Cytoreductive Combined Therapy in Essential Thrombocythemia Patients: Report of the Registro Italiano Trombocitemia (RIT)
Authors: Scalzulli Potito Rosario , Tieghi Alessia , Liberati Anna Marina , Crugnola Monica , Specchia Giorgina , Cacciola Emma , Ciancia Rosanna , Candoni Anna , Balleari Enrico , Latagliata Roberto , Gubbiotti Marta , Valvano Maria Rosa , Melillo Lorella , Cascavilla Nicola , Gugliotta Luigi 
Published: April 2020

Abstract
Background: in the Essential Thrombocythemia (ET) patients considered at high risk for thrombosis, a treatment with low-dose aspirin is usually performed and a cytoreductive therapy is recommended. Hydroxyurea (HU), Interferon alpha (IFN) and Anagrelide (ANA) are largely used, but their side effects/toxicity or inefficacy are not rarely cause of drug withdrawal. Since HU, IFN, and ANA have different activity and toxicity patterns, the combined use of two drugs at lower dose may result very useful to overcome the limits of a single drug at conventional or high dose.
Aim: to evaluate the ET patients enrolled into the RIT who received a combined cytoreductive therapy, with particular interest for feasibility, efficacy and toxicity.
Patients: fifty-six ET patients, 18 males and 38 females, diagnosed in the years 1998–2008 according to the PVSG or WHO criteria, are object of this study. The patients at diagnosis had a median platelet count of 792 × 109/L (600–2009), with disease related symptoms in 18 cases (32%) and previous thrombotic or haemorrhagic events in 6 (12 %) and 1 (2%) cases, respectively.
Results: the patients received as first cytoreductive drug HU (n 32, 57%) at a median dose of 1 g/day (0.5–3.0), or ANA (n 13, 23%) a median dose of 1.5 mg/day (0.5–4.0), or IFN (n 11, 20%) at a median dose of 9 MU/week (3–9). The 32 patients receiving HU started a combined therapy HU+ANA as a consequence of hematological toxicity (n 23), fever (n 4), cutaneous ulcers (n 2), inefficacy (n1), other causes (n 2); the 13 patients receiving ANA started a combined therapy
ANA + HU (n10) or ANA + IFN (n 3) as consequence of cardiovascular side effects (n 10), anemia (n 2), or GI side effects (n 1); the 11 patients receiving IFN started a combined therapy IFN+ANA as consequence of unaccepted side effects. All patients who started the combined therapy had reduced the dosage of the initial drug. The median follow-up of the patients on combined therapy was 11 months (1–75). A hematological response (platelet count &lt;500 × 109/L), with WBC &gt;4 × 109/L and Hb &gt;12.5 g/dl, was registered in 21 of 42 (50%) patients on HU + ANA and in 11 of 14 (79 %) patients on IFN + ANA. Diseaserelated or drug-related symptoms (headache, dizziness, palpitation, abdominal pain) were registered in 7 of 56 (12 %) patients; no thrombotic or hemorrhagic complications occurred.
Conclusion: in these ET patients the combined therapy HU + ANA or IFN + ANA was well tolerated and able to control the symptoms and to obtain a satisfactory hematological response (particularly with IFN + ANA). These promising results could be due to the low dosage and to synergic effect of the combined drugs, but controlled studies are needed to prospectively evaluate the role of the combined therapy in ET patients.