Initial Therapeutic Approach and Relationship with Clinical and Biological Characteristics at Diagnosis in 2418 Patients of the Registro Italiano Trombocitemie (RIT)
Authors: Gugliotta Luigi , Iurlo Alessandra , Gugliotta Gabriele , Tieghi Alessia , Candoni Anna , Cattaneo Daniele , Ricco Alessandra , Lunghi Monia , Rumi Elisa , Scalzulli Potito Rosario , Dragani Alfredo , Antonioli Elisabetta , Martinelli Vincenzo , Randi Maria Luigia , Maschio Nilla , De Biasi Ercole , Appolloni Viviana , Cantore Nicola , Palmieri Raffaele , Santoro Cristina , Polverelli Nicola , Rago Angela , Cacciola Rossella R , Villa Maria Rosaria , Codeluppi Katia , Pierri Ivana , Fama Angelo , Piccin Andrea , Martino Bruno , Vianelli Nicola , Rupoli Serena , Santoro Umberto , Miglio Rossella , Monari Paola , Mazzucconi Maria Gabriella 
Published: November 2019

Abstract
Background. The therapeutic approach in thrombocythemic patients with Philadelphia negative chronic myeloproliferative neoplasms (Ph- MPN), in order to result cost-effective (primum non nocere), is commonly driven by the risk factors considered in the gradually updated guidelines. However, no studies were addressed to evaluate if and how the real-life therapeutic approach changed in the last decades.
Objective. To evaluate, in a large series of thrombocythemic patients with Ph- MPN, the impact of clinical and biological characteristics at diagnosis on the therapeutic approach adopted before and after the publication of the Italian guidelines for essential thrombocythemia therapy [1].
Methods. The analysis considered, in the patients of the Registro Italiano Trombocitemie (RIT), the clinical and biological characteristics at diagnosis, and the treatment ongoing after 3, 6, 12, and >12 months from diagnosis (antiplatelet alone [AntiPLT]; cytoreductive alone [CYT]; CYT+AntiPLT).
Results. The analyzed patients were 2418, 914 (38%) males and 1504 (62%) females, with a diagnosis (PVSG or WHO criteria) performed before and after 2005 in 51% and 49% of cases, respectively.
The rate of ongoing treatment with AntiPLT, CYT, and CYT+AntiPLT increased as follows: at 3rd month 16%, 12%, and 31%; at 12th month 17%, 14%, and 39%; after 12 months 19%, 16%, and 55%, respectively.
Patients treated with CYT or CYT+AntiPLT did not significantly differ in their characteristics at diagnosis.
The analysis of data at the 3rd month (initial phase) showed that:
1) CYT±AntiPLT treatment, ongoing in 43% of patients, was significantly related, in univariate analysis, to male gender, older age, prior thrombosis, higher thrombocytosis, leukocytosis, higher HCT level, CVRFs, comorbidities, symptoms, splenomegaly, hepatomegaly, and bone marrow fibrosis grade >0 (no relationship with JAK2 V617F mutation, and prior hemorrhage); in multivariate analysis, it was significantly related to age >60 y, age 40-60 y, prior thrombosis, PLT >1000 x109/L, PLT 700-1000 x109/L, symptoms, and comorbidities.
2) patients with standard high risk (age >60 y, and/or prior thrombosis, and/or PLT >1500 x109/L ) were receiving CYT±AntiPLT (59%), AntiPLT (7%), and no treatment (34%).
3) patients with standard low risk were receiving CYT±AntiPLT (22%), AntiPLT (27%), and no treatment (51%).
Low risk patients receiving CYT±AntiPLT had age 40-60 y (73%), CVRFs (59%), symptoms (53%), comorbidities (42%), PLT 1000-1500 x109/L (35%), PLT 700-1000 x109/L (42%), JAK2 V617F mutation (30%), WBC >10 x109/L (22%).
4) in patients receiving CYT±AntiPLT, the initial cytoreductive drug and the median age were: hydroxycarbamide (80%, 68 y), anagrelide (6%, 49 y), interferon alpha (9%, 42 y), pipobroman (2%, 72 y), busulfan (3%, 70 y).
The AntiPLT drug mostly used was low dose ASA (86-90% of cases, at any age).
5) Patients diagnosed after 2005, compared with those diagnosed before, showed a higher rate of CYT±AntiPLT treatment when at standard high risk ( 64% vs 53 % p <0.001), and a higher rate of AntiPLT treatment both when at high risk (11% vs 3% p <0.001) and at low risk (39% vs 15%, p <0.001). Moreover, the rate of use of the specific drugs and median age did not significantly change.
Conclusion. The initial (within the 3rd month) therapeutic approach in the thrombocythemic Ph- MPN patients of the RIT was after 2005 relatively compliant with the 2004 Italian guidelines. In fact, the rate of CYT±AntiPLT treatment in patients with standard high risk was higher than before (64% vs 53%, p<0.001). Nevertheless, the rate of untreated high risk patients remained rather high (34%). Moreover, 22% of patients with standard low risk received CYT±AntiPLT treatment, we surmise because they had supplementary characteristics (CVRFs, JAK2 V617F mutation, leukocytosis, age 40-60 y, and PLT 1000-1500 x109/L), considered as risk factors in clinical studies[2,3] and/or in recent risk scores [4,5].
[1] Barbui T et al. Haematologica 2004; [2] Harrison C et al. NEJM 2005; [3] Gisslinger H et al. NEJM 2013;
[4] Passamonti F et al. Blood 2012; [5] Barbui T et al. Blood 2012
*The RIT is a project of the GIMEMA Foundation

Disclosures
Gugliotta: Shire : Honoraria.