Patnaik, Mrinal M.

e18556 Background: RARS is a subtype of myelodysplastic syndromes (MDS) defined by < 5% blasts and ≥15% ring sideroblasts (WHO 2008). Hereditary hemochromatosis is a disorder characterized by dysregulations in iron absorption, largely associated with C282Y and H63D mutations of the HFE gene. Iron levels are elevated in both disorders and pathophysiologic correlations were suggested. HFE gene mutations were previously found higher in MDS compared to controls (50% vs 36%) ( Nearman et al, Am J Hematol 2007). Methods: A total of 168 RARS patients’ data from 1994 to 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our center. We searched patients’ records retrospectively to Identify those tested for HFE gene (C282Y, H62D, S65C) mutations, done inside or outside our institution. Survival estimates were calculated using Kaplan-Meier curves. Results: Out of the 168 RARS patients, only 17 (10%) were tested for HFE gene mutations. Out of the 17 tested, 11 (65%) were found to have mutations; 2 of which (18%) had homozygous H63D mutation, 1 patient (9%) had double heterozygous H63D and C282Y mutations, 5 (45%) had only one H36D heterozygous mutation vs 3 patients (27%) with only one C282Y heterozygous mutation. Only one patient was tested for the additional S65C mutation and it was not detected. H63D mutation was present in a total of 8 patients (73%) vs C282Y mutation which was present in 4 patients (36%). Bone marrow iron stores were increased in all 17 tested patients, except one who had decreased stores, this patient had one heterozygous C282Y mutation. Median overall survival (mOS) was 117 months in the HFE mutated patients vs 75 months in the non-mutated (p = 0.6). Conclusions: Our study found the HFE gene, when tested, to be mutated in higher frequencies among patients with RARS compared to that reported in the general population (65% vs 36%), with H63D mutation in almost three quarters of all mutated patients. Although it did not reach statistical significance, the longer survival observed among HFE mutated patients compared to the wild-type raises the question whether testing for HFE gene mutations among patients with MDS-RARS should be further explored.

e18514 Background: Standard induction therapy for acute myeloid leukemia (AML) includes “cytarabine and anthracycline”. Anthracyclines are known to cause acute, subacute and chronic cardiac complications ( Lefrak , EA et al, Cancer 1973:32(2):302-314; Singal, PK et al, NEJM 1998;339(13):900-905). It is recommended to do base line cardiac function assessment with echocardiogram prior to induction therapy containing anthracycline. This study was done to find the frequency of changes made in avoiding anthracycline usage following this evaluation. Methods: The Mayo clinic data base was interrogated to identify patients with newly diagnosed AML who underwent echocardiogram prior to anthracycline containing induction chemotherapy. Echocardiogram results, including left ventricular ejection fraction (LVEF), diastolic dysfunction, valvular disease, and any resultant treatment alterations were reviewed. Results: Three hundred twenty six patients were identified. The median (range) age was 61 (17-82) years and 62% were male. The median (range) LVEF was 65% (30-87), and 3 (0.9%) patients had LVEF < 50% (range 30-47%). Of these 3 patients, 1 had 4 vessel CABG a decade ago, his EF was 46% and treated with full dose idarubicin; 2 of them presented with blastic crisis, 1 had EF 46% and improved to 51% after 5 days and then given daunorubicin, the other one had an EF of 30% and treated with 50% dose reduced cytarabine alone. Sixty five (23%) patients had previous chemotherapy or radiation exposure, including 24 (7.4 %) with previous anthracycline, 14 (4.3%) had prior radiation to the chest wall. No patient with previous chemotherapy or radiation exposure had a reduced LVEF. Conclusions: Echocardiography prior to anthracycline therapy rarely detects abnormal LVEF. Screening echo may be helpful in those presented with leukemic blastic crisis or had previous exposure to chemo-radiation.

7058 Background: The 2016 WHO classification includes myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U), as an MDS/MPN overlap syndrome not meeting criteria for well-defined entities such as CMML. No standard prognostication or treatment guidelines exist for such patients. Methods: We retrospectively identified MDS/MPN-U cases from 1990-2016 through our myeloid malignancies database. All bone marrow reports were reviewed to ensure compliance with 2016 WHO criteria. Clinical & cytogenetic parameters at diagnosis were assessed & compared with treatment outcomes. Results: Eighty nine patients met study criteria, with a median age of 69 years (range: 37-93); 58 (65%) males. Median follow-up was 22.2 months (range: 0-172), with 41 (46%) deaths & 13 (15%) leukemic transformations. Median OS was 24.8 months (range: 0-172). 43 (53%) patients had an abnormal karyotype, with common abnormalities being trisomy 8 (12%), complex karyotype (9%) & del (20q) (6%). Given the fewer types of abnormalities identified, the IPSS cytogenetic stratification was more effective than IPSS-R, with risk categorization including; 45 good (55%), 20 intermediate (25%) & 16 high risk (20%) respectively (8 unavailable). On univariate analysis, increased age (p = 0.05), decreased hemoglobin (p = 0.02), higher ANC (p = 0.03), circulating immature myeloid cells (p = 0.02), higher LDH (p = 0.009), absence of bone marrow ring sideroblasts (p = 0.001) & higher risk (intermediate & high) IPSS cytogenetic categories (p = 0.01) adversely impacted OS. In a multivariate model that included the aforementioned variables, higher risk IPSS cytogenetics retained a negative prognostic impact (p = 0.04). 28 patients received a median of 6 cycles (range: 1-21) of hypomethylating agent therapy (HMA), with an overall response rate of 18% (CR-3, PR-2). All responders had an abnormal karyotype (p = 0.01). However, HMA did not affect either OS or LFS. Conclusions: Intermediate & high risk IPSS cytogenetic categories independently & adversely impact survival in WHO defined MDS/MPN-U patients. HMA use did not impact OS; however, patients with abnormal karyotypes were more likely to respond.

7034 Background: In a phase II study in 50 elderly patients (pts) with AML who were not eligible for intensive chemotherapy, treatment with pracinostat + azacitidine (AZA) was well tolerated, led to 42% complete remission (CR) rate and a median overall survival (OS) of 19.1 months (Blood 2016: 128;100). Here we investigate the impact of somatic mutations and their clearance on disease response and patient outcomes. Methods: 88 samples from 41 study pts were sequenced. All 41 pts were analyzed pre-treatment, and a median of 3 longitudinal samples were analyzed from 19 pts between Cycle 2 and 9. Mutations were assayed by SureSelect targeted capture exon sequencing (Agilent) of 295 genes that are recurrently mutated in hematologic malignancies. Longitudinal mutation clearance was analyzed by plotting variant allele frequency (VAF). Results: At baseline, 96 mutations in 28 genes were detected in 38 pts, with the most frequent being in SRSF2 (27%), DNMT3A (20%), IDH2 (17%), RUNX1 (17%), and TET2(17%). Mutations associated with CR rate and OS are indicated in the Table. A CR was achieved in 10/19 pts that had longitudinal sequencing analysis and at the time of CR, 9 (90%) had persistently detectable mutations in their bone marrow. In 7 of them, continued exposure to pracinostat + AZA lowered the VAF or cleared residual mutations. In 2 pts, relapsed samples showed re-expansion of the founder clone. Conclusions: Mutations in NPM1, and DNA methylation pathway were associated with a better response to pracinostat + AZA, while TP53 mutation was associated with a poor response. Persistent mutation at the time of CR suggests residual preleukemic clonal hematopoiesis in this elderly population. Benefit of prolonged exposure to pracinostat + AZA was also confirmed at molecular level where continued decline of mutation VAF was seen after achieving CR. Clinical trial information: NCT01912274. [Table: see text]

e13073 Background: We observed several patients with a personal history of both RCC and myeloid malignancy, and aimed to explore a possible association, especially given the similarity in their epigenetic landscape, with both being characterized by widespread aberrant hypermethylation (Hu C et al, CCR 2014; Jiang Y et al, Blood 2009). Methods: Mayo Clinic’s ‘Advanced Cohort Explorer’ database was used to identify patients with a history of both RCC and a myeloid malignancy - Acute Myelogenous Leukemia (AML), Myeloproliferative Neoplasms (MPN), Myelodysplastic syndromes (MDS) - and to determine the clinical characteristics. The incidence of MDS in patients ≥65 years with a history of RCC was compared to that in the general population ≥65 years (SEER- Medicare database) as well as the general patient population at Mayo Clinic, using one sample test of proportions. Results: A total of 59 patients were identified, with both biopsy proven RCC and a myeloid malignancy during their life time (12 AML, 9 MPN, 9 low risk MDS and 29 intermediate- high risk MDS). The cohort was characterized by marked male predominance (4.4: 1). Median age at RCC diagnosis was 64 years (range 37-87) and myeloid malignancy was 75 years (range 44-90). 46/59 patients had the RCC antecedent, 10/59 concurrent and 3/59 subsequent to the myeloid malignancy with a median time of myeloid malignancy diagnosis after RCC diagnosis of 7.7 years. For patients ≥65 years, the risk of developing MDS with a history of stage I/II RCC and nephrectomy was 5.26 times that of the general population based on the SEER-Medicare database (Cogle, Blood 2011)(395/100,000 vs 75/100,000; p value < 0.001), and 3.07 times that of the general population at Mayo Clinic (395/100,000 vs 128.4/100,000; p value < 0. 001). Conclusions: We observed an association between RCC and myeloid malignancies, particularly MDS; with a history of RCC conferring a substantially increased risk of developing MDS. We hypothesize that the perturbation of epigenetic landscape in the form of widespread hypermethylation may explain, in part, the association between the two malignancies; and aim to explore the potential aberrancy of epigenetic regulators in our patient cohort with a genomic, epigenomic and transcriptomic analysis.