR, or TR. Survival after relapse by site and time to relapse Site MR CNSR TR Time to Relapse n *survival(%) n *survival(%) n *survival(%) *3-year survival Early 498 10 175 49 15 50 Intermediate 378 23 179 73 35 57 Late 488 53 52 77 54 70 Overall survival for any bone marrow relapse was best for late MR and worst for early MR. Early MR was linked to HR presenting features and T-cell disease. Survival after intermediate or late MR was superior for SR patients (p <.05). Survival was better for CNSR or TR than for MR. Older age at diagnosis, male sex, T cell immunopheno-type, and CNS disease at presentation were significant adverse factors for survival after adjustment for site and time to relapse in multivariate analyses (p<.05). Importantly, in the same multivariate analysis, patients treated on more contemporary trials (CCG1952CCG1953CCG1961, and 1962) had inferior survival rates after relapse when compared to patients treated on earlier trials (CCG 1881CCG 1882CCG 1883CCG 1891CCG 1901, and 1922) (p<.001). Importantly, these data from the analysis of a large, unselected group of patients indicates that features at initial presentation and prior therapy influences outcome following relapse. The inferior survival rates of those relapsing on more intensive protocols likely reflects particularly aggressive and chemoresistant disease leading to poor salvage. Increasing the intensity of retrieval therapy is unlikely to improve after relapse and novel therapeutic approaches that target these resistant leukemias are urgently needed for successful treatment of relapsed ALL.

Abstract Abstract 1732 Background: In addition to chronic myelogenous leukemia (CML), the classic myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The JAK2 V617F mutation (V617F) can be detected through genomic analysis of peripheral blood in 95% of PV and 50–60% of ET and MF patients (pts). These MPNs are often associated with debilitating symptoms and decreased quality of life (QOL). Systemic mastocytosis (SM) is an uncommon MPN in which proliferation of mast cells can result in mediator symptoms, as well as organ damage in advanced disease. We sought to compare the symptom burden of individuals with CML and SM to pts with classic MPNs in a more quantitative manner using a web-based recruitment design. Methods: Individuals with MPN were recruited through a web-based outreach effort. Participants gave IRB-approved consent, and completed on-line surveys of demographic information and questions based on the validated MPN-symptom assessment form (MPN-SAF). In addition, pts submitted saliva samples which were genotyped with SNP arrays based on the Illumina OmniExpress BeadChip, including probes for V617F. Regression analysis was used to evaluate the correlation between symptom responses and genotype data for 495 pts (118 PV, 121 ET, 97 MF, 85 SM, and 74 CML). For each MPN diagnosis, mean scores were calculated based on six fatigue-focused questions (Fatigue-6) and for six other symptoms (Symptom-6): early satiety, abdominal pain/discomfort, inactivity, night sweats, pruritis, and bone pain (ranked from 0–10; 10 = worst). ET pts' scores were used as the reference in the regression analysis based on prior data showing that ET pts have the lowest symptom burden among the classic MPNs. Individual symptoms, Fatigue-6, Symptom-6, and QOL (ranked 0–10; 10=worst) were analyzed using regression analysis against age, gender, diagnosis and V617F status. Results: Median age was 56 years (7–87), with 70% women. V617F was detected in 63% of classic MPN pts (87% PV, 46% ET, 56% MF). Analysis of Fatigue-6 scores revealed that age in years was negatively correlated with reported fatigue (β=-0.007 per year, P=0.032), while female gender and SM diagnosis were positively correlated with fatigue (female: β=0.33, P=2.4×10−4; SM: β=0.46, P=7.6×10−4). This trend was also seen for the Symptom-6: age (β=-0.025, P=5.8×10−4), female gender (β=0.73, P=1.4×10−4), and SM (β=1.8, P=5.0×10−10). Both Fatigue-6 and Symptom-6 were positively correlated with QOL, but Fatigue-6 had a much stronger association with QOL than did Symptom-6 (β=1.3, P=1.5×10−28 vs. β=0.36, P=1.2×10−11). When analyzed individually, abdominal pain/discomfort, pruritis, and bone pain were significantly correlated with V617F (β=0.676, P=0.0371; β=0.768, P=0.0241; β=0.791, P=0.0341, respectively), though these associations were not significant when all six symptoms were evaluated together (Symptom-6: β=0.315, P=0.171). There was no statistically significant correlation between V617F and Symptom-6. In addition, there was no correlation between any symptom and a germline variant in telomerase reverse transcriptase (TERT) rs2853677, identified as a novel predisposition allele for MPNs using a genome-wide association study of this cohort. Conclusion: Using a novel, web-based recruitment design combining MPN symptom assessment and genotyping of saliva samples, we identified significant correlations between 3 specific symptoms (pruritis, abdominal pain/discomfort, and bone pain) with V617F. Fatigue was also more strongly associated than other symptoms with QOL. There was no association between symptoms and TERT. This design is a powerful tool for future studies seeking to correlate symptoms with genotyping analysis. Disclosures: Hinds: 23andMe: Employment, Equity Ownership, Patents & Royalties. Barnholt:23andMe, Inc.: Employment. Kiefer:23andMe, Inc.: Employment. Do:23andMe, Inc.: Employment, Equity Ownership, Patents & Royalties. Eriksson:23andMe, Inc.: Employment, Equity Ownership, Patents & Royalties. Mountain:23andMe, Inc.: Consultancy, Employment, Honoraria, Patents & Royalties, Research Funding. Francke:23andMe, Inc.: Employment, Honoraria, Research Funding; Locus Development: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tung:23andMe, Inc.: Employment. Zehnder:23andMe, Inc.: Unpaid advisor and collaborator Other. Gotlib:23andMe, Inc.: Unpaid advisor and collaborator Other. Mesa:23andMe, Inc: Unpaid advisor and collaborator Other.