Major Hematological Response Is the Main Factor for Achieving a Major Molecular Response in JAK2V617F-Positive Essential Thrombocythemia and Polycythemia Vera Patients Treated with Hydroxyurea

Background. Hydroxyurea (HU) remains the cytoreductive drug of choice in high-risk patients with essential thrombocythemia (ET) and polycythemia vera (PV). There is scarce information about its effect upon the JAK2V617F allele burden in these patients.

Aim. To analyze prospectively the JAK2V617F response to HU treatment in newly diagnosed patients with ET or PV and to investigate the clinical and/or biological variables associated to a good molecular response.

Material and Methods. Sixty patients (25 PV and 35 ET) consecutively diagnosed in a single institution according to WHO criteria were included in the study. All PV patients were JAK2 V617F positive (14 homozygotes) whereas 21 (60%) ET patients were positive for the mutation (all in heterozigosity). Cytoreductive treatment was started according to standard guidelines with the mean HU daily dose being 894 ± 171 mg and 867±223 mg for PV and ET, respectively. Blood samples were taken immediately before starting treatment, at 3 months and then every 6 months. A mean number of 4.6 samples per patient were analyzed by quantitative real-time PCR assay after a median of 16 months (range: 3.5–57) of cytoreductive treatment. Determination of the relative change of the allelic ratio of JAK2V617F was calculated as follows: (% last V617F minus % first V617F) divided by % first V617F × 100. Major molecular response (MMR) was defined when pre-treatment V617F allele burden was reduced by > 50%. Major hematological response (MHR) was defined in PV when Hct <45 L/L (M), < 42 L/L (F), > 50% decrease in palpable splenomegaly, > 50% reduction in phlebotomies and normal platelet (< 400 × 10⁹/L) and leukocyte (≤ 10 × 10⁹/L) counts were achieved. MHR was defined in ET when normal platelet and leukocyte counts and > 50% reduction in palpable splenomegaly were obtained. The probability of major hematological and molecular response was calculated by the Kaplan-Meier method, followed by the log-rank test.

Results. MHR was seen in 46 (77%) patients. Median time to MHR was 4 months with the probability of response at 6 and 12 months being 55% and 71% respectively in the whole series. MHR was faster and more frequently observed in ET patients than in PV (MHR probability at 6 months: 36% in PV and 69% in ET, p=0.009). Patients with a higher JAK2 allele burden showed a significantly lower probability of response (MHR at 6 months: 36% in patients with 50% of mutated JAK2 alleles versus 63% in patients with < 50% of mutated JAK2 alleles, p=0.01). MMR was observed in 15 out of 46 assessable patients (33%). Median time to MMR was 7.5 months (range 2–57) with the probability of response at 12 and 18 months being 21% and 30%, respectively, in the whole series. JAK2V617F mean decrease was −22.7±45.5% in PV and −31.8±39.1% in ET, respectively. Six out of 25 PV patients switched from homozygous to a heterozygous status. The probability of obtaining a MMR was significantly higher in patients achieving a MHR than in those who did not obtained a MHR (MMR at 18 months: 41% versus 0%, p=0.02). Age, gender, spleen size, leukocyte count, platelet count, serum LDH level and JAK2V617F allele burden prior to cytoreductive treatment were not associated with the likelihood of MMR. ET patients with an Htc 0.45 L/L at diagnosis obtained a MMR more frequently than those patients with Htc < 0.45 L/L (MMR probability at 18 months: 57% versus 16%, p=0.003).

Conclusions. Major hematological response is the main factor predictive for attaining a major molecular response in JAK2V617F-positive PV and ET patients treated with HU.