Thrombosis with Non-Proliferative Complete Blood Count Indicative of Underlying Myeloproliferative Neoplasm, Sythrom, a Study on Behalf of the FIM Group

Introduction

Thrombosis is the main cause of morbidity in myeloproliferative neoplasms (MPN) and can be the mode of revelation of these malignant diseases. Most of them are characterized by specific driver mutations such as JAK2 V617F, CALR or MPL. An idiopathic or atypical thrombotic event justifies looking for MPN by searching these MPN-related mutations, even in the absence of myeloproliferative features on the complete blood count (CBC). This is especially crucial in case of splanchnic and cerebral thromboses, but not only. In this context the diagnosis of MPN and the choice of treatment are made difficult by the absence of increased blood counts.

Objectives

- To constitute an observational cohort of patients (pts) presenting an arterial or venous thrombotic event leading to a suspicion of MPN without signs of myeloproliferation in CBC.

- To study the characteristics of pts at diagnosis, the rate of recurrence of thrombosis and the rate of hematological progression.

Patients and method

Inclusion criteria were as follows: i)-diagnosis of an arterial or deep venous thrombotic event, ii)-CBC not suggestive of polycythemia vera (PV), essential thrombocythemia (ET) or myelofibrosis (MF) (CBC below WHO 2016 thresholds) but iii)-detection of a molecular abnormality (JAK2, CALR or MPL driver mutations) and/or an abnormality on bone marrow trephine in favor of MPN and/or spontaneous progenitor growth. Data were collected retrospectively and prospectively. The study is registered on ClinicalTrial.gov (NCT04539678).

Results

Between 05/2019 and 06/2022, the participation of 31 centers in France and Switzerland allowed the collection of data from 216 pts. The analysis is presented for 208 pts after exclusion of incomplete non-evaluable cases (n=5) or those not meeting inclusion criteria (n=3). The M/F sex ratio was 1.3 with a median age of 55 years (22-91) at the date of molecular testing. Inaugural thrombosis was venous (80%) or arterial (20%) and involved either splanchnic (50%), cerebral (24%), other locations (23%) or multiple territories (3%). Median CBC values were hemoglobin 14 g/dL, hematocrit 43%, platelets 298x109/L and leukocytes 7,1 x109/L. Pts had either a driver mutation of JAK2 V617F (n=201), CALR (n=2) or MPL (n=2), or none of these but spontaneous progenitor growth (n=3). According to WHO criteria, the diagnoses retained were MPN in 91 (44%) cases (including 26 PV, 4 MF and 61 unclassifiable MPN), while 38 pts (18%) lacked MPN criteria and 79 (38%) were not assessable (no trephine).

A clinical follow-up of at least 3 months was available in 197 pts, with a median of 61 months (range 3 months - 36 years). Recurrent thrombosis occurred for 42 pts (21%, respectively 24% of initially arterial and 19% of initially venous). Recurrence was splanchnic for 13 pts (31%). The median delay of recurrence was 37 months (12 days - 18 years) after the thrombotic event that led to a suspicion of MPN. Recurrence occurred more often in pts with initially non-splanchnic thrombosis (30% vs. 13% p=0.004). Thrombosis recurrences were not significantly different between pts classified as MPN and those without MPN criteria (18% vs. 30% p=0.1). Hematological progression was observed for 27 pts with a median delay of 31 months (1 - 105) since thrombosis. According to WHO MPN criteria, they were 9 PV, 14 TE and 4 MF. Pts with thrombotic recurrence more frequently presented hematological progression or died (31 month progression-free survival [PFS] 85% vs 94% p=0.008). PFS was significantly reduced in cases of initially non-splanchnic thrombosis (86% vs 97% at 31 months p<0.0001). An explanation could be that pts with splanchnic thrombosis were more frequently treated with cytoreductive agents (CRA) (71% vs 41% p=0.03). Analysis of the effect of antithrombotic therapy is ongoing.

Conclusion

Thrombosis cases with a non-proliferative CBC but with MPN driver mutations leading to MPN suspicion constitute a heterogeneous group of pts, with many cases of non-splanchnic involvement. The latter pts show more frequent thrombotic recurrences and hematological progression than pts with splanchnic involvement. The role of cytoreduction and antithrombotic therapies needs to be explored in this context.