Fonstad, Rachel

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 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.