Page 93 - 2019_08-Haematologica-web

Very young patients with ET and PV
of these treatments modifying the genetic environment. Similarly, there are no data about the occurrence of other diseases which might be significant during the MPN, such as autoimmune, cardiac or inflammatory diseases.
Surprisingly, only one study reported data on pregnan- cy: six young women experienced 15 pregnancies which resulted in nine healthy babies and six miscarriages (40%). This latter percentage is much higher than in the latest cohorts of young adult women with MPN, but should be interpreted with caution.69
Survival and death
The mortality rate seemed low (3 cases, 0.65%): two patients died after the occurrence of Budd-Chiari syn- drome despite adequate management, highlighting the fact that this event has a very high risk of morbidity and mortality, and one patient died of pneumonia that devel- oped following a stroke. It should be noted that informa- tion about death was probably subject to reporting bias, and the median follow-up was short.
Treatments
It is not clear in the published literature whether adult or pediatric staff made decisions on these patients nor what age cut-off, if any, might have been used to decide thera- py. Also, it is not clear what strategy for venesection was used for these young patients. In our review, we observed a relatively high frequency of prescription of “antithrom- botic” drugs (51.2% in ET and 62.7% in PV patients). The description of the treatments is provided in Table 2. The rate of prescription of aspirin was higher in ET patients than in PV patients (43.3% vs. 32%) whereas, PV patients were more frequently treated with vitamin K antagonists or low molecular weight heparin (22.1% vs. 8.8% in ET patients, respectively). These differences were probably due to the rate of thrombosis observed among PV patients (mostly Budd-Chiari syndrome). It is difficult to know whether these medications could have been responsible for the occurrence of the hemorrhages reported during the follow-up.
As expected in this population, there was a very low number of high-risk patients (5.7%) based on a history of thrombosis (data on the number of patients with platelet counts over 1500x109/L were not available). Despite the low percentage of high-risk patients, most of the subjects were treated with a cytoreductive drug or related therapy (60.8%). The description of the treatments is available in Table 2. The reasons for prescribing these treatments were not explained.
Most of the ET patients received what would be regarded as non-leukemogenic drugs, such as anagrelide (20.9%) or interferon (4.6%). Most of the PV patients were treated with phlebotomy (45.2% plus 6.5% erythropheresis), but a sub- stantial proportion of them also received hydroxycarbamide (25.8%). The use of interferon seemed quite uncommon (9.7%), even for the pegylated formulation (one-third of the interferon-treated population). Interestingly, ruxolitinib (a JAK1 and JAK2 inhibitor) was prescribed in only one explicit case (three other cases were cited in a phase II trial, but with- out available data). Surprisingly, 16.1% of the PV patients were treated with melphalan, busulfan, radioactive phos- phorus or allogeneic stem cell transplantation: most of these patients were treated in the 1980s and are represented by one cohort of patients.9
Discussion
We have described here the clinical and biological parameters of very young patients (aged <20 years at diag- nosis of ET or PV) whose data have been published since 2005. Interestingly in this cohort of over 470 cases the clear majority (84%) had ET, which remains unexplained. Another interesting fact is that only a few cases were dis- covered because of the presence of symptoms (mostly headaches or migraines) or due to a thrombotic event. Importantly, the occurrence of thrombosis, hemorrhage or evolution of disease seemed quite rare.
We found that a comprehensive, or total, description of all the published cases is almost impossible. As a possible bias, some cases could also have been published in large series of young patients (under 40 years old) and we were unable to extract data specifically pertinent to our age group of interest. Furthermore, almost all the information was reported in a global way, i.e. not for individual cases and, as shown, a lot of information concerning each spe- cific data point was lacking (the amount of missing data varied from 10.7% to 74.7%), illustrating the difficulties of our approach.
Concerning the diagnosis of MPN, bone marrow biopsy is generally regarded as essential, as illustrated recently by Putti and colleagues who demonstrated, in a descriptive study of biopsies from very young ET patients, that only 16 (76%) of the 21 bone marrow biopsies were compati- ble with a diagnosis of ET. Furthermore, they also con- firmed the usefulness of this examination by identifying one case of PV, three cases of prefibrotic myelofibrosis and even one non-MPN case.19 There is no such study on bone marrow biopsies among PV patients. It should be noted that there is no evidence to tell us that the management or the outcome of very young patients with prefibrotic myelofibrosis needs to be different from that of ET patients, so this remains a matter for further evaluation. In fact, it is interesting to speculate that had more biopsies been performed, the large excess of ET diagnoses may have changed.
Surprisingly, a large proportion of this cohort of young patients with MPN was found to be negative for all com- mon driver mutations. For the patients with ET, this pro- portion was 57%, which is higher than that reported in adult series (between 10% to 20%).70,71 About three-quar- ters of the patients with PV were also negative for any JAK2 mutations, with the proportion varying between 63% and 75% depending on the cohorts.9,13,24 This raises the question of whether these were real cases of MPN. As many of them were old cases, were they misdiagnosed MPN or real MPN but with different mechanisms of pro- liferation than the JAK2 pathway? This suggests a poten- tial place for next-generation sequencing in the population of patients negative for driver mutations. A new evalua- tion with recent cases will be useful to confirm or refute this observation.
With regards to complications, we observed a low rate of both thrombosis and transformation (4.7% and 1.9%, respectively), which is in accordance with the numbers observed in the young population in general (people aged less than 40 years old) (Table 3) but, far less than in old people.5-8,67,68,72 Concerning the thrombotic risk, the classifi- cation of this population as a low- or very low-risk cate- gory seems appropriate (based on their age and history of thrombosis).2 Concerning the risk of transformation, reas-
haematologica | 2019; 104(8)
1585