Ross, Julie A.

Abstract Overweight [body mass index (BMI) 25.0-29.9 kg/m2] and obesity (BMI ≥30 kg/m2) are risk factors for several malignancies. The Iowa Women's Health Study was examined to determine whether increased BMI was associated with leukemia development. Over 40,000 Iowa women (ages 55-69 years) completed a self-administered lifestyle and health questionnaire in 1986 that included current height and weight. Two hundred women developed leukemia during the period 1986 to 2001 including 74 acute myelogenous leukemia (AML) and 88 chronic lymphocytic leukemia. The risk of AML was increased among women who reported being overweight or obese (relative risk, 1.9; 95% confidence interval, 1.0-3.4; relative risk, 2.4; 95% confidence interval, 1.3-4.5; Ptrend = 0.006) compared with women of normal weight. There was little evidence of a positive association for chronic lymphocytic leukemia (Ptrend = 0.6). Given the prevalence of overweight and obesity in the United States, the population attributable risk of AML due to obesity could approach 30%.

Abstract Recent studies have reported an increased risk of breast, endometrial, ovarian, and gall bladder cancer associated with ERT. One proposed mechanism by which ERT increases risk is through the binding of estrogen to receptors at the tissue site. Estrogen receptors are also present on certain hematopoietic cells as well as on myeloid leukemia cells. Further, downregulation of the estrogen receptor through DNA methylation has been associated with increased acute myeloid leukemia (AML) survival. We evaluated whether ERT is associated with an increased risk of leukemia, particularly AML, in the Iowa Women’s Health Study. A cohort of 37,172 post-menopausal Iowa women ages 55 to 69 years with no history of prior cancer was linked annually to the population-based state cancer registry through 2001. In addition to other self-reported cancer risk factors, participants were asked about current and former use of ERT in 1986 and on four subsequent follow-up questionnaires. A total of 201 cases of leukemia were identified over 16 years of follow-up including 64 AMLs and 87 chronic lymphocytic leukemias (CLLs). Compared to never users of ERT at study baseline, current [multivariate relative risk (RR), 1.09; 95% Confidence Interval (CI) 0.70–1.72) and former users (RR=0.81, 95% CI=0.58–1.14) were at no increased risk of developing leukemia. For AML, current users also had no increased risk (RR=0.86, 95% CI=0.39–1.92) and there was a suggestion that former users had a slight decreased risk (RR=0.68, 95% CI=0.38–1.22). For CLL, all results were around unity. Duration of ERT or time-dependent use had no appreciable effect on the RRs. We conclude that ERT use is unlikely to be a risk factor for leukemia, including AML. Supported by NCI R01 CA39741.

Abstract Introduction Expanding treatment options for MDS have changed therapeutic decision-making for clinicians. To better characterize therapeutic choices in newly diagnosed MDS, we report the practice patterns captured during the first year of MDS diagnosis for patients enrolled in our statewide population-based study. We highlight a comparison of treatment in community and academic centers. Methods Adults in Minnesota with MDS (AIMMS) is a statewide prospective population-based study conducted by the University of Minnesota (UMN), Mayo Clinic, and Minnesota Department of Health. Starting in April 2010, all newly diagnosed adult cases (ages 20+) of MDS were invited to participate. After patient enrollment, central review was performed consisting of independent hematopathology and cytogenetic review coupled with oncologist chart review assigning prognostic risk scores [International Prognostic Scoring System (IPSS) and IPSS-R (Revised)] and abstracting treatment exposures. All enrolled patients with one year follow-up were included in this analysis. Treatment was divided into supportive, active, transplant, or other. Supportive care included observation, growth factors, and transfusions. Active care included azacitidine, decitabine, lenalidomide, or 7+3 chemotherapy. Academic centers were defined as the UMN and Mayo Clinic; all other centers were designated as community based practices. Results The median patient age was 73 years, with 68% males. IPSS and IPSS-R risk scores were calculated for 100% and 97% of patients, respectively. Treatment choices stratified by IPSS risk group showed 89% low risk, 53% INT-1, 31% INT-2, and 13% high risk with supportive care; active and transplant strategies were utilized for 9% low risk, 44% INT-1, 64% INT-2, and 88% high risk. INT-1 in the community received 70% supportive treatment, in academic 35%. Active treatment for INT-1 was 30% in community and 45% in academic. Community INT-2 received supportive care in 45% of cases, in academic 23%. Transplants were limited to academic centers, with the highest rate in INT-2 at 34%. Among community diagnoses, 100% of high risk, 52% INT-2, 26% INT-1, and 13% low risk were referred to an academic center. Comparison of age <65 and 65+ years showed 83% of transplants occurred in those <65. INT-2/high risk group patients <65 received 95% active therapy or transplant, compared to 51% of those 65+. Discussion This prospective, population based study provides a well-defined patient cohort based on central review of pathologic and clinical data. Evaluation of practice patterns during the first year after diagnosis showed higher utilization of active and transplant treatment strategies as IPSS risk score increased. Further, compared to community, higher utilization occurred for patients at academic centers, suggesting more aggressive treatment in these settings. Age was also a predictor of treatment choice. In addition, referral patterns followed IPSS score. Whether these treatment differences are driven by patient preference and/or translate into improved disease control and decreased mortality requires continued prospective analysis and will be detailed in future reports. 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 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 Abstract 3841 Introduction: The International Prognostic Scoring System (IPSS) has recently been revised (IPSS-R) to capture more inclusive cytogenetic characterization, more stringent blast description, and more detailed cytopenia assignments. To validate the IPSS-R in a prospective cohort of patients, we compared IPSS and IPSS-R categorization within a group of newly diagnosed MDS patients in a prospective population-based epidemiologic study in Minnesota. Methods: We identified all newly diagnosed MDS cases in Minnesota between the ages of 20 and 85 years from April 1, 2010 to April 2012. Our process includes rapid case identification by the Minnesota Cancer Surveillance System (MCSS), patient contact and enrollment, central medical review including: 1) independent review by two hematopathologists to confirm diagnosis and WHO subclassification; 2) independent cytogeneticist's review for classification as defined by IPSS and IPSS-R; and 3) medical chart review with prospective calculation of IPSS, IPSS-R, and WPSS by a an oncologist. Results: Classification of the 128 patients by IPSS versus IPSS-R is shown (Table) Kendall's Tau = 0.77 In this comparative classification, IPSS-R scoring refined the MDS prognostic risk groups. Low IPSS remained low risk in the IPSS-R spanning the Very Low and Low groups, while all high risk IPSS remained in the Very High risk group in the IPSS-R. However, those in the INT-1 and INT-2 IPSS categories were inconsistently reclassified in the IPSS-R. INT-1 IPSS spanned from Very Low to High and INT-2 IPSS spanned from Intermediate to Very High in the IPSS-R. While reclassification of this prospective cohort resembles results in the IPSS-R reports, ongoing follow-up will be needed to determine if the survival and AML progression measures are reproducible. Conclusion: Until molecular data are available to refine future prognostic scoring systems, the IPSS-R enhances our prognostic risk stratification abilities and is applicable to the general MDS population. As treatment decisions are based on this initial prognostic risk assessment, the more diverse differentiation of risk within the IPSS-R will directly refine prognosis and impact decisions on therapy. Disclosures: Miller: Celgene: Membership on an entity's Board of Directors or advisory committees; Coronado Bioscience: Membership on an entity's Board of Directors or advisory committees.

Polymorphisms in mitochondrial DNA (mtDNA) are used to group individuals into haplogroups reflecting human global migration and are associated with multiple diseases, including cancer. Here, we evaluate the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State driver's license/identification card list. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non‐Hispanic whites. We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation. We used SAS v.9.3 (SAS Institute, Cary, NC) to calculate odds ratios (OR) and 95% confidence intervals (CI) overall and stratified by MDS subtype and IPSS‐R risk category. We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. 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 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 = 0.58, 95% CI 0.36, 0.92, P = 0.02). No statistically significant heterogeneity was observed in subgroup analyses. In this population‐based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. While previously published studies provide biological plausibility for the observed association, further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes. © 2016 Wiley Periodicals, Inc.