Page 94 - 2019_08-Haematologica-web

J-C. Ianotto et al.
Table 3. Comparison of the characteristics of the very young patients in this cohort versus those of other reported series of young patients less than 40 years old with polycythemia vera or essential thrombocythemia.
Essential thrombocythaemia
Polycythaemia vera
Boddu Lussana Passamonti
2018 2014 2003
43 97 70
28 35 42
16-39 18-40 18-49
51% 44% 70%
9.4 10.7 12 149 190 210 547 476 544
92% 100% ? 21% ? ?
14% 12% 24% ? 67% 29%
3.6 7.9 14 2% 18% 11% 5% ? ?
na na na 0% 9% 7% 0% 3% 7% 0% 4% 26%
Our cohort
Number 396
Median age, years 9.3
Age range, years 0.2-20 Male 42%
White blood count, 109/L 10.6 Haemoglobin, g/L 131 Platelets, 109/L 1192
JAK2V617F cases 33.5% JAK2V617F allele burden 24.1%
Thrombosis before diagnosis 4% Venous events 86% Median follow-up, years 4.5 Thrombosis after diagnosis 3.8% Hemorrhage after diagnosis 4.8%
Transformation into PV 0% Transformation into MF 1.8% Transformation into AML 0% Death 0%
Boddu 2018
105
Palandri 2015
197
Lussana 2014
375
Barbui 2012
178
Our cohort
75
25
16-39
27%
8.2 134 763
53% 15
6% ? 2.6 2% 2%
? 0% 2% 8%
34 32,3 33
16-40 16-41
32% 29% 38%
8.6 8.6 8.4 142 142 14 850 708 796
63% 100% 56% 21% ? ?
8% 9% 13% 68% 55% 62% 10.3 7.3 7.6 10% 10% 8%
? ? 5%
0% 0% 0% 5.5% 3% 3% 0.5% 0% 0% 2.7% 0.5% 0%
13-40
12
0.6-19
55%
13.2 157 799
40% 43.5%
14.7% 78% 4.3 9.3% 4%
na 2.7% 0% 4%
PV: polycythemia vera; MF: myelofibrosis; AML: acute myeloid leukemia.
suringly, there were no cases of post-ET PV or acute myeloid leukemia, and the death rate was very low. However, we note a possible bias since most of the papers described particular data (e.g., thrombosis, bone marrow examinations, molecular analysis) as the main message, not reporting the parameters at diagnosis or detailed follow-up information; furthermore, we should also be cautious because of the short median follow-up of the patients included in this review (around 50 months). These factors could have led us to underestimate the rates of long-term complications. Thus, while the overall sur- vival seems long, there are no published survival curves and the median follow-up, as discussed already, is quite short for this population of subjects who would normally be expected to live a further 60-70 years, if their life expectancy is similar to that of the general population.
We noted a clear prevalence of venous thrombosis with a complete inversion of the ratio of arterial/venous throm- botic events (0.2), compared to that in cohorts of adults in whom this ratio is close to 0.67 (Online Supplementary Table S1).1 Interestingly, we observed a predominance of portal vein thrombosis and Budd-Chiari syndrome, most- ly at diagnosis, a situation similar to that in the adult pop- ulation in whom these thromboses are frequently associ- ated with MPN and induce significant morbidity and mor- tality (2 of the 3 deaths reported in this review).9 On the other hand, 83% of the arterial events occurred during the follow-up and all these events were localized in the cere- bral area. Given the age of the patients and the very low supposed rate of cardiovascular risk factors (not evaluated here as unavailable), and the different mutation profiles it will be interesting to understand the mechanism of these thromboses.
Since the ECLAP study, the prescription of low-dose aspirin is highly recommended in older patients, especially with PV, to reduce the risk of thrombosis.73 The benefit of using this drug has not been proven for either ET patients
or for very young patients. Furthermore, Alvarrez-Larran and colleagues have published a retrospective study on the use of antiplatelet drugs among young (defined as less than 60 years old) patients with ET, and found that CALR- positive patients experienced more hemorrhages when treated with aspirin.74 Effectively, given their metabolism, children are exposed to a higher risk of aspirin-related gas- trointestinal and intracranial hemorrhages. Children below 12 years old seem particularly at risk of Reye syn- drome because of the interaction between aspirin and coenzyme A reductase in mitochondria.75,76 In Reye syn- drome, gastrointestinal symptoms (nausea and vomiting) are followed by progressive encephalopathy (i.e. somno- lence) until coma and death due to multi-organ failure. Unfortunately, stopping the administration of aspirin does not automatically reverse the process. The incidence of Reye syndrome among very young patients with ET and PV is unknown and there have been no published cases in the past 12 years.
According to international guidelines, in the adult ET and PV population, the prescription of a cytoreductive drug is limited to patients who are classified as being at high risk of thrombosis based on age (recommended if >60 years or younger with a cardiovascular risk factor) or platelet count >1500x109/L or a history of thrombosis.2 For patients belonging to the low-risk group, no other drug than aspirin is recommended. Thus, in this very young population with low rates of prior thrombosis, aspirin should often have been the only therapy. However, the proportion of patients receiving cytoreductive drugs was unexpectedly high in this population (60.8%), and the rea- sons were not explained.
Given ongoing concerns about the safety of hydroxycar- bamide it seems surprising perhaps that this drug was so frequently prescribed in this population of young patients. On the other hand, the relative innocuity of hydroxycar- bamide has been proven in many cohorts of patients with
1586
haematologica | 2019; 104(8)