Is There a Role for Red Cell Mass (RCM) Assessment To Classify Myeloproliferative Disorders (MPD) in the JAK2 Era?.
Authors: Cassinat Bruno , Laguillier Christelle , Gardin Claude , De Beco Virginie , Burcheri Sara , Fenaux Pierre , Chomienne Christine , Kiladjian Jean-Jacques 
Published: October 2019

Abstract
Background: The discovery of JAK2V617F mutation has lead to the proposal of new algorithms to diagnose and classify MPD. Separation of PV from ET could become less clear, especially in JAK2V617F patients, if one considers that mutated PV and ET are similar conditions. However, the short-term risk of thrombosis, and long-term risk of evolution to leukemia have not yet been shown to be similar in JAK2V617F ET and PV. Current WHO criteria for PV require either RCM >125% of predicted value, or Hb level >18.5 g in men and 16.5 g in women. Some investigators recently proposed a threshold for Ht at 52% in men and 48% in women to diagnose PV in JAK2V617F patients. Diagnosis of ET requires excluding PV, and using Hb or Ht values for this purpose could avoid RCM measurement.
Aims: To evaluate the prevalence and prognostic impact of erythrocytosis determined by RCM measurement in MPD patients classified as ET on peripheral blood counts.
Methods: We reviewed all RCM measurements performed in patients suspected of MPD in 2 nuclear medicine laboratories during a 10-year period.
Results: Among 566 patients referred for RCM measurement, 71 had isolated thrombocytosis (i.e. both Hb and Ht < values used for PV diagnosis as defined above). RCM was normal in 38/71, but was >125% of predicted value, revealing inapparent erythrocytosis, in 33 cases. Thus, after RCM measurement, final diagnosis was ET in 53.5% (38/71), and PV in 46.5% (33/71) of the patients, respectively. Pts with elevated RCM had significantly higher Ht (p<0.0001), lower platelets (p=0.012), and higher WBC (p=0.041). Serum EPO (p=0.49) and EEC (p=1) could not distinguish between patients with and without erythrocytosis. JAK2 mutational status was available in 49/71 pts, and JAK2V617F was found in 28/49 of them (57.1%), in 10/28 pts (35.7%) with normal RCM (reclassified as ET), and in 18/21 pts (85.7%) with increased RCM (reclassified as PV) (p=0.0005). PV pts presenting with isolated thrombocytosis tended to have higher rate of thrombosis (39.4%), and 3 progressed to myelofibrosis, including 1 subsequent progression to acute leukemia, compared to 21% thrombotic events (p=0.12) and absence of hematological evolution in the ET group (p=0.09). Comparing the risk of thrombosis according to JAK2V617F instead of RCM, we found a similar trend to higher rate of thrombosis in patients with compared to those without JAK2V617F (36% and 24%, respectively), but this difference was not significant (p=0.53).
Conclusion: ET is now clearly considered a heterogeneous disease. For example, some patients clinically diagnosed as ET have polyclonal myelopoiesis, while others have in fact early stage myelofibrosis. This study shows that another proportion of ET (46.5%) has early stage PV when RCM is systematically measured. Polycythemia was mainly but not only found in JAK2V617F pts, and its presence tended to predict a higher risk of thrombosis and of hematological transformation, which will have to be confirmed. Our results suggest that, at least in cases presenting with isolated thrombocytosis, RCM measurement is useful for proper MPD classification and management until prospective data support the proposal of a molecular instead of “clinical” classification of Ph-negative MPD.