How to Manage Children and Young Adults with Myeloproliferative Neoplasms

Home , Polycythemia vera, Primary myelofibrosis

HOW TO MANAGEy How to manage children and young adults with myeloproliferative neoplasms

T Barbui

On the basis of my personal clinical and research experience and validated by the current literature, my approach to the management of pediatric (age o18 years) and young patients (age o40 years) with classic myeloproliferative neoplasms is presented by focusing on diagnosis, patient communication, risk stratification and therapy. The WHO-2008 diagnostic criteria are recommended, even though in children suspected with essential thrombocythemia (ET), a specific set of diagnostic features may be required. Patient communication includes information on natural history, genetic abnormalities and counseling in all women of child-bearing age. The main challenge in children and young adults with ET and polycythemia vera (PV) is to avoid recurrence of major thrombosis by selecting those patients who ultimately can benefit from cytotoxic and antithrombotic therapy without increasing the incidence of drug-induced side effects. In asymptomatic low-risk patients no therapy is prescribed while in high-risk low-dose aspirin, hydroxyurea and interferon-alpha are my first line drugs. My first decision when considering treatment of a young patient with primary myelofibrosis (PMF) or post-PV or post ET-myelofibrosis, is whether he/she qualifies for bone marrow allotransplantation. In the remaining young PMF patients palliative therapy or experimental drugs are considered.

Leukemia (2012) 26, 1452--1457; doi:10.1038/leu.2012.12 Keywords: myeloproliferative neoplasms; treatment; young people

INTRODUCTION I will discuss my approach to the management of pediatric Polycythemia vera (PV), essential thrombocythemia (ET) and (ageo18 years) and young patients (ageo40 years) with classic primary myelofibrosis (PMF) are currently classified among the MPNs focusing on the salient points as diagnosis, patient bcr/abl-negative, ‘classic’ myeloproliferative neoplasms (MPNs) and communication, risk stratification and therapy. represent a stem cell-derived clonal myeloproliferation. Hemato- poietic progenitors derived from patients with MPNs are hyper- sensitive to the stimulation of physiological growth factors such as HOW TO DIAGNOSE MPN IN CHILDREN AND YOUNG ADULTS 1 thrombopoietin or erythropoietin (EPO). Since 2005, the patho- In 2007/8, the WHO investigators proposed criteria and algorithms physiology of these diseases has advanced considerably with the for MPN diagnosis.3,4 These criteria combine genetic, clinical and discovery of an acquired mutation of JAK2 V617F in a vast majority pathological characteristics and emphasize the neoplastic nature 2 of PV patients and in almost half of those with ET and PMF. of the previously termed myeloproliferative diseases and renamed The mutation, located within the negative regulatory pseudokinase, them MPNs. or Janus homology 2 domain, causes cytokine-independent activa- tion of several biochemical pathways implicated in EPO receptor signaling. Subsequently, mutations in MPL were reported in B4% Polycythemia vera of patients with ET or PMF. The significance of JAK2 and MPL For PV diagnosis, the WHO requires the demonstration of mutations for the evolution of the MPNs and their relative roles increased hemoglobin/hematocrit levels with the presence of in determining disease phenotype as well as progression to JAK2 mutation (major criteria) and one minor criterion as well. myelofibrosis and leukemic transformation are unclear at present. In the absence of the second major criterion (JAK2 or related In this context, it should be underscored that most of the mutations), at least two of three minor supportive criteria should information in terms of diagnosis, prognosis and therapy focuses be demonstrable that are low EPO blood level, characteristic on the ‘average’ MPN patients of whom median age ranges morphological features of bone marrow biopsies and spontaneous between 60 and 65 years. On the other hand, less consistent data erythroid colonies. Contrary to previous recommendations, red are available in the groups of MPN patients who are presenting cell mass measurement is no longer required. below this median age such as pediatric and young adults (20% of In my practice, in children with elevated hemoglobin and MPN patients). This issue is now becoming more and more hematocrit (HCT) levels the diagnostic algorithm includes a important, because with the advent of automatized blood cell number of steps: the first is to exclude congenital heart diseases, counters in the past years, new cases of MPNs are diagnosed in then it is necessary to check the EPO levels. If EPO level turns out young patients with increasing frequency. to be low, primary erythrocytosis might be suspected and the This article is based on my personal clinical and research work-up is focused on the diagnosis of PV (JAK2 mutation) or experience and is validated by the currently published literature. familial and congenital polycythemia (EPO receptor gene mutations),

Hematology and Research Foundation, Ospedali Riuniti di Bergamo, Bergamo, Italy. Correspondence: Professor T Barbui, Hematology and Foundation for Research, Ospedali Riuniti di Bergamo, Largo Barozzi 1, Bergamo 24128, Italy. E-mail: [email protected] Received 10 January 2012; accepted 11 January 2012; accepted article preview online 18 January 2012; advance online publication, 7 February 2012 Myeloproliferative neoplasm vs children and young adults T Barbui 1453 particularly in cases of JAK2 or JAK2 exon-12 negativity. If EPO MPN cases are sporadic and that the genetic mutation of JAK2 is levels are normal or elevated, extrinsic influences have to be not a predisposing factor. However, familial clustering of PV, ET considered such as secondary causes of increased EPO production and PMF has been well described and patients should know that and other conditions including hemoglobin variants, von Hippel-- occasionally other members of the family may present these Lindau gene mutations and 2,3 phosphoglycerate deficiency. disorders.16,17 In accordance with the European Leukemia Net (ELN) investi- 18 Essential thrombocythemia gators, in the absence of hematological or clinical abnormalities, I do not routinely genotype for JAK2 mutations or JAK2 Diagnosis of ET requires the meeting of four criteria: first, platelet 46/1 (GGCC) haplotype the relatives of individuals with MPNs.19 count of at least 450 109/l; second, bone marrow biopsy Patients should be notified that follow-up of PV, ET and to specimens showing proliferation mainly of the megakaryocytic lesser extent early/prefibrotic PMF20 is marked by thrombo- lineage with increased numbers of enlarged, mature mega- hemorrhagic complications, constitutional symptoms, such as karyocytes and no significant increase or left-shift of neutrophil pruritus, night sweats, fatigue and a propensity to transform granulopoiesis or erythropoiesis; third, not meeting the WHO into overt myelofibrosis (10--25%), and acute leukemia ( 5%), criteria for PV, PMF, chronic myeloid leukemia (CML), myelo- o however, at different incidence concerning the disease entities. dysplastic syndromes (MDS) or other myeloid neoplasms; fourth, It has to be emphasized in detail that drugs are chosen to reduce demonstration of JAK2 or other clonal marker, or, in the absence, thrombosis and bleeding events and should be balanced in no evidence for reactive thrombocytosis. My approach in children consideration of the risks associated with their long-term use. with thrombocytosis who are negative for the JAK2 mutation Therefore, in children and young adults, cytotoxic agents will be (40--50%), is the exclusion of any infectious, rheumatological, prescribed to prevent severe vascular recurrences and it should be autoimmune or neoplastic conditions. Of note is that the WHO clarified that with exception of allotransplantation, current drug diagnostic recommendations in children suspected with ET are therapy is not able to eradicate the malignant clone. In my thought to be not adequate and a specific set of diagnostic criteria opinion, the relevance of coexisting thrombophilic factors to is required.5,6 Contrary to adults, most of children with ET present justify cytoreductive therapy in low-risk asymptomatic patients is polyclonal, rather than monoclonal hematopoiesis, the capacity to not yet well established. Thus, in the absence of familial recurrent form spontaneous colonies is present less often and the presence vascular events, I consider it not to be very helpful to test for of JAK2 mutation is significantly less frequent than in the general hereditary thrombophilic or acquired factors such as the MPN population. Therefore, the WHO criteria cannot be used for congenital deficiencies of natural anticoagulants (antithrombin, the diagnostic screening of these young patients. Diagnosis of ET protein C and protein S) and genetic mutations (factor V Leiden in children may require exclusion of hereditary manifestations and prothrombin G20210A). transmitted as hereditary character, involving genetic defects of Regarding PMF, patients should be informed about prognosis thrombopoietin receptor, thrombopoietin and MPL mutations that usually is even in the prefibrotic stages more severe expressed in both somatic and germ line cells.7 compared with PV and ET.14 The International Prognostic Scoring System (IPSS) for classical-advanced PMF uses five indepen- Primary myelofibrosis dent predictors of inferior survival (age 465 years, hemoglobin The proposed 2008 WHO criteria for PMF are applicable in children o10 g/100 ml, leukocyte count 425 109/l, circulating blasts and young adults. Bone marrow histology is essential to exclude 41% and presence of constitutional symptoms) to stratify secondary causes of myelofibrosis (neoplastic and non-neoplastic) patients into low, intermediate-1, intermediate-2 and high-risk and the prefibrotic phase of PMF that presents a different natural categories based on the presence of 0, 1, 2 or 43 risk factors, history in comparison with true ET.8 It should be considered that respectively; the corresponding median observed survivals are both the familial and idiopathic forms of PMF may be associated estimated at 135, 95, 48 and 27 months.15 On the other hand, it with congenital anomalies and chromosomal abnormalities.9 has to be tested whether this International Prognostic Scoring Del(20q) or del(13q) as well as normal karyotype are associated System may be also applicable on patients with early PMF that with a favorable prognosis, whereas most other cytogenetic infrequently present with constitutional symptoms. aberrations render a negative prognostic impact.10,11 Fewer than All women of child-bearing age should adequately be coun- 100 cases of pediatric myelofibrosis have been reported world- selled concerning the potential dangers and complications of the wide and approximately half of published cases occurred in disease during pregnancy and potential consequences for the children younger than 3 years. These latter patients are more likely child.21,22 Concerning contraception, there is currently insufficient to have Down’s syndrome, rickets or a familial (possibly autosomal evidence either to support or refute an association between recessive) form of myelofibrosis. Among older children, systemic estrogen-based hormonal treatment and thrombosis in MPNs.23 lupus erythematosus, tuberculosis and acute myeloid leukemia My suggestion is to avoid the use of estrogen-based contra- (AML), which has usually a fulminant course (survival o1 year), are ceptives in MPNs and to use alternative methods. In the event that the most common associations.12,13 reproductive therapy is indicated, patient should be informed that ovarian hyperstimulation may be associated with increased risk of thrombosis and that antithrombotic prophylaxis may be indicated. HOW TO COMMUNICATE THE DISEASE As soon as the diagnosis is established, I explain in details the natural history of the disease. The onset of the MPNs is often a very slowly advancing process and both in the WHO-defined PV HOW TO MANAGE CHILDREN and ET, disease-specific survival (loss in life expectancy) is not Polycythemia vera substantially different from that of a control population, especially PV in children and adolescents is very rare. The incidence before in younger adults.14 PMF is a more serious disease with expected the age of 25 years, accounts 1/10 000.000. On the contrary in median observed survival of about 6 years,15 whereas in prefibrotic adults, with a median age at presentation of 60 years, the myelofibrosis median survival is about 10 years.14 incidence is around 10--20 cases per 1 000 000. Owing to the rarity Information on the genetic abnormalities most commonly of MPN in children o18 years, very few studies with limited encountered in MPNs has to be explicitly discussed. The concern number of patients are available.5,24 regarding the possibility that MPNs can be heritable should be An extensive review of the literature describing the clinical addressed in this context by emphasizing that the vast majority of course and treatment modalities of 35 PV cases in children was

& 2012 Macmillan Publishers Limited Leukemia (2012) 1452 --1457 Myeloproliferative neoplasm vs children and young adults T Barbui 1454 25 recently reported. The youngest was 7 months and the oldest Table 1. Risk-adapted therapy in young adults with PV and ET 17.5 years old (median age 11 years). Budd-Chiari syndrome was the prevalent complication and it is recommended to take this Risk stratification: high-risk patients are defined by previous life event into account even though diagnosis may not be clinically threatening major thrombotic or severe hemorrhagic complication. obvious. In fact, concurrent hypersplenism, occult gastrointestinal Low-risk patients PV: target hematocrit below 45% plus aspirin 100 mg/day by phlebotomy. bleeding or hemodilution can mask blood count abnormalities. ET: aspirin 100 mg/day if microcirculatory symptoms (that is, Of significant diagnostic help is the determination of JAK2 mutation, erythromelalgia) or concomitant cardiovascular risk factors. which is found in about 45% of adult patients with Budd-Chiari syndrome and in 34% with portal vein thrombosis. However, High-risk patients as above, plus myelosuppressive therapy: it should not be overlooked that negativity of this mutational hydroxyurea as first choice; PEG-interferon in special situations status does not exclude MPDs. Other described complications (that is, pregnancy); in ET patients intolerant or refractory to hydroxyurea PEG-interferon or Anagrelide. in children include stroke, cerebral vein thrombosis and severe hemorrhage.26 Abbreviations: ET, essential thrombocythemia; PV, polycythemia vera.

Essential thrombocythemia median observed survival of 12.6 years for this type of ET is also rare in children 18 years and no sufficient data to o treatment.34 However, some experts have cast doubts on these recommend treatment are available, especially as in the current findings, noting that up to 50% of patients treated with literature the WHO criteria for ET were not stringently applied.8,27 phlebotomy alone had to switch to other therapies by the fifth Moreover, no evidence for a risk stratification particularly useful to year.35 Moreover, in the ECLAP (European Collaborative Low-dose guide therapeutic decisions is available and there are no indications Aspirin in Polycythemia) Study, multivariate analysis considering on how to monitor cytoreductive therapy. In adults, ELN recently all the confounders failed to show any correlation between HCT reported criteria for monitoring therapy.28 In particular, It has been values in the range from 40 to 50% and incidences of throm- emphasized that all studies in PV and ET failed to show a clear bosis.36 This uncertainty prompted Italian investigators to activate association between platelet count and thrombotic events. Rather, a prospective, multicenter, randomized clinical study (CYTO-PV) functional and structural platelet abnormalities are of more addressing the issue of the optimal target of cytoreduction in PV relevance. Paradoxically, very high platelet counts can induce a (EudraCT 2007-006694-91). While waiting for the results of this bleeding tendency, mainly due to an acquired Von Willebrand’s trial, my practice is to follow ELN recommendations and to disease.29 I fully agree with ELN recommendations that cytoreduc- perform phlebotomy withdrawing 250 to 500 ml of blood daily or tive drugs in children with PV and ET should be prescribed as a last every other day until a HCT value between 40 and 45% is possibility and I suggest that, in the rare cases that need treatment, obtained. Once normalization of the HCT has been obtained, the selection of a cytotoxic or cytoreductive agent should be done blood counts at regular intervals (every 4 to 8 weeks) will establish after discussion with the child and parents. Hydroxyurea (HU) and the frequency of future phlebotomies. Supplemental iron therapy interferon-alpha (IFN-a) are first line therapy at any age including should not be given as iron depletion may impose a constrain to children and young adults. The long-term leukemogenicity of HU erythropoiesis. may be a special concern, although none of the pediatric patients The use of low-dose ASA is considered the second mainstay for treated with this agent have yet undergone malignant transforma- patients with PV. This statement is based on the ECLAP double tion.27,30 Adverse effects of IFN-a such as flu-like syndrome, blind placebo controlled randomised clinical trial, in which a neuropsychiatric symptoms and autoimmune phenomena can be benefit of 100 mg ASA in reducing major thrombosis in PV was particularly dangerous for children. Anagrelide is not licensed as demonstrated.37 In this trial, after a follow-up of about 3 years, first-line therapy for ET in Europe and the ELN group recommends there was a statistically significant 59% reduction of major throm- this drug as second line therapy.18 The use of aspirin (ASA) in bosis (both arterial and venous) without a significant increase in children less than 12 years of age should be prescribed with caution hemorrhagic complications in the ASA group. because of the risk of Reye’s syndrome. Overall, according to ELN Contrary to PV, there are many uncertainties to indicate ASA as experts, there are insufficient data to recommend a specific agent primary prophylaxis in low-risk ET. A recent publication questions in children, and the choice should be individually tailored. the benefit of low-dose ASA in this group of patients.38 These investigators concluded that antiplatelet therapy may be asso- Primary myelofibrosis ciated with a reduction of the incidence of venous thrombosis in Natural history of PMF in children seems different from the adult JAK2-positive patients and that ASA may decrease the frequency variant. Variable outcomes with either fulminant course rapidly of arterial thrombotic events in patients with associated cardio- evolving to acute leukemia or relative indolent courses have been vascular risk factors. In the remaining low-risk patients (JAK2 described. A thorough search for an underlying disease should be negative and no risk factors), the net benefit of ASA in terms of made in order to exclude secondary myelofibrosis.31 --33 The only reduction of thrombosis associated with no increase in bleeding effective therapy in acute leukemia phase lies in allogeneic bone was not favorable. Interestingly, the bleeding risk of ASA has marrow transplantation. Indolent disease may respond to corti- been reported significantly higher in thrombocythemic patients costeroid.31 --33 presenting with a bone marrow morphology of early PMF (12% of bleeders) as opposed to those with bone marrow pictures typical of true ET (6% of bleeders). In this series of more than 1000 strictly WHAT TO DO IN ASYMPTOMATIC YOUNG ADULT PATIENTS the WHO-defined patients, the crucial role of leukocytosis, in WITH PV AND ET addition to thrombocytosis, has been demonstrated by correcting The main challenge in young adults with classic MPNs is to select with meaningful confounders.39 those patients who ultimately can benefit from a therapy without In my daily routine I prescribe low-dose ASA (75--100 mg) in increasing the incidence of life threatening side effects of the long low-risk patients with erythromelalgia and limit the long-term use use of cytotoxic drugs (Table 1). of this drug in young ET asymptomatic cases in which serious Cornerstone of treatment for PV is represented by phlebotomy. hemorrhagic problems can occur at any age including children.26 The immediate goal of this practice is to reduce hyperviscosity by Thus, I carefully assess the individual thrombotic and hemorrh- decreasing the venous HCT level to less than 45%. This strategy is agic risk by looking in particular, at previous conditions with a based on PV Study Group investigations that reported the best high bleeding risk (that is, gastric ulcers or esophageal varices

Leukemia (2012) 1452 --1457 & 2012 Macmillan Publishers Limited Myeloproliferative neoplasm vs children and young adults T Barbui 1455 secondary to splanchnic vein thrombosis and portal hypertension), combination with clopidogrel antiplatelet drugs are used accord- and in patients with extreme thrombocytosis I require that ing to current guideline. ristocetin cofactor activity should be 430%. In asymptomatic In regard to cytoreductive drugs, HU is my first choice when a ET and PV young patients a safer alternative is an aggressive young patient with PV or ET has experienced a life-threatening management of modifiable thrombotic risk factors, such as major thrombotic event (stroke, myocardial infarction, peripheral diabetes, hypertension, obesity and metabolic syndrome, and in arterial thrombosis, deep-vein thrombosis, including cerebral particular, patients should be requested to stop smoking. In line thrombosis and Budd-Chiari syndrome). The latter applies also with other clinicians, in otherwise low-risk patients carrying to patients with poor tolerance to, or high need for phlebotomy, well-controlled cardiovascular risk factors, I do not use cytotor- symptomatic or progressive splenomegaly and severe disease eductive drugs.40 related symptoms, platelet counts greater than 1.5 109/l or More recently, JAK2 mutation and leukocytosis have been progressive leukocytosis. The starting dose of HU is 15--20 mg/kg/ recognized as independent predictors of major thrombosis, day until response is obtained. To keep the response, a particularly in low-risk ET patients.41 However, these novel maintenance dose is administered without reducing white blood biomarkers might be incorporated in the risk classification, cell count values below 2500 109/l and supplemental phlebotomy possibly allowing better definition of the low-risk group, once should be performed if needed in PV patients. My practice is to they have been eventually validated in prospective studies. control the complete hemogram in every 2 weeks during the first 2 months, then every month, and, in steady state responding patients, every 3 months. It is unclear if ELN criteria for response WHAT TO DO IN YOUNG PATIENTS WITH THROMBOSIS are valuable in daily routine of these patients. In a recent paper Although it is generally recognized that young age identifies the rate of thrombosis was reported to be significantly reduced by patients at lower thrombotic risk, the actuarial rate of major HU, independently on the achievement of complete or partial thrombosis is higher than in general population of the same age. response.48 Some patients may be reluctant to use HU because of Therefore, a proportion of PV and ET patients with age o40 years fear regarding its possible leukemogenicity, but they should be needs to receive cytoreductive drugs. Limited information is informed that to date, no robust data supporting such hypothesis available regarding results of therapy that varies enormously. In in either ET or PV is available. In a nationwide cohort of 11 039 the reported series of young adults with PV and ET, the most used MPN patients, a nested case--control study including 162 AML drugs were ASA, phlebotomy, HU, IFN-a, and also alkylating patients and 242 matched controls showed that the risk of AML agents as pipobroman, busulfan, melphalan. In one study the was similar to that of controls and not significantly increased by standardized mortality ratio in 70 PV patients younger than 50 HU given as sole therapy.49 Remarkably, 25% of patients who years was 5.3%, indicating a life expectancy markedly lower than developed leukemia were never exposed to cytotoxic therapy the control population.42 Causes of death in this study were supporting the notion of a major role for intrinsic MPN-related mainly owing to an excess of hematological transformation in factors in overall leukemogenesis. However, in a recent long-term AML or post-PV myelofibrosis. These latter events occurred after 9 analysis of a randomized clinical trial comparing HU with years of follow-up and were likely due to long-term exposure of pipobroman in 292 PV patients (median follow-up 16.3 years), cytotoxic drugs that were pipobroman in 73% and HU in 9%. Only median survival was 20.3 years in the HU arm and 15.4% in 18% of this young people received phlebotomy as the sole pipobroman arm. Cumulative incidence of AML/MDS at 10, 15 and therapy. In contrast, in a cohort of 36 PV patients, median age of 20 years was 6.6%, 16.5% and 24% in the HU and 13%, 34% and 37 years (range 19--45 years), treated exclusively with phlebot- 52% in the pipobroman arm, respectively, (P ¼ 0.004).50 Importantly, omy, ASA and HU, no secondary leukemia or cancer were HU-associated leukemia could be a relatively frequent event when observed during a follow-up of 14 years and the incidence of given before or after alkylating agents or radiophosphorus.51 thrombosis was comparable to other series.43 Major side effects of HU include neutropenia, macrocytic anemia The largest prospective evaluation of risk factors for survival, and muco-cutaneuos toxicity, most frequently presenting as oral incidence of thrombosis and hematological transformation is the and leg ulcers and skin lesions. In a recent survey the rate of these ECLAP observational cohort study.44 Patients younger than 65 events was less than 5%.52 years in the ECLAP Study had the lowest rate of thrombosis As suggested by the ELN, an alternative option as first line (2.5% patients per year), while with age older than 65 years and therapy in high-risk PV and ET is IFN-a.18 This drug is known to be a positive history of thrombosis, the corresponding rate ranged non-leukemogenic, but it is associated with side effects leading to from 6 to 10% patients per year. Of note were a consistent withdrawn in about 20% of patients. Pegylated forms of IFN-a association between age 465 years and risk of leukemia and allow weekly administration, potentially improving compliance between duration of disease with risk of overt myelofibrosis. and possibly providing more effective therapy. In PV complete In ET patients younger than 40 years, thrombosis varies from 10 responses according to ELN criteria both in PV and ET were to 16% at 10 years and the development of leukemia or overt reached in a great proportion of cases and no thrombo- myelofibrosis is rarely reported.45,46 hemorrhagic complications were registered during follow-up. Antithrombotic drugs and the use of cytoreductive therapy to Interestingly, the malignant clone tested in PV, as quantitated control the myeloproliferative process are the mainstay of by the percentage of the mutated JAK2V617F, was reduced.53,54 secondary prophylaxis. However, whether this drug is more efficacious than HU in Concerning prophylaxis with antithrombotic drugs, I suggest to reducing the rate of thrombosis remains to be demonstrated. The define whether the thrombotic event has been provoked by some evidence to indicate IFN-a as the drug of choice in any ET and PV triggers or has occurred without demonstrable possible causes. patient younger than 60 years and in hypercellular/early PMF55 is In patients with unprovoked vein thrombosis including splanchnic not yet supported by clinical trials. There is great expectation from vein thrombosis and Budd-Chiari syndrome, I prescribe long-term an ongoing clinical trial that compares head to head HU (standard use of oral anticoagulants. This is supported by a large series of treatment) and IFN-a (experimental drug). My current practice is to patients showing a 68% risk reduction of recurrent thrombosis.47 prescribe IFN-a in very selected young patients resistant or In contrast, in provoked leg vein thrombosis, warfarin prophylaxis, intolerant to HU56 and in special situations such as pregnancy. along with cytoreductive drugs, may last 1 year. Antiplatelet In regard to anagrelide, the UK-PT1 Study has compared the agents given as maintenance showed to lead to a 58% risk drug with HU.57 Patients in the anagrelide arm showed an reduction of recurrence.47 In patients with coronary syndromes or increased rate of arterial thrombosis, major bleeding and any other peripheral arterial thrombotic event, ASA alone or in myelofibrotic transformation, but a decreased incidence of venous

& 2012 Macmillan Publishers Limited Leukemia (2012) 1452 --1457 Myeloproliferative neoplasm vs children and young adults T Barbui 1456 Table 2. PMF or post-PV/ET myelofibrosis in young patients MY ADVICE TO YOUNG PATIENTS IN RELATION TO CLINICAL TRIALS WITH JAK2 INHIBITORS? Risk stratification: The efficacy of novel JAK2 inhibitors seems promising,63,64 so that In low risk and intermediate I, I suggest palliative therapy to correct cytopenias, symptomatic splenomegaly and I encourage PMF and PV/ET patients with symptomatic refractory constitutional symptoms. splenomegaly and severe constitutional symptoms to participate in clinical trials. However, I underscore that there is no evidence In intermediate II or high risk, as well as in those with either that these novel drugs can eradicate or modify the natural history red blood cell transfusion need or unfavorable cytogenetic of disease. I believe that widespread use of JAK inhibitors in PV or abnormalities, I indicate allogeneic stem-cell bone marrow ET should be limited to selected cases as safety of their long-term transplantation. use remains uncertain. Abbreviations: ET, essential thrombocythemia; PMF, primary myelofibrosis; PV, polycythemia vera. CONFLICT OF INTEREST The author declares no conflict of interest. thrombosis compared with HU. In addition, anagrelide was more poorly tolerated than HU and presented significantly greater rates of cardiovascular, gastrointestinal, neurological and consti- REFERENCES tutional side effects. Transformation to AML was comparable 1 Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med 2006; 355: between the two arms (four patients in the anagrelide versus six in 2452 --2466. the HU arm), although the small number of transformations and 2 Tefferi A, Vainchenker W. 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