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Abstract Introduction Myelofibrosis (MF) and Post PV/ET MF represents a group of debilitating hematological disorders in which quality of life (QOL) is severely compromised in most patients as a result of persistent constitutional symptoms, progressive cytopenias, and splenomegaly. Conventional therapeutic modalities have largely focused on symptoms palliation rather than cure. Allogeneic stem cell transplantion (ASCT) remains the only potential curative option for intermediate and high risk disease. Till now, outcome data for MF have historically focused on survival benefit. Until now, few studies have evaluated the QOL, financial burden, and symptom response in MF patients undergoing treatment including ASCT. The development of the Myeloproliferative Symptom Assessment Form Total Symptom (MPN-SAF TSS) score in 2012 allows us to objectively quantify with a standardized tool these crucial aspects of patients care. The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify symptomatic response to standard available treatments by utilizing the MPN-SAF TSS. We introduce two MPN-QOL prospective trials currently in active enrollment: The MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) Trial and the Symptoms Yielded in Myelofibrosis Patients after Transplant as Objectified by MPN-SAF TSS (SYMPTOMS) Trial. Our intention with these studies is to quantify the QOL and symptom burden of PMF and post PV/ET MF patients undergoing treatment including ASCT. Methods The MEASURES trial is a prospective questionnaire based study evaluating the responsiveness of the MPN-SAF TSS in detecting symptomatic changes in target symptoms for an anticipated 180 ET, PV and MF (including primary MF, post-ET and post PV MF) patients receiving non-experimental medical therapy (aspirin, hydroxyurea, anagrelide, interferon, busulfan, melphalan, cladribine, thalidomide, lenalidomide, prednisone, danazol, ruxolitinib) and/or phlebotomy. Patients complete the MPN-SAF for seven consecutive days at the time of enrollment and repeat the survey for an additional seven consecutive days between 90 days and six months. Patients also complete the MDASI, EORTC and Global Impression of Change Items on the first day of the second assessment. Physicians acquire demographic, laboratory, physical examination and radiographic data, along with serial response assessments. In parallel, the SYMPTOMS trial is prospective questionnaire based study evaluating the QOL of patients undergoing ASCT utilizing MPN-SAF TSS, the FACT-BMT, Global Impression of Change, and a financial questionnaire. Patients will be evaluated at various time points pre-transplant, day 30, day 100 and 1 year post-transplant. Participants (N=110) will be prospectively enrolled from Mayo Clinic Arizona (MCA) with other centers to soon join. To date we have enrolled 5 patients from MCA on the SYMPTOMS trial and 32 patients on the MEASURES trial. Results Both trials began open enrollment in the summer of 2012 and remain in recruitment phase. Our updated preliminary data will be presented at the ASH 2013 meeting Conclusion Myeloproliferative Neoplasms have been associated with debilitating symptom profile that can significantly impair the QOL. We recognize the burden of this disease and treatment and have therefore initiated two ongoing parallel prospective trials with goals to quantify the QOL and symptom burden of MPN patients. By quantifying degree of burden and impairment in QOL in a standardized format in MPN patients undergoing a range of treatments, we will in the future be better able to inform our patients of the likely benefits and toxicities of the available treatment options. Disclosures: Birgegard: Vifor Pharma: Honoraria.

Abstract Introduction: Surveillance, Epidemiology, and End Results (SEER) registry captures data on acute leukemias (AL) that morphologically do not conform to well characterized acute leukemic entities in the established French-American-British (FAB) nomenclature. Not much is known about population level outcomes of these rare AL. We performed a comprehensive survival analysis of these rare AL over a forty-year period using the SEER registry. Methods: SEER 18 dataset was queried to identify adult patients (pts > 18 years) diagnosed with Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL) and rare AL from 1973-2012. Rare AL cases were identified using ICD-O-3 morphology codes and included Leukemias, Not Otherwise Specified (NOS) (9800-01, 9860) and myeloid sarcoma (9930). Data on demographics,follow up and survival was abstracted. Univariate and multivariate analysis was performed to identify factors influencing survival of rare AL and survival patterns were compared to AML and ALL. Hazard ratios (HR) with 95% confidence intervals (CIs) are reported. Results: We identified 61,550 AML pts, 13,457 ALL pts, 525 myeloid sarcoma pts and 13,446 pts with leukemia NOS. Median age at diagnosis was 68 years (yrs, range 18-100) for AML, 54 yrs (18-100) for ALL, 65 yrs (18-95) for myeloid sarcoma and 76 yrs (18-100) for leukemia NOS. Gender distribution was similar with females comprising 45.9% of AML, 43% of ALL, 42.3% of myeloid sarcoma and 47.2% of leukemia NOS cases. Over 80% pts in all categories were Caucasian. Median survival was as follows: 0.4 (0-40) yrs for AML; 1.4 (0-39.8) yrs for ALL; 0.7 (0-32.9) yrs for Myeloid Sarcoma; and 0.3 (0-38.9) yrs for leukemia NOS. In univariable analysis, younger age predicted for better survival for both myeloid sarcoma and leukemia NOS (p<0.0001). Improvement in survival over time period was observed for pts with leukemia NOS (p < 0.0001). In multivariable analysis, advancing age was an independent prognostic factor for rare AL, both as a continuous variable and when categorized as older vs. younger pts using age cutoff of 60 yrs. Compared to younger pts, HR for pts > 60 yrs with rare AL was as follows: 2.68 (2.13-3.37; p <0.0001) for myeloid sarcoma; and 2.18 (2.07-2.31; p<0.0001) for leukemia NOS. No difference in survival over time was seen for myeloid sarcoma. Pts with leukemia, NOS diagnosed in yrs 2006-2012 (HR=0.87; 0.82-0.92; p < 0.0001) had better survival compared to the referent years 1973-80. Race and gender did not impact survival. In multivariable analysis, pts with leukemia NOS did worse overall compared to AML (HR=1.13; 1.11-1.53; p<0.0001) and ALL (HR=1.86; 1.81-1.91; p<0.0001). Interestingly, younger pts had a poorer outcome than AML (HR=1.10; 1.04-1.16; p=0.0003), but pts > 60 yrs had a better outcome (HR=0.93; 0.91-0.95; p<0.0001). Both younger (HR=1.33; 1.26-1.41; p<0.0001) and older pts (HR=1.45, 1.40-1.50: p<0.0001) compared unfavorably to ALL (Figure 1). Pts with myeloid sarcoma had a better survival compared to AML pts (HR=0.77; 0.7-0.85; p<0.0001) (Figure 2). This was uniform for pts <60 yrs (HR=0.77; 0.64-0.93; p=0.006) and > 60 yrs (HR= 0.77; 0.69-0.87; p<0.0001). Conclusion: Pts with leukemias NOS have poor outcomes compared to AML and ALL but prognosis has improved in recent years. The most probable explanation is identification of prognostic molecular mutations that has allowed accurate risk-stratification of pts using the WHO classification and in turn better selection of treatment strategies. Several reasons have limited our understanding of these rare AL - small numbers, exclusion from clinical trials and wide variability in treatment options used. Efforts at better molecular characterization of these AL holds the most promise for improving outcomes. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

7061 Background: Glasdegib is a small molecule inhibitor of the Sonic Hedgehog pathway, and data from the single arm, lead-in cohort of a phase 1b/2 trial in myelofibrosis (MF) are shown. Methods: Patients (age ≥18 yrs) with primary/secondary MF previously-treated with ≥1 Janus Kinase inhibitor (JAKi) were enrolled and received glasdegib 100 mg QD orally in 28 day cycles. AEs and laboratory abnormalities were assessed. Key efficacy endpoints were proportion of patients with spleen volume reduction (SVR) ≥35% and ≥50% reduction in total symptom score (TSS) measured by the MPN Symptom Assessment Diary (MPN-SAD) at Week 24. Results: 21 patients were enrolled between Oct '14-Oct '15 in this ongoing study. Mean age was 69.3 yrs (range 58-83). Median duration of treatment was 85 days (22-343). 52% were refractory patients with inadequate response to prior JAKi. Baseline symptoms were mostly mild (1-4), except fatigue (>4). No patients achieved SVR ≥35%, 5 patients had some SVR (maximum 2.3-21.4% reduction from baseline), and no progressive disease prior to Day 71. At week 24, 1 patient had ≥50% reduction in TSS, but 3/21 and 4/21, respectively showed 30% and 20% TSS reduction. Of 14 patients with severe baseline symptoms (1 with ≥5, or ≥2 with ≥3), 1, 1, and 2 achieved 50%, 30%, and 20% TSS reduction, respectively at week 24. TSS, spleen-related, and constitutional symptom scores showed a trend of reduction over 24 weeks with spleen-related symptoms, inactivity, and fatigue showing greatest improvement (52%, 58%, and 36%, respectively). Dysgeusia (N=13), muscle spasms (N=12), alopecia (N=8), decreased appetite (N=7), fatigue (N=7), lipase increase (N=5), and weight decrease (N=5) occurred in ≥20% patients. None, except 1 episode of fatigue, were considered serious AEs. Glasdegib steady state PK was consistent with previous single agent data. Conclusions: Glasdegib has an acceptable toxicity profile in patients with primary/secondary MF previously treated with JAKi. Symptom responder definition for refractory patients may not be the same as for JAKi naïve patients. Patient reported symptom improvement may be a more sensitive indicator of treatment benefit vs SVR. Further study of glasdegib may be warranted. Clinical Trial Information: NCT02226172.

Purpose To investigate the risk and outcomes of second hematologic malignancies (SHMs) in a population-based cohort of patients with well-differentiated thyroid cancer (WDTC) treated or not with radioactive iodine (RAI). Methods Patients with WDTC were identified from SEER registries. Competing risk regression analysis was performed to calculate the risks of SHMs that occurred after WDTC treatment and outcomes after SHM development were assessed. Results Of 148,215 patients with WDTC, 53% received surgery alone and 47% received RAI. In total, 783 patients developed an SHM after a median interval of 6.5 years (interquartile range, 3.3 to 11.2 years) from WDTC diagnosis. In multivariable analysis, compared with those undergoing thyroidectomy alone, RAI treatment was associated with an increased early risk of developing acute myeloid leukemia (AML; hazard ratio, 1.79; 95% CI, 1.13 to 2.82; P = .01) and chronic myeloid leukemia (CML; hazard ratio, 3.44; 95% CI, 1.87 to 6.36; P < .001). This increased risk of AML and CML after RAI treatment was seen even in low-risk and intermediate-risk WDTC tumors. Occurrence of AML but not CML in patients with WDTC was associated with shorter median overall survival compared with matched controls (8.0 years v 31.0 years; P = .001). In addition, AML developing after RAI trended toward inferior survival compared with matched controls with de novo AML (median overall survival, 1.2 years v 2.9 years; P = .06). Conclusion Patients with WDTC treated with RAI had an increased early risk of developing AML and CML but no other hematologic malignancies. AML that arises after RAI treatment has a poor prognosis. RAI use in patients with WDTC should be limited to patients with high-risk disease features, and patients with WDTC treated with adjuvant RAI should be monitored for myeloid malignancies as part of cancer surveillance.

Purpose To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS). Patients and Methods We examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT. Results Blood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 × 109/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (≥ 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort. Conclusion The proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS.

Abstract Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.