Citations

Background: Genetic variants resulting in quantitative defects in the production of α-spectrin are associated with autosomal recessive hereditary spherocytosis (HS). Because erythroid cells produce α-spectrin in a 3-4:1 ratio in relation to β-spectrin, one defective allele is typically well-tolerated and a single null allele combined with a second partially defective allele may display a sub-clinical phenotype. Protein expression can be reduced by nonsense, frameshift, missense or splicing variants but reported large deletion events are extraordinarily rare (n = 1). Splicing variants include the low expression alleles αLELY - Low Expression LYon (SPTA1:c.6531-12C>T, p.?) and αLEPRA-Low Expression PRAgue (SPTA1:c.4339-99C>T, p.?) which reduce protein expression by 50% and 16%, respectively. Here, we present a family study with a whole gene SPTA1 deletion that characterizes the patient phenotype when a full gene mutation is co-inherited with the αLEPRA and αLELY low expression alleles. Methods: The 6 month-old male proband had a history of congenital Coombs negative hemolytic anemia requiring transfusion from 3 months of age and in whom a red cell membrane disorder was clinically suspected. Pretransfusion CBC and peripheral blood smear results were unknown. Transfused CBC indices were as follows: RBC 4 x 1012/L, HGB 11 g/dL, MCV 76 fL, MCH 27 pg, MCHC 36 g/dL and a reticulocyte count of 1.8%. The proband's mother, of Cuban descent, and father, of European descent, had no history of anemia or HS. Targeted high throughput sequencing of genes related to hereditary hemolytic anemia was performed for the detection of single nucleotide variants (SNVs) and small insertion/deletion variants (indels). Relative quantitative real time PCR (RT-PCR) was utilized to confirm large structural variants. Results: Sequencing identified a large heterozygous deletion that spanned the entire SPTA1 gene (NC_000001.11:g.(?_158656337)_(158581024_?) in the proband and his mother. In addition, the proband had inherited hemizygous αLEPRA from his father. The mother had hemizgous αLELY. The father showed heterozygous αLEPRA and no other SPTA1 variants (Table 1). Conclusion: To our knowledge, only Iolascon et al in 2011 has reported a SPTA1 gene large deletion (SpectrinExeter, exon 11-exon 12 deletion, loss of 83 amino acids) which resulted in a structurally abnormal protein and ellipto-poikilocytosis phenotype when in trans to αLELY. Our current case is the first reported SPTA1 full gene deletion and our family study allows comparison of the effects of coinheritance of the low expression alleles αLEPRA and αLELY. When in combination with complete absence of the SPTA1 gene in trans configuration, αLELY manifests in subclinical effects and αLEPRA causes a recessive HS phenotype, which resulted in severe anemia. This contrast further demonstrates that, unlike αLEPRA, αLELY does not decrease the α-spectrin concentration sufficiently to contribute to the baseline phenotype regardless of the severity of the second allele mutation for quantitative disorders such as HS. Disclosures No relevant conflicts of interest to declare.

Background Maintenance of telomere length has long been established to play a role in the biology of cancer, and several lines of evidence suggest that it may be especially important in myeloid malignancy. Measuring leukocyte telomere length (LTL) directly in case control studies is problematic because telomere length is likely to be influenced by the disease process. Recent studies have led to the identification of a robust genetic predictor of LTL, which we have used to compare differences in predicted telomere length in case control studies of myeloid leukemia and myelodysplastic syndromes (MDS) using Mendelian randomization (MR). MR is a method used to measure the association between a trait (e.g. telomere length) and an outcome (e.g. myeloid malignancy) that can't be measured directly by utilizing genetic variants known to be associated with the trait as instrumental variables. The use of genetic predictors of telomere length reduces the possibility that the association is explained by reverse causation and confounding likely to be relevant in case-control studies where telomere length is measured directly because genotypes in the general population should be randomly distributed. Additionally, predicted telomere length has the added advantage of representing telomere length over the lifetime of the individual while measuring LTL directly will represent only one time point in an individual's life. Methods Myeloid leukemia (AML and CML) and MDS cases were identified by rapid case ascertainment through the Minnesota Cancer Surveillance System (MCSS). Centralized pathology and cytogenetics reviews were conducted to confirm diagnosis and classify by subtypes. Controls were identified through the Minnesota State driver's license/identification card list. We used the Sequenom platform to genotype seven SNPs that were validated predictors of LTL in a recently published meta-analysis. We estimated associations between individual SNPs and myeloid malignancy using multivariable logistic regression. Mendelian randomization was used to evaluate the association between predicted LTL and risk of myeloid malignancy. Results We included 253 AML cases, 353 MDS cases, 145 CML cases, and 1,042 controls. We observed a significant association between longer predicted telomere length and AML in analyses adjusted for sex and age (OR 4.82 per additional kilobase of average telomere length, 95% CI 1.32-17.63). The individual SNP analyses suggest that the association is largely driven by rs10936599, located in TERC (OR 1.47 per allele, 95% CI 1.14-1.90; Figure). We did not observe statistically significant associations between predicted LTL and MDS or CML. Discussion In this analysis of predicted telomere length and myeloid malignancy, we identified a significant association between longer predicted leukocyte telomere length and AML. In contrast, no significant association was observed for MDS or CML although we did observe an elevated OR for longer predicted telomere length and MDS that did not reach statistical significance. Figure Disclosures No relevant conflicts of interest to declare.

Background: Voxelotor (GBT440) is a small molecule allosteric effector with high specificity for hemoglobin (Hb) that inhibits Hb S polymerization by increasing hemoglobin oxygen affinity. Developed as an oral, once-daily medication, it is undergoing phase 3 randomized clinical trials in sickle cell disease patients. Therapeutic monitoring of Hb quantitative fractions is routine in sickle cell disease patients to assess medication and transfusion effects and future treatment requirements. In the clinical laboratory, some therapies can alter the Hb fraction percentages or characteristic protein migration/elution patterns and can mimic complex hemoglobinopathy disorders causing misinterpretation or unnecessary additional testing. We present the effects of voxelotor on hemoglobin identification/monitoring testing in multiple testing platforms. Methods: A whole blood anticoagulated sample from a male patient who was undergoing treatment for sickle cell disease was received for routine hemoglobin testing. Five additional samples with similar features were also received from three male patients (age range of all patients was 18 to 22 years) with sickle cell disease. Hemoglobin protein analysis was performed using standard methods including cation-exchange high performance liquid chromatography (HPLC), capillary electrophoresis (CE), isoelectric focusing (IEF), intact globin chain mass spectrometry (MS), sickle solubility and hemoglobin stability studies. DNA sequencing of the alpha (HBA1/HBA2) and beta globin (HBB) genes was performed on one sample. Results: CE (initial and 50:50 mix, figures 1A and 1B, respectively) revealed a Hb S peak with a shoulder and additional small peaks at position 203 (D zone) and 234 (cusp of zones E/A2). In some cases the 234 peak interfered with instrument designation of the A2 peak (50:50 mix with normal) and shifted the Hb S peak into the E zone which risks variant misidentification (figure 1C). Our laboratory overcame this limitation by substituting the normal sample with beta thalassemia trait to enhance the Hb A2 peak after mixing. HPLC tracings (figure 1D) showed a duplex peak pattern in the D and S windows with separate peak quantification percentages (index case showed elution at 4.18 and 4.37 minutes with 14.9% and 66.4%, respectively). The dual peaks detected by HPLC partially mimicked compound Hb S/D-Punjab. IEF (figure 1E) showed additional bands at -4.7, and -11.5 (Schneider-Barwick ratios). The additional peaks identified by CE and IEF mimicked an alpha chain hemoglobin variant; however, the expected hybrid patterns were atypical prompting further investigation. Sickle solubility was positive, heat stability studies were negative and mass spectrometry did not definitively detect abnormal peaks other than βS. DNA sequencing of the alpha and beta globin genes did not reveal abnormalities other than homozygous Hb S. Similar hemoglobin patterns were identified in all samples tested. Conclusion: Voxelotor treatment in sickle cell patients results in a distinctive pattern alteration in hemoglobin testing. Methods may not give accurate variant percentage estimation and the treatment may result in shifts in variant mobility causing erroneous laboratory results. Novel therapies are increasing in the treatment of hemoglobin disorders and medication effect should be a consideration when atypical patterns are encountered in the laboratory. Knowledge of these artifacts by clinicians and laboratorians is paramount to avoid erroneous diagnosis, unnecessary additional testing and inaccurate Hb variant quantitation for monitoring purposes. Notification of current treatment regimens to testing facilities is highly recommended in these patients. Figure 1 Disclosures No relevant conflicts of interest to declare.

Abstract Introduction Myelodysplastic syndromes (MDS) are heterogeneous myeloid disorders characterized by dysplasia in one or more hematopoietic cell lines, peripheral cytopenia(s), and distinct cytogenetic abnormalities. The presence of certain cytogenetic abnormalities [e.g. 7/del(7q), -5/del(5q), 13/del(13q), i(17p)], in the setting of unexplained persistent cytopenia, has been considered presumptive evidence of MDS, despite definitive morphologic features of MDS. Conversely, chromosomal abnormalities such as isolated 20q- are not considered definitive evidence for MDS, in the absence of dysplasia. Based on our previous findings, patients with isolated 20q- without morphologic features of a myeloid neoplasm have varied clinical outcomes (Jawad MD et al. Am J Hematol.2016). In this study, we investigate the frequency of recurrent somatic gene mutations in these patients, and their relationship to progression to a myeloid neoplasm. Methods We retrospectively reviewed the bone marrow pathology reports of patients evaluated at our institution from 01/2005 to 09/2015 who had isolated 20q- in at least 2 of 20 metaphases. Patients with isolated 20q- and without myeloid neoplasms were included in the study, along with medical record review. A 35-gene next generation sequencing (NGS) panel (OncoHeme) targeting myeloid neoplasms was performed on available archived bone marrow aspirate pellets. Statistical analyses were performed using JMP Pro software version 13. Parametric (t-test) or nonparametric tests such as the Fisher-exact test, chi-square test, or Wilcoxon rank-sum test, were utilized as appropriate for test variables. Statistical significance was based on a 2-sided significance level of .05. Kaplan-Meier analysis was used for analyzing time to progression to myeloid neoplasms and progression-free survival (i.e. time to progression to myeloid neoplasms or death from any cause). Results Fifty-six (42 males, 14 females) patients with isolated 20q- were identified. The average percentage of 20q- was 38.5 % (±29.3). The median age was 68 years (range: 44-90) and the median hemoglobin (Hb), absolute neutrophil count (ANC) and platelet count (Plt) were 11.7 g/dL (range: 8.3-15.1), 2.7 x 10(9)/L (range: 0.6-9.4) and 138 x 10(9)/L (range: 16-392), respectively. The indications for bone marrow biopsies ranged from cytopenia (21), multiple myeloma (20), non-Hodgkin lymphoma (10), amyloidosis (2), CLL (2) and transplant donor evaluation (1). Twenty-three patients harbored pathogenic mutations (15 had one mutation, 1 had two mutations and 7 had three mutations). The identified pathogenic mutations included ASXL1 (8), TET2 (8), SRSF2(3),PHF6 (2), SF3B1 (2), CBL (2), U2AF1 (2), IDH1 (1), IDH2 (1), BCOR (1), JAK2 (1), PTPN11(1), TP53 (1) and RUNX1 (1). Nine patients (16.1%) progressed to myeloid neoplasms (5 MDS, 2 acute myeloid leukemia, 2 chronic myeloid neoplasm-not otherwise specified) at a median follow-up of 36.7 months (range: 1.9-57.4). Of these 9 patients, 5 had one mutation (BCOR, TET2, DNM3TA, CBL, IDH2), 1 had two mutations (SF3B1/CBL) and 3 had three mutations (ASXL1/IDH1/SRSF2,DNM3TA/PTPN11/TET2, PHF6/TET2/TET2). In contrast, only 29.8% of non-progressed cases showed at least 1 mutation. Kaplan-Meier analysis demonstrated the presence of genetic mutations in patients with isolated 20q- carried significantly higher chance of progression to myeloid neoplasms (p<.05, Figure 1A and 1B). However, the number of genetic mutations was not predictive of progression in our relatively small study cohort (p=.66). There was no significant difference between those who did and did not progress with respect to age, gender, Hb, ANC, Plt, 20q- or mutational allele burden. Conclusions Most of the patients with isolated 20q- and without morphologic features of a myeloid neoplasm did not harbor myeloid neoplasm associated gene mutations and further did not develop a myeloid neoplasm during the course of our study. Among patients with pathogenic mutations, nearly one-third showed progression to a myeloid neoplasm. Of the clinical and laboratory variables, the presence of genetic mutation is a significant risk factor for progression to a myeloid neoplasm. This study revealed the underlying molecular heterogeneity of isolated 20q- in the absence of morphologic features of a myeloid neoplasm, and underscored the prognostication value of genetic mutation analysis in these cases. Disclosures No relevant conflicts of interest to declare.

Abstract Myelodysplastic syndromes (MDS) are a heterogeneous collection of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis, dysplasia, and risk of progression to secondary acute myeloid leukemia (AML). Despite the development of numerous prognostic scoring systems (MDS Comorbidity Index (MDS-CI),International Prognostic Scoring System (IPSS) and IPSS-R, updated WHO classifications, and WHO prognostic scoring system (WPSS)), little prospective data regarding the influence of these and other factors on patient outcomes is available. To better elucidate the features of early mortality in MDS we compare characteristics of patients dying within one year of MDS diagnosis with those surviving longer in our Adults in Minnesota with MDS (AIMMS) population based case-control study. The AIMMS study is a statewide prospective population-based case-control study (R01 CA142714) conducted by the University of Minnesota (UMN), Mayo Clinic, and the Minnesota Department of Health. Adults (age 20-85 years) with a new diagnosis of MDS between April 2010 and October 2014 were recruited through the Minnesota Cancer Surveillance System. Patients completed a comprehensive questionnaire to capture retrospective epidemiologic data. All cases went through central medical review including pathology review by two independent hematopathologists, cytogenetic analyses, and oncologist medical record review with assignment of IPSS, IPSS-R, WPSS 1.2 noting past medical history, exposures, and treatment history and response. Annual clinical review of all patient cases for four years after initial enrollment is ongoing in a batched, non-real time manner. Three hundred and ninety-nine patients with a confirmed diagnosis of MDS based on central review and one year of clinical follow-up review were included in the analysis. For the entire group, we observed early mortality in those with abnormal cytogenetics, three or greater cytogenetic abnormalities, treatment at a community medical center only (versus academic), and with 2-3 concurrent medical comorbidities (Table 1). Treatment with hypomethylating agents also correlated with early mortality but when adjusted for WPSS and IPSS-R, this association was no longer significant. To investigate varied impact of disease and patient characteristics within different groups of MDS patients, we did multivariable regression analysis within the following categories: High/Very High Risk IPSS-R; Very low/Low/Intermediate Risk IPSS-R; Treated Patients; Supportive Care Only Patients. In patients with high or very high risk IPSS-R, the presence of 3 or more cytogenetic abnormalities was the only significant predictor early mortality in a multivariable adjusted model (OR: 3.66, 95% CI: 1.57-8.53). Similarly, in those with very low, low, or intermediate IPSS-R, abnormal cytogenetics was the only significant predictor of early mortality in an adjusted model (OR: 3.71, 95% CI 1.49-9.26). In patients receiving supportive care only, early mortality was seen in those who had diabetes (OR: 3.06, 95% CI 1.11-8.42), had complex cytogenetics (OR for ≥ 3 abnormalities: 4.94, 95% CI 1.25-19.46), and had very high or high IPSS-R (OR: 4.20, 95% CI 1.43-12.34). Likewise, complex cytogenetics remained the sole significant predictor of early mortality in treated patients (OR: 4.84, 95% CI 1.43-16.37). Complex cytogenetics and prognostic risk category (either by WPSS or IPSS-R) have previously been associated with higher risk disease and early mortality without intervention. Our data confirm this association in a large prospectively followed MDS cohort and highlight the significance of cytogenetic abnormalities and complexity regardless of IPSS-R risk categorization or treatment. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: The revised international prognostic scoring system (IPSS-R) for myelodysplastic syndrome (MDS) is widely accepted and has been validated in multiple studies. Patients with adverse cytogenetics do poorly and that is reflected in this scoring system by having the highest score for cytogenetics; 2 for intermediate, 3 for poor and 4 for very poor. Little is known about the effect of marrow blasts in adverse cytogenetic in the high-grade MDS defined by IPSS-R intermediate (>3), high (>4.5) and very high (>5). The goal is to examine the effect of marrow blast percentage on outcome in patients with adverse cytogenetics that is present in the high-grade MDS. Methods: We performed data collection from the Mayo clinic records for patients with confirmed MDS after obtaining appropriate IRB approval. Patients were divided based on their total IPSS-R score and we extracted high-grade MDS cases with intermediate, high and very-high IPSS-R only. Cytogenetics and baseline CBC were available for analysis. We calculated the survival difference in patients with blasts <5% and patient with blasts of 5% to 19% for every group. Survival estimates were calculated by Kaplan-Meier method and compared by log-rank testing using JMP v.13. Results: Our database had 1300 patients with confirmed MDS, 41% (N=536) are high-grade MDS. From those, the median age was 70 and 70% were males. Median bone marrow blast was 6% (0-19). Baseline hemoglobin is 9.2 g/dL, WBC 2.7, ANC 1.05, and platelets 69. Their cytogenetics were 1% very good, 31% good, 23% intermediate, 16% poor and 29% very poor. The total IPSS-R groups were 39%,31%, and 30% for the intermediate, high, and very-high groups respectively. The overall survival (OS) for the high-grade MDS with marrow blast <5% was 12.3 months and for patients with marrow blasts ≥5% 11.4 months (P=.4). At each high-grade MDS; intermediate, high and very high, there were no statistically significant differences for patients with marrow blasts below or above 5%. In term of risk of progression to AML, patients with blasts ≥5% were at higher risk of progression compared with <5% (25% vs 10% , P<.001), with no statistically significant difference in term of time-to-AML progression. Conclusion: The percentages of bone marrow blasts had no impact on overall survival among patients with high grade MDS. However, patients with ≥5% marrow blasts are at a higher risk for progression to AML. Disclosures Al-Kali: Novartis: Research Funding.

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: 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.