Young platelet millionaires with essential thrombocythemia
Authors: Naseema Gangat, Natasha Szuber, Tabinda Jawaid, Curtis A. Hanson, Animesh Pardanani, Ayalew Tefferi
Journal: American Journal of Hematology (2021)

The platelet count threshold for World Health Organization classification system-compliant diagnosis of essential thrombocythemia (ET) is ≥450 × 109/L.1 Extreme thrombocytosis (ExT), on the other hand, is arbitrarily defined by platelet count of ≥1000 × 109/L and occurs in approximately 22% of patients with ET, at time of diagnosis.2 Note, ExT is most frequent in the context of young patients with ET with incidence rates of 44%/29%/29% in patients aged ≤40, 41–60, and > 60 years respectively.3 The presence of ExT in ET has been shown to confer a lower risk for arterial thrombosis4; additionally, its association with hemorrhage has been linked to aspirin use.5 Nevertheless, ExT often poses a therapeutic dilemma with low-risk young ET patients in terms of the need for cytoreductive therapy, stemming from an unsubstantiated concern for a heightened thrombotic risk, or to ameliorate bleeding tendency and microvascular symptoms. In light of inadequate published literature on ExT in ET, we compiled this report specifically focusing on young patients. Our main objectives were to (a) characterize the clinical phenotype of “young” platelet millionaires with ET via comparison with their counterparts without ExT and (b) assess long term outlook in terms of thrombosis, myelofibrotic/leukemic transformation and overall survival. Study patients were retrospectively recruited from the Mayo Clinic myeloproliferative neoplasms (MPN) database which is maintained under an institutional review board approved protocol and included 3023 MPN patients evaluated over five decades (1967 through 2017).2 Of 1070 adult patients with ET; 192 (18%) were aged below 40 years. Major arterial thrombosis included myocardial infarction, angina, cerebrovascular accidents, transient ischemic attack, peripheral arterial thrombosis, aortic thrombosis, mesenteric artery thrombosis, and central retinal thrombosis. Major venous thrombosis included deep venous thrombosis, pulmonary embolism, portal/splenic/mesenteric/hepatic vein thrombosis, and cerebral sinus thrombosis. Bleeding events that required red cell transfusions were classified as major hemorrhage. Follow up for each patient was updated in December 2020 by means of either a phone call or electronic communication with the patient or referring physician. Conventional statistical methods were utilized using JMP Pro 14.0.0 software package, SAS Institute, Cary, NC and included Cox proportional hazards model for multivariable analyses and Kaplan-Meir estimator for comparison of overall, leukemia-free, myelofibrosis-free and thrombosis-free survival. Median age of our study cohort (n = 192) was 31 years (range; 18–39) with a female preponderance (70%). Half of the patients (n = 96) presented with ExT. In order to accurately define the clinical phenotype of patients with ExT, we compared their clinical and laboratory features with their counterparts without ExT (n = 96) (Table S1). Young ET patients with ExT frequently harbored the CALR mutation (46% vs 25%) as opposed to JAK2 (35% vs 56%; P = .05), and also presented with a higher leukocyte count (median 9.5 vs 7.8 × 109/L; P = .03). The incidence of arterial thrombosis at or prior to diagnosis was significantly lower amongst patients with ExT (2% vs 8%; P = .04). On the other hand, the prevalence of cardiovascular risk factors was similar amongst those with or without ExT. Despite these findings, a much higher proportion of young patients with ExT received initial cytoreductive agents mainly hydroxyurea or anagrelide (64% vs 47%; P = .04) that suggested differences in individual physician discretion. As expected, a trend towards a higher rate of major hemorrhage before or after diagnosis was observed in patients with ExT (15% vs 7%, P = .09) which might be accounted for by a higher prevalence of acquired Von Willibrand's syndrome (AvWS) in 8/15 (53%) patients with ExT vs 4/13 (31%; P = .23) without ExT. Interestingly, microvascular symptoms were similar in patients with or without ExT (18% vs 22%, P = .55). All 192 young patients with or without ExT were followed for a median of 16 years (range; 2–51 years); a total of 34 deaths were recorded; 25 of which occurred amongst those who presented with ExT. Of note, the international prognostic score for survival in ET (IPSET) risk categories were similar amongst patients with or without ExT (P = .86). On an age-adjusted multivariable analysis, presence of ExT emerged as an independent predictor of shortened overall survival (HR, 2.32. 95% CI, 1.1–4.99; P = .02; Table S2). Figure 1(A) highlights the difference in long term survival beyond three decades, amongst young ET patients with or without ExT. Leukemic and fibrotic transformations were recorded in five and thirty-two patients respectively. All five patients with leukemic transformation presented with ExT with median time to transformation of 27.5 years (range; 20.1–36.6 years). It is to be noted that two of five patients directly transformed to acute leukemia without development of myelofibrosis; three were JAK2 mutated, and two CALR mutated; next generation sequencing (NGS) panel was obtained at ET diagnosis in one patient and did not harbor high risk mutations; karyotype at time of diagnosis was available in four patients of which only one was abnormal with del (20q). No leukemogenic therapies were administered and specific agents were limited to hydroxyurea (n = 4), anagrelide (n = 3) and interferon (n = 2). As was the case for overall survival, presence of ExT also emerged as an independent predictor for shortened leukemia-free survival (P = .01, Table S2; Figure 1(B)). On the other hand, similar rates of fibrotic transformation were observed in patients with or without ExT (P = .98; Figure 1(C)). Interestingly, on mutational analysis performed in a subset of young patients (n = 53), patients with ExT did not harbor high risk spliceosome, or P53 mutations.6 Moreover, the only mutations detected in the context of ExT were DNMT3A (n = 2) and RUNX1 (n = 1). In terms of thrombotic events after diagnosis, a trend towards a lower incidence was observed in those with ExT (17 vs 23%), which was primarily accounted for by arterial (9% vs 15%) as opposed to venous events (8% vs 10%). On a multivariable analysis for thrombosis-free survival which included all relevant variables known to impact thrombosis namely age, leukocytosis ≥11 × 109/L, gender, driver mutations, prior thrombosis, cardiovascular risk factors, along with platelet count ≥1000 × 109/L, the latter emerged as borderline significant, conferring a reduced thrombotic risk (P = .14, HR 0.62; Table S2, Figure 1(D)). The current study defines young platelet millionaires with ET as a distinct clinical subset with salient genotypic and phenotypic characteristics. Both the presence of ExT and lower incidence of arterial thrombotic events are consistent with mostly CALR driver mutation status.7 The exceedingly long follow up of our young ET cohort which spans five decades enabled us to appreciate the shortened long-term overall and leukemia-free survival amongst young platelet millionaires in spite of similar rates of fibrotic progression. This is consistent with our previous work implicating ExT as an independent risk factor for leukemic progression in ET.8 These observations which warrant further investigation, suggest underlying biological differences in patients with ExT, and underscore the importance of long-term follow up of young ET patients in order to accurately delineate the natural history. Importantly, counseling should be provided regarding their lower thrombosis risk obviating the need to lower platelet counts with cytoreductive therapy in low risk asymptomatic patients. Naseema Gangat and Ayalew Tefferi designed the study, collected data, performed analyses and wrote the paper. Natasha Szuber and Tabinda Jawaid collected and analyzed data. Curtis A. Hanson reviewed bone marrow morphology. Animesh Pardanani provided study patients. All authors reviewed the final draft of the paper. None. None. Table S1 Clinical and laboratory characteristics of 192 “young” (age < 40 years patients with essential thrombocythemia (ET) stratified by presence or absence of extreme thrombocytosis (≥ 1000 × 109/L) Table S2 Univariate and multivariable analysis of risk factors for overall, leukemia-free, myelofibrosis-free and thrombosis-free survival amongst 192 patients below age 40 years with essential thrombocythemia (ET). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.