Clinical and Biological Features in Patients with Ph-Negative Chronic Myeloproliferative Neoplasm Showing Different Molecular Pattern. Comparative Study in 596 Patients of the Registro Italiano Trombocitemie (RIT)
Authors: Gugliotta Luigi , Iurlo Alessandra , Gugliotta Gabriele , Tieghi Alessia , Specchia Giorgina , Gaidano Gianluca , Candoni Anna , Randi Maria Luigia , Scalzulli Potito Rosario , Dragani Alfredo , Martinelli Vincenzo , Tagariello Giuseppe , Antonioli Elisabetta , Liberati Anna Marina , Palmieri Raffaele , Langella Maria , Rago Angela , Cacciola Rossella R , Pierri Ivana , Ricco Alessandra , Cattaneo Daniele , Santoro Umberto , Rupoli Serena , Santoro Cristina , Mastrullo Lucia , Martino Bruno , Mazzucconi Maria Gabriella , Vianelli Nicola , De Stefano Valerio , Passamonti Francesco , Vannucchi Alessandro M. 
Published: October 2019

Abstract
Background. In patients with Ph-negative chronic myeloproliferative neoplasm (MPN) the molecular pattern, beside other characteristics at diagnosis, has been related to the disease prognosis.
Aim. To compare clinical and biological features at diagnosis and during the follow-up in gender/age-matched MPN patients showing different molecular pattern.
Material and methods. The Registro Italiano Trombocitemie (RIT) is a web-based registry that includes thrombocythemic MPN patients diagnosed according to PVSG or WHO criteria, registered after 2005, and then prospectically followed. The JAK2 V617F mutation (JAK2+) was reported in 941 (58.4%) out of 1610 tested patients. On the basis of subsequent tests, performed in part of the JAK2 WT (JAK2-) subjects, 103 patients were JAK2-/CALR+ (CALR+), 14 patients were JAK2-/CALR-/MPL+ (MPL+), and 46 were JAK2-/CALR-/MPL- (3NEG).
The 103 CALR+ patients were compared with 309 (103 x 3) JAK2+ patients matched for gender, age, and revised diagnosis (WHO 2008 criteria). A similar comparison was done between 46 3NEG patients and other 138 (46 x 3) JAK2+ matched patients.
Results. CALR+ and matched JAK2+ patients had, as expected, the same gender distribution (males 41%), the same median age (51 years), and no significant difference (p 0.42) in the WHO diagnosis distribution.
CALR+ patients, as compared with JAK2+ patients, showed at diagnosis: higher median platelet (PLT) count (839 vs 718 x109/L, p<0.001); lower median white blood cell (WBC) count (7.3 vs 8.9 x109/L, p<0.001); lower median hemoglobin (Hb, 14.2 vs 14.8 g/dL in males, p 0.01; 12.9 vs 14.0 g/dL in females, p<0.001); lower median hematocrit (HCT, 42.4 vs 45.0 %, p 0.002 in males; 38.7 vs 42.2 in females, p<0.001); lower rate of low (<5) serum erythropoietin (0 vs 32%, p 0.003); lower rate of prior thrombosis (PrTh, 5/103, 4.9% vs 60/309, 19.4%, p<0.001), observed for both arterial and venous PrTh; lower rate of high/intermediate thrombotic risk (IPSET, 37% vs 55%, p 0.003).
CARL+ and JAK2+ patients had the same rate of antiplatelet and cytoreductive treatment (96% vs 96%, and 86% vs 84%, respectively). During the follow-up the incidence of thrombotic and hemorrhagic events was not significantly different (1.3 vs 1.1/100 pt-years, and 1.0 vs 0.6/100 pt-years, respectively). Moreover, no significant difference was observed in the incidence of evolution to overt primary myelofibrosis (PMF, 0.76 vs 0.61/100 pt-years), polycythemia vera (PV, 0 vs 0.24/100 pt-years), and AL/MDS (0.08 vs 0.10/100 pt-years).
Finally, the same overall survival was found after 5, 10. 15, and 20 years (99, 97, 94, 93%, respectively).
3NEG patients, as compared with JAK2+ matched patients, showed at diagnosis: lower median WBC count (7.9 vs 10.9 x 109/L, p 0.03); lower Hb and/or HCT level (p 0.006); lower rate of splenomegaly (7% vs 28%, p 0.003); lower rate of symptoms (35% vs 51%, p 0.049). No significant difference was found in: median PLT count (700 vs 720 x 109/L, p 0.61); PrTh (7% vs 16%, p 0.11); prior hemorrhage (4.7% vs 7.5%, p 0.52); high/intermediate thrombotic risk (IPSET, 36 vs 48%, p 0.37). Moreover, no significant difference was observed during the follow-up in: antiplatelet and cytoreductive treatment; thrombosis and hemorrhage rate; PMF, PV, and AL/MDS evolution; overall survival.
Conclusion. CALR+ patients, as compared with JAK2+ matched patients, although showed a lower thrombotic risk (lower WBC and HCT levels, lower PrTh rate), received the same antiplatelet and cytoreductive treatment, had the same incidence of adverse events during the follow-up (vascular complications and disease evolution/transformation), and had the same overall survival.
3NEG patients, as compared with JAK2+ matched patients, showed results similar to those observed by comparing CALR+ and JAK2+ matched patients.
To better define the role of the precise definition of molecular pattern in Ph-MPN patients, new prospective controlled studies seem necessary.

Disclosures
De Stefano: Janssen Cilag: Research Funding; Roche: Research Funding; Novartis: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Bruno Farmaceutici: Research Funding; Celgene: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Shire: Speakers Bureau. Passamonti:Novartis: Consultancy, Honoraria, Speakers Bureau.