Initial Therapeutic Approach and Relationship with Clinical and Biological Characteristics at Diagnosis in 2418 Patients of the Registro Italiano Trombocitemie (RIT)

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 3^rd month 16%, 12%, and 31%; at 12^th 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 3^rd 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 3^rd 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