The Combined Use of Hydroxyurea and Anagrelide Allows Better Hematologic Control in Patients with Chronic Myeloproliferative Disorders and Thrombocytosis. A Report on 13 Patients with Poor Tolerance to Hydroxyurea Monotherapy.
Authors: Micheletti Moira , D’Adda Mariella , Drera Monica , Ferrari Samantha , Rossi Giuseppe 
Published: October 2019

Abstract
Background: Anagrelide has proven effective in selectively lowering platelet count in patients with chronic myeloproliferative disorders (CMPD). It has been approved for the control of thrombocytosis in patients with CMPD and in patients with essential thrombocytemia (ET) refractory or intolerant to hydroxyurea (HU). In spite of their different mechanisms of action, its use in combination with other active agents, particularly HU, has not been explored.
Aim of the study: We have reviewed the records of patients with CMPD treated at our Institution and report herein on the combined use of anagrelide and HU in a series of 13 patients, mean age 66,7 years, followed for 1–21 years. Their diagnoses were: essential thrombocythemia (7), polycythemia vera (3), chronic myeloid leukaemia (CML) (1), and idiopathic myelofibrosis (1). Previous treatments included HU (13), phlebotomy (2), busulphan (4), r-interferon (1), imatinib mesylate (1). All had thrombocytosis (mean platelet count: 948.9 × 109/L), with coexistent risk factors for vascular events in 11 of 13.
Results: Anagrelide was started because of poor platelet control by a HU daily dose of 0,5– 3 g (median: 1,5 g), which caused anemia (Hb < 10,5 g/dL) (3 transfusion-dependent) and/or leukopenia (WBC < 4.0 × 109/L) in 12/13 cases and because of HU-related cutaneous ulcers in 1. Initial anagrelide daily dose was 0,5 – 2 mg. It was associated with HU at the significantly reduced daily dose of 0,25 – 2 g (median 1g) (Wilcoxon: P<0.001). After a median of 1 month on combined therapy (range 0,5 – 4) the mean peripheral blood cell (PBC) count changes compared to treatment with HU alone were as follows: platelets: 507.5 vs 948.9 × 109/L (P=0.013); WBC: 8.392 vs 5047 × 109/L (P=0.039); hemoglobin: 11,28 vs 10,15 g/dL (P:=0.026) (1 vs 3 pts transfused). In 6 patients HU was stopped after a median of 1,5 months and anagrelide was continued as monotherapy. In 1 CML patient in accelerated phase anagrelide was associated with imatinib mesylate to control thrombocytosis, without side effects. In 6 patients anagrelide and HU combined treatment has been carried on for 19 – 40+ months (median 28 months) by modulating doses according to PBC counts. Anagrelide’s dosage had to be reduced in 1 patient because of fatigue. Further mild side effects included peripheral edema (1) dyspepsia and abdominal meteorism (1), dyarrhoea (2). Three patients had gastrointestinal bleeding from duodenal ulcer (1), intestinal polyps (1), stomach angiodysplasia while on oral anticoagulation (1). One patient had cerebral TIA during a transient thrombocytosis rebound after haemorrhage. Their CMPD did not show evidence of progressive disease. In one pt a marrow trephine biopsy after 18 months showed a slight increase of fibrosis from grade 1–2 focal to grade 1–2 diffuse. Two patients died, both of comorbid conditions.
Conclusion: This preliminary clinical experience shows that the association of anagrelide and hydroxyurea allows a significant reduction of the dose of HU needed to control thrombocytosis and causes significant less toxicity on the erythroid series. Compared to anagrelide monotherapy it should allow costs saving as well as a better control of WBC count, whose correlation with thrombotic risk is currently debated. The combination was well tolerated, although the frequency of gastrointestinal bleeding needs careful monitoring. This innovative therapeutic approach merits further investigation.