Long-term follow-up of essential thrombocythemia in young adults: treatment strategies, major thrombotic complications and pregnancy outcomes. A study of 76 patients

Essential thrombocythemia (ET) is a chronic myelo-proliferative disorder typical of middle age. However, it has also been observed in children and young adults.1–2 Major thrombotic episodes and microvascular disturbances have been described in young ET patients, but the real risk for vascular complications has not been clearly established, and specific therapeutic approaches have been investigated.3–7 In this study, we retrospectively analyzed a cohort of 76 thrombocytemic patients, younger than 40 years at diagnosis, with the following aims: (1) to evaluate thrombotic and hemorrhagic complications; (2) to specify the treatment adopted; and (3) to report pregnancy outcomes.

Permission was obtained from the institutional review board to examine the medical records of ET patients who were diagnosed at the Institute of Hematology/Oncology “L. and A. Seràgnoli”, Bologna. Between 1977 and 2008, 76 consecutive patients under 40 years of age (25 males and 51 females; median age: 32 years, range 18–40; median platelet count: 830×10/L, range 452–2045; 23 patients with a platelet count >1000×10/L; median leukocyte count: 8.7×10/L, range 4–19.6) were recorded. The diagnosis was carried out according to the PVSG8 or the WHO9 criteria.

Forty-seven patients (63.5%) were asymptomatic at presentation. Twenty-three (30%) were experiencing vasomotor symptoms, including headache (n=11), dizziness (n=10), visual disturbances (n=5). At diagnosis, major thrombotic and minor hemorrhagic events occurred in 7 (9%) and in 2 (2.6%) patients, respectively. Nine patients had palpable splenomegaly. Cardiovascular risk factors were present in 27 (35.5%) patients.

Median follow-up is 13.5 years (range, 1–32.5). Overall, 3 patients (4%) died (acute leukemia, non-ischemic cardiac disease, second neoplasia).

Timing and type of cytoreductive treatment was based on the discretion of the physician (Table 1). Over the years, a progressive decrease in the use of cytoreductive therapies was observed; concomitantly, busulfan (BU) was replaced with interferon-alpha (IFN-alpha) and anagrelide (ANA).

Ten patients (13%) experienced one or more thrombotic events. A total of 4 arterious (transient ischemic attack, acute myocardial infarction, peripheral arterial thrombosis, stroke) and 16 venous thrombosis (12 deep vein thrombosis and 4 superficial thrombophlebitis) were recorded throughout the follow-up (Table 2). At the time of the first thrombotic episode, 3 patients were on cytotoxic therapy (2 patients with BU and one patient with IFN-alpha) and 6 patients received an antiplatelet drug; after the first episode, all patients started a cytoreductive therapy (3 patients with BU, 2 patients with hydroxyurea and 2 patients with IFN-alpha) but a second thrombotic episode occurred in 4 cases. The cumulative risk of thrombosis during follow-up was 7.5% at ten years and 11.8% at 15 years.

JAK2 mutational analysis was performed, as previously described,10 in 59 patients (78%). The mutation was detected in a heterozygous status in 44% of the patients, an incidence which is inferior to that observed in cohorts of general ET patients.10,11 JAK2 mutation correlated with higher hemoglobin and lower platelets (P<0.001) at diagnosis.

No baseline characteristics (previous thrombotic events, platelet/leukocyte count, additional cardiovascular risk factors including smoking, JAK2 mutation) correlated with thrombosis; however, the number of the events was relatively small.

Twenty hemorrhagic episodes were reported during follow-up in 10 out of 76 (13%) patients; in 13 cases, bleeding was not associated with concomitant use of antiplatelet drugs. A history of bleeding and extreme thrombocytosis (platelet count >1000×10/L) did not predict subsequent bleeding.

Table 1.Timing and type of cytoreductive and antiplatelet therapy.

Twenty-four pregnancies in 13 females were followed and 15 normal babies were delivered, with 9 abortions (37.5%) and one abruption placentae; in the other cases, delivery was uneventful. During pregnancy, IFN-alpha was administered in 3 cases (in 2 cases, in combination with aspirin) and antiplatelet therapy alone was administered in 9 cases. Treatment at conception did not significantly influence the live birth rate (treated vs. untreated: 8/12 vs. 7/12, P=0.99). The JAK2 mutation did not influence pregnancy outcome: in 24 pregnancies the occurrence of fetal loss was comparable (mutated vs. unmutated: 3/6 vs. 6/18, P=0.6).

Table 2.Clinical and hematologic characteristics at time of thrombotic event during follow-up.

We report the long-term outcome of a particular cohort of patients, aged from 18 to 40 years old, followed for a prolonged period of time (median, 13.5 years). Only one patient experienced a leukemic transformation, 16 years after diagnosis, and no patient evolved to myelofibrosis. Although it is generally recognized that young age identifies patients at lower thrombotic risk, our cohort of patients presents a prevalence of thrombotic complication (13%) which is higher than that previously reported in other cohorts of young (<50 yrs) ET patients treated with pipobroman5 or with hydroxyurea,3 although our population is younger and follow-up is longer. Moreover, this prevalence was comparable to that observed in young, high-risk patients treated with anagrelide4 and to that observed in general ET studies.12

Footnotes

• Funding: the study was supported by the Italian Association for Cancer Research (A.I.R.C.), by Fondazione del Monte di Bologna e Ravenna, by European LeukemiaNet funds and by BolognAIL grants.