Patnaik, Mrinal M.

Abstract Systemic mastocytosis (SM) is a clinically heterogeneous disease with prognosis chiefly assigned based on World Health Organization (WHO) morphologic subclassification. We assessed the feasibility of developing contemporary risk models for SM based on clinical and integrated clinical-genetics information. Diagnosis of SM was per WHO criteria, and karyotype and next-generation sequencing data were available in a subset of the total 580 patients (median age, 55 years; range, 18-88 years) seen at the Mayo Clinic between 1968 and 2015. Morphologic subcategories were indolent/smoldering in 291 (50%) and “advanced” in 289 (50%): SM with an associated hematological neoplasm in 199, aggressive SM in 85, and mast cell leukemia in 5. Multivariable analysis of clinical variables identified age >60 years, advanced SM, thrombocytopenia <150 × 109/L, anemia below sex-adjusted normal, and increased alkaline phosphatase (ALP) as independent risk factors for survival; respective hazard ratios (HRs) 95% confidence intervals (95% CIs) were 2.5 (1.9-3.4), 2.7 (1.8-4.0), 2.5 (1.9-3.4), 2.2 (1.6-3.1), and 2.1 (1.5-3.0). In addition, ASXL1 (HR, 4.5; 95% CI, 2.6-7.6), RUNX1 (HR, 4.3; 95% CI, 1.3-10.8), and NRAS (HR, 5.0, 95% CI, 1.5-13.2) mutations were independently associated with inferior survival. Combined clinical, cytogenetic, and molecular risk factor analysis confirmed the independent prognostic contribution of adverse mutations (2.6, 1.6-4.4), advanced SM (4.0, 1.8-10.0), thrombocytopenia (2.8, 1.7-4.5), increased ALP (2.1, 1.2-4.0), and age >60 years (2.2, 1.3-3.6). These data were subsequently used to develop clinical and hybrid clinical-molecular risk models. The current study advances 2 complementary risk models for SM and highlights the independent prognostic contribution of mutations.

AbstractFirst‐line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second‐line drugs of choice include pegylated interferon‐α, busulfan and anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928‐1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis‐free (MFFS) and thrombosis‐free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1‐1.7) and MFFS (P < .001; HR 4.2, 95% CI 2.7‐6.5), in favor of patients diagnosed prior to 1997; the difference was sustained during multivariable analysis that included IPSET. Similarly stratified survival data in polycythemia vera (n = 665) and primary myelofibrosis (n = 1282) showed no similar impact on survival (P = .3 and .17, respectively). The current study represents a retrospective analysis and suggests significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of anagrelide. Whether or not anagrelide therapy was to blame for the worsening of OS and MFFS over time cannot be assumed and requires validation in a prospective study.

e18560 Background: Myelodysplastic syndromes (MDS) are rare hematological neoplasms typically seen in the elderly. Young MDS (yMDS) patients ( < 50 years old) have been reported to comprise between 3-6% in the Surveillance, Epidemiology and End Results (Ma X et al, Cancer 2007; Rollison R et al, Blood 2008) with a better overall survival (OS). Methods: 1012 MDS patients from 1993 to 2015 were found after IRB approval was obtained. All cases had their bone marrow slides reviewed at our institution. yMDS Patients were included as cohort 1, while the rest as cohort 2. Survival estimates were calculated using Kaplan-Meier curves and univariate and multivariate analyses was based on log-rank testing using JMP software version 10. Results: We found 68 (7%) yMDS patients with a median age of 42 years (range, 18-49). Female gender was more common (43% vs 31%, p = 0.05) while platelets were lower in yMDS (61 vs 102, p < 0.0001). Therapy related MDS (t-MDS) was more frequent (33% vs 17%, p = 0.005), as was transformation to acute myeloid leukemia (AML) in yMDS (28 % vs 11%, p = 0.0004). Allogenic hematopoietic cell transplantation (HCT) was more frequent in yMDS (42% vs 4%, p < 0.0001). Survival outcome: Median OS was longer for cohort 1 vs cohort 2 but did not reach statistical significance (43 vs 21 months, p = 0.1). Median progression free survival (PFS) was shorter for cohort 1 vs cohort 2 but also did not reach statistical significance (8 vs 12 months, p = 0.3). Median OS for cohort 1 based on R-IPSS was 44, 105, 40, 18, and 12 months for very low, low, intermediate, high and very high risk groups, respectively (p = 0.09). Median OS was shorter in t-MDS vs de novo MDS in yMDS (13 vs 47 months, p = 0.04). yMDS patients who transformed to AML had worse median OS (18 vs 93 months, p = 0.001). On multivariate analysis neither t-MDS nor R-IPSS had a statistically significant impact on OS. Conclusions: MDS is rarely diagnosed under the age of 50 with IPSS-R being less powerful in detecting mOS. Among yMDS patients, there was a higher proportion of t-MDS compared to older patients with subsequent higher rates of AML transformation and higher rates of allogeneic HCT. In our study, we did not find an improved OS for yMDS patients compared to older patients.

e18559 Background: Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms defined by ineffective hematopoiesis, dysplastic morphologic features, and variable risks of progression to acute myeloid leukemia (AML). Refractory anemia with ring sideroblasts (RARS) is a subtype of MDS defined by < 5% basts and > 15% ring sideroblasts (per 2008 WHO). Because RARS is a lower risk disease which does not frequently require HMA therapy, very little is known about the effects of HMA on RARS. Methods: A total of 1325 MDS patients’ data from 1993-2016 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our center. Patients were considered for our study if they received HMA for their RARS. Response was identified based on MDS IWG 2006 criteria. Prognostic factors were analyzed by univariate and multivariate analyses. Survival estimates were calculated using Kaplan-Meier curves. Results: 168 of the initial 1325 patient were RARS (14%); only 14 (8%) were treated with HMA. Median age was 72 years (range, 51-85); half were males, with median overall survival of 91.3 months. The median number of ring sideroblasts (RS) at diagnosis was 40% (range 10-85%). Of the 14 patients, 11 (79%) received azacitidine (AZA), 2 (14%) decitabine (DAC) and one received both (7%). The median number of cycles for AZA was 6.5 (range, 2-28) vs 6 cycles for DAC (range, 1-24). Of the 14 patients receiving HMA, only 3 responded (21%) achieving hematologic improvement. All 3 responders received AZA. 6 of the 14 RARS patients (43%) had their bone marrow biopsy repeated after HMA therapy, 3 of whom were among the responders to AZA therapy and 3 were non-responders. In 5 patients, ring sideroblasts decreased after HMA therapy by a median of 15% (range 0-80); they remained the same in 1 patient; one patient who had developed AML had a decrease in RS from 85% to 5%. Conclusions: RARS is a low-risk subtype of MDS that is infrequently treated with HMA (8% in our study). Response rate to HMA (21%) was inferior to known rates in MDS. HMA therapy seems to decrease the number of ring sideroblasts irrespective of response. RARS patients should be treated on clinical trials if available.