Page 15 - 2019_11 Resto del Mondo-web
P. 15

Editorials
PV as proposed by the PVSG, the British Committee for Standards in Hematology (BCSH), and the WHO.13 It was suggested either to reduce the thresholds for the Hb-con- centration, or to include the HCT as a major diagnostic criterion in association with the JAK2V617F mutation. In this review, the existence of prodromal (latent PV-dis- ease), named “masked” PV and defined by Barbui et al.,13 was also addressed, covering patients not meeting the required Hb or HCT threshold levels as defined in the WHO and BCSH criteria.22,23 With regards to the impact of lowering the Hb and the HCT thresholds for PV, influ- enced by the above studies,3,5-8,22,23 the 2016 revised WHO criteria have not resolved the conflicting opinions,24,25 as recently addressed and discussed in depth.26,27 However, very interestingly, applying the lower Hb thresholds as reported by the WHO 2016 criteria in the Canadian pop- ulation, Ethier et al. found an Hb value at or above the threshold in 4.1% of all complete blood counts from uns- elected males and in 0.35% of females. These figures increased the incidence of “potential PV patients” by up to 12-fold in males and 3-fold in females.The same pat- tern was demonstrated when including the neutrophil and platelet count, implying that up to 60 times more males and three times more women would be suspected of suffering from MPN and would accordingly require diagnostic investigations.24 According to the screening procedure in clinical practice as described by Rumi and Cazzola,25 the best compromise between the need for an early diagnosis of PV patients and the risk of excessively expanding the number of potential PV patients would be a threshold of 17 g/dL in men. Applying this Hb cut-off value, Barbui et al. found that 14% of their 375 patients presenting with WHO-defined PV did not meet the 2016 criteria.26 In the context of screening procedures in clinical practice and which blood cell counts to use, according to the Canadian data, the Hb/HCT thresholds as defined in the 2016 WHO criteria will markedly increase the number of individuals with suspected PV in the general popula- tion.24 Given this, it is important to note that a very recent Danish study has found MPN to be massively underdiag- nosed with an estimate of 10,000 undiagnosed MPN in Denmark, corresponding to approximately 550,000 US citizens having an undiagnosed MPN and accordingly being at a considerable risk of thrombosis.28 In this per- spective, it might be much more cost-effective to screen high-risk MPN individuals and obtain a diagnosis earlier rather than later when the individual has already suffered one or more potentially life-invalidating thrombotic events before being diagnosed with ET or PV.28
Consequences of misclassification of PV as ET
There are several consequences of misclassifying PV patients as ET.
1) Misclassification of JAK2V617F positive ET patients as ET instead of PV implies that these patients are not phlebotomized and are, therefore, exposed to an increased risk of potentially life-invalidating or life-threat- ening thrombotic complications due to the increased RCM. This is not a trivial risk, in particular in those patients aged <60 years without a prior thrombosis but with leukocytosis and platelet counts < 1500 x 109/L , since these patients are categorized as “low-risk” accord-
ing to international guidelines and are not offered cytore- ductive treatment, irrespective of the fact that both leuko- cytes and platelets are deeply involved in the develop- ment of atherothrombosis,29-33 the JAK2V617F mutation promotes atherothrombosis, being associated with e.g. transitory cerebral ischemia, completed stroke and ischemic heart disease, and leukocytosis per se is consid- ered a risk factor for thrombosis in the background popu- lation,34 and a causative factor for thrombosis in ET and PV patients.35 Importantly, the most recent studies, including a meta analysis study, have provided evidence that leukocytosis is a risk factor for thrombosis in the MPN-population as well.36,37
2) Misclassifying JAK2V617F positive “ET” patients as “ET” instead of PV has a huge impact on any prognostic model that compares the prognosis of ET and PV patients, the potential outcome being that JAK2V617F positive ET patients have an inferior prognosis as compared to those who are JAK2V617F negative or CALR-positive.38 In sev- eral published studies these differences might be explained by the fact that PV patients - not being phle- botomized - have been included in the ET-cohorts. This may also hold true for mPV patients who have an increased risk of thrombosis (young patients)39 and poorer survival than PV patients. This is likely explained by the fact that several mPV patients have not been phle- botomized despite an expanded RCM.
3) Results from studies on safety and efficacy of any drug, both those conventionally used [e.g. hydroxyurea (HU), interferon-α2 (IFN) and anagrelide] and novel agents such as ruxolitinib or experimental drugs (in clini- cal trials for future approval for the indication of ET or PV) may be severely undermined, impossible to interpret, and therefore not credible.
4) Building future therapeutic recommendations and prognostic models on a diagnostic platform that does not take into account the true nature of a disease (e.g. a higher rate of thrombosis in PV than ET, a higher rate of trans- formation to myelofibrosis and acute myelogenous leukemia in PV than in ET, a reduced life expectancy in PV as compared to ET) due to diagnostic misclassification undermines our current understanding and concepts on MPN in highly important issues. These include patho- genetic mechanisms for disease evolution both in terms of molecular phenotypes, clinical phenotypes and associ- ations between them, diagnostic classification in the bio- logical continuum from early cancer stages (ET, PV) to the advanced myelofibrosis stage, and, not least, when and how to treat MPN. The cornerstone treatment of PV is phlebotomies, carried out to alleviate the hyperviscosity state due to an expanded RCM and thereby to reduce the risk of the deadly thrombosis seen in median survival fig- ures for PV patients of 18 months without such treat- ment. This approach may, however, be misguided by using only the Hb concentration and the HCT as these are profoundly influenced by the iron-deficient state in patients with PV and also in JAK2V617F positive ET patients in whom erythropoietin (Epo) and ferritin levels and the mean corpuscular volume (MCV) values have been repeatedly reported to be lower than in JAK2V617F negative ET patients.40
5) Without an estimation of RCM and plasma volume
haematologica | 2019; 104(11)
2121


































































































   13   14   15   16   17