Vascular Events and Risk Factors for Thrombosis in Refractory Anemia with Ring Sideroblasts and Thrombocytosis (RARS-T)

Background: Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) is a provisional entity in the MDS/MPN overlap syndromes, with diagnostic features of RARS, along with a platelet count > 450 x 10(9)/L and large atypical megakaryocytes.  Mutations involving SF3B1 (~80%), JAK2 (~60%), TET2 (~25%) and ASXL1 (~15%) have been reported. The frequency of thrombotic events in RARS-T is thought to be similar to that of essential thrombocytosis (ET) (3.6 vs 3.9/100 patient years; Hematologica 2012; 1036-41).  However, unlike in ET, it remains unclear as to whether thrombotic events in RARS-T impact overall (OS) or thrombosis-free (TFS) survival.

Methods: 82 patients with WHO-defined RARS-T were included in the study. All patients had bone marrow (BM) biopsies, iron stains for detection of BM ring sideroblasts (RS) and cytogenetics performed at diagnosis.  Mutational analysis for JAK2, CALR, MPL, SF3B1, SRSF2 and ASXL1 was carried out on BM DNA obtained at the time of diagnosis.  Details of type of thrombotic event and cardiovascular (CV) risk factors including; hypertension, diabetes, smoking and dyslipidemia were obtained by careful review of the medical record. OS was calculated from time of initial diagnosis to the time of last follow-up or death. TFS was calculated from the time of diagnosis of RARS-T to development of thrombosis in uncensored patients and date of last follow up or death in patients censored for thrombosis. Conventional statistics were utilized for all analyses.

Results:  Among the 82 study patients, 46 (56%) were males and median age was 72 years (range, 48-93).   At a median follow-up of 26.5 months; 48 (59%) deaths and 2 leukemic transformations were documented. Median OS was 44 months.  Karyotype was diploid in 61 (74%) and analyzed mutational frequencies were; SF3B1 67% (28/42), JAK2V617F 40% (25/61), ASXL1 21% (9/41), SRSF2 6% (2/31), MPL 1% (2/41) and CALR 0, respectively. Cardiovascular risk factors were present in 52 (63%).

a)       Thrombotic events and their impact on thrombosis free survival:

Eight (10%) patients had a thrombotic event prior to or at the time of diagnosis of RARS-T (venous-8, arterial-0). Nine (11%) patients developed subsequent thrombotic events (venous-7, arterial-2), with no fatalities. In univariate analysis, lower hemoglobin level (p=0.008), lower BM RS % (p=0.04), history of thrombosis (p=0.02), and absence of SF3B1 mutations (p=0.017) were associated with an inferior TFS. Age (p=0.07), JAK2 mutation status (p=0.56) and CV risk factors (p=0.95) did not have prognostic impact. Given the association between SF3B1 mutations and BM RS, in a multivariable model that included these two as covariates, only the absence of SF3B1 mutations retained prognostic significance (p=0.02). Absence of SF3B1 mutation remained significant when history of thrombosis or lower hemoglobin level were introduced into the multivariable model.

b)       Risk factors for overall survival:

In univariate analysis, hemoglobin <10 gm/dl (p=0.007), presence of circulating blasts (p=0.002) and presence of CV risk factors (p=0.04) were associated with an inferior OS. Neither history of thrombosis (p=0.59) nor SF3B1 (p=0.12) mutations affected OS. In multivariable analysis, hemoglobin <10 gm/dl (p=0.03) [HR 1.9; 95% CI 1.1-3.5] and circulating blasts (p=0.002) [HR 1.3; 95% CI 1.1-1.6] remained significant.  

Conclusions:  In contrast to what is observed in ET, thrombosis history does not appear to affect either overall or thrombosis-free survival in RARS-T. The current study suggests a lower thrombosis risk in SF3B1-mutated patients with RARS-T, compared to their SF3B1 wild-type counterparts.