Myeloproliferative Neoplasms in Children, Adolescents, and Young Adults

Abstract

Purpose of Review:

Myeloproliferative neoplasms are traditionally seen in older adults, making them poorly understood in younger patients. Clinical presentation, genetic landscape, outcomes, and best management practices are inadequately described in this group. Over the past decade, more research has focused on younger patients, and this paper seeks to review and describe the current status of the field.

Recent Findings:

A recent review analyzed the available pediatric MPN literature and highlighted the paucity of published data. Pediatric patients showed lower rates of the common mutations found in adults, thrombotic events, and disease transformation to myelofibrosis and acute leukemia. A number of centers have recently shared their experience with young adult patients. Better survival outcomes were confirmed for young adult patients compared to older patients.

Summary:

There is still much to learn about myeloproliferative neoplasms in pediatric and young adult patients, but currently available data showing better outcomes is reassuring.

Introduction

The classical myeloproliferative neoplasms (MPNs) include the BCR-ABL1 negative disorders essential thrombocytosis (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). These diseases are largely due to somatic driver mutations in the JAK2, MPL, or CALR genes [1–3], and other somatic mutations have been found (in genes such as ASXL1 and EZH2), which affect prognosis [4]. PV is almost exclusively caused by the JAK2V617F mutation, with a smaller percentage harboring mutations in JAK2 exon 12/13. ET is caused by JAK2V617F in 50–60% of patients, with MPL and CALR mutations accounting for 3–5% and 25–30% of cases, respectively. 10–15% of ET patients are “triple negative” for these common mutations. In PMF, JAK2V617F accounts for 50–60% of cases, MPL mutations for 5–10%, and CALR mutations for 3035% of cases. Approximately 10% of PMF patients are triple negative as well [4]. These disorders can predispose to significant hemostatic complications and a variety of clinical symptoms. PV and ET can transform to secondary myelofibrosis, and all can transform to acute myeloid leukemia (AML).

These rare, clonal marrow disorders were traditionally diseases of older patients, with median ages in their early 60’s. Young adult patients (traditionally those aged 40 years or below) and pediatric aged patients (ranging from 0–18 or 21 years, depending on the center) represent a small portion of MPNs [5]. Recent literature has estimated that the global incidence of MPNs in pediatric patients is approximately 0.82 per 100000 patients annually [6], while it has been estimated that MPNs are 100 times more common in adults than children [7]. However, with the advent of automated blood counters and more frequent routine labs being performed, more cases of MPNs are being diagnosed in younger patients [5].

Despite the rising number of new diagnoses, many of the recent advances made in the MPN field have not benefited younger patients. Until recently, large descriptive patient cohorts did not focus on younger patients, but there are now a number of groups that have described their young adult cohorts. Diagnostic criteria utilized to help classify patients and provide necessary information for counseling and risk stratification were not designed with children in mind. Clinical trials for a variety of different compounds, including targeted therapies, have greatly broadened the potential therapeutic landscape for MPNs, but these studies and treatments have not been available to patients under 18 years old. All these added together make the workup and care of a young patient with an MPN a challenge. This paper will review the current literature on MPNs in children, adolescents, and young adults, and raise questions for the field. Pediatric studies will be those focused on patients under 21 years old (including children and adolescents). The NCI describes the adolescent and young adult, or “AYA”, population as people between 15 and 39 years old, and for this review, studies largely focused on adults under the age of 40 (even if they include small groups of older teenagers or adults aged 40–45) will be considered young adult studies. Table 1 summarizes some key features of the pediatric and young adult cohorts to be discussed.

Table 1.

Summary of Pediatric and Young Adult Studies

Pediatric Studies	DeLario, et al	Ianotto, et al		An, et al
	PMF (n=19)	ET (n=396)	PV (n=75)	PMF (n=14)
Median age (years)	1.2	9.3	12	13.5
JAK2V617F mutation n (%)	0/12 (0)	n/a of 206 (31)	n/a of 55 (24)	0
MPL mutation n (%)	0/6 (0)	n/a of 206 (2)	n/a	0
CALR mutation n (%)	n/a	n/a of 206 (10)	n/a	7 (50)
Splenomegaly present n (%)	12 (63)	129 (55)	9 (15)	3 (21)
Thrombosis pre/at diagnosis n (%)	n/a	16 (4)	11 (15)	n/a
Hemorrhage pre/at diagnosis n(%)	n/a	4 (1)	3 (4)	n/a
Thrombosis after diagnosis n (%)	n/a	15 (4)	7 (9)	n/a
Hemorrhage after diagnosis n (%)	n/a	19 (5)	3 (4)	n/a
Fibrotic Transformation n (%)	n/a	7 (2)	2 (3)	n/a
Leukemic Transformation n (%)	0	0	0	6 (43)
Death n (%)	8 (42)	0	3 (4)	7 (50)

Young Adult Studies	Boddu, et al			Szuber, et al
	ET (n=105)	PV (n=43)	PMF (n=37)	ET (n=219)	PV (n=79)	PMF (n=63)
Median age (years)	25	28	33	32	32	37
JAK2V617F mutation n (%)	31/59 (53)	30/33 (92)	9/26 (35)	62 (48)	73 (100)	17 (39)
MPL mutation n (%)	n/a	n/a	n/a	1 (1)	0 (0)	3 (7)
CALR mutation n (%)	n/a	n/a	n/a	45 (35)	0 (0)	21 (48)
Splenomegaly present n (%)	6 (6)	13 (30)	18 (42)	61 (28)	43 (57)	40 (68)
Thrombosis pre/at diagnosis n (%)	6 (6)	6 (14)	3 (8)	28 (13)	21 (27)	10 (16)
Hemorrhage pre/at diagnosis n(%)	5 (5)	2 (5)	1 (3)%	n/a	n/a	n/a
Thrombosis after diagnosis n (%)	2 (2)	1 (2)	1 (3)%	36 (16)	21 (27)	3 (5)
Hemorrhage after diagnosis n (%)	2 (2)	2 (5)	0 (0)	n/a	n/a	n/a
Fibrotic Transformation n (%)	0	0 (0)	n/a	36 (16)	17 (22)	n/a
Leukemic Transformation n (%)	2 (2)	0 (0)	1 (1)	5 (2)	3 (4)	6 (10)
Death n (%)	8 (8)	0 (0)	4 (11)	13 (16)	13 (16)	16 (25)

	Barzilai, et al			Palandri, et al	Stein, et al.
	ET (n=54)	PV (n=37)	PMF (n=15)	ET (n=197)	PV (n=120)
Median age (years)	31	38	31	34	36.5
JAK2V617F mutation n (%)	35/47 (75)	31/34 (91)	9/15 (60)	124 (63)	108 (98)
MPL mutation n (%)	n/a	n/a	n/a	3 (2)	n/a
CALR mutation n (%)	n/a	n/a	n/a	47 (24)	n/a
Splenomegaly present n (%)	n/a	n/a	n/a	33 (17)	60 (51)
Thrombosis pre/at diagnosis n (%)	n/a	n/a	n/a	n/a	n/a
Hemorrhage pre/at diagnosis n (%)	n/a	n/a	n/a	n/a	n/a
Thrombosis after diagnosis n (%)	n/a	n/a	n/a	22 (10)	n/a
Hemorrhage after diagnosis n (%)	n/a	n/a	n/a	10 (5)	n/a
Fibrotic Transformation n (%)	8 (15)	4 (11)	n/a	11 (6)	18 (15)
Leukemic Transformation n (%)	0 (0)	0 (0)	2 (13)	1 (0.01)	2 (2)
Death n (%)	n/a	n/a	n/a	n/a	9 (8)

Pediatric MPN

Genetics and diagnosis

The genetic lesions driving disease pathogenesis in pediatric MPNs are not well defined as they are in adults. Few groups have reported on the frequency of known somatic mutations in pediatric MPNs, and reports of germline mutations are rare. A systematic review of the pediatric literature by Ianotto, et al. [6] included 396 ET and 75 PV patients less than 20 years old. Of 55 PV patients reported with full JAK2 testing, 24% were JAK2V617F-positive and 2% were JAK2 exon 12 mutation-positive, which is drastically lower than what is seen in adult PV patients. The authors recognized how unexpected this was, and appropriately raised the issue of whether many children were being misdiagnosed as PV instead of an alternative form of polycythemia [6]. Among the ET cohort with comprehensive MPN mutation assessment, 31% were positive for JAK2V617F, 10% had CALR mutations, and 2% had MPL mutations. 57% of this ET cohort was triple negative, which is also higher than what is reported in the adult literature [6]. Detailed bone marrow reports were not available for many of the patients in the studies this review included, further bringing into question whether all patients truly had an MPN.

Primary myelofibrosis is exceedingly rare in children and there are only a small number of cases described. One retrospective case series from a large US children’s hospital identified 19 children over a 27-year period who had primary myelofibrosis (children with obvious secondary fibrosis were excluded). 17 subjects were evaluated for JAK2V617F, and 6 for MPLW515L. All samples tested were negative for these mutations [8]. Another larger case series from China identified 14 patients over a 6year period with PMF. Sequencing of bone marrow mononuclear cells in all 14 patients showed no JAK2V617F or MPLW515K/L mutations, and 7 of the patients were found to have a CALR type 2 mutation [9].

Making the correct diagnosis of MPN type can be important for counseling patients on prognosis and making treatment recommendations. A challenge faced by pediatric providers is that the world health organization (WHO) diagnostic criteria for MPNs were developed with adults in mind. The PV criteria, for example, require either a hemoglobin (Hb) or hematocrit (Hct) above a certain cutoff, or an increased red cell mass. The numeric cutoffs are based on adult normal ranges, so there may be a child with an abnormally elevated Hb for age who would not meet this criterion, and red cell mass testing is virtually never performed in pediatrics. While the recent WHO revisions for the diagnosis of PV, ET, and PMF do not absolutely require the presence of an identified clonal driver mutation, they are included among the major criteria for each of these disorders [10]. Bone marrow findings classically seen in MPNs may be seen in children [11,12], and it is important that children undergo a bone marrow biopsy (including assessment of cellularity and morphology, and staining for reticulin fibrosis) as part of their work-up.

An example of this is a case of a 4-year-old boy, who was referred to our program for thrombocytosis after being found to have a JAK2 mutation. Upon review of his prior labs, it was noted that he also had persistent leukocytosis and a Hb and red blood cell (RBC) count that were high for age. His serum erythropoietin level was very low at 1 mU/mL, and his bone marrow exam was consistent with PV, showing hypercellularity, absence of storage iron, and pleomorphic megakaryocytes. While he did not meet the WHO criteria for PV, his overall picture fit a diagnosis of PV, so he was given a diagnosis of MPN-unclassified (MPN-U) [12]. Our group published proposed alternative criteria for PV and ET in children, with PV criteria including Hb or RBC count above the 97.5^th percentile for age, and ET criteria giving the absence of reactive causes of thrombocytosis equal weight to identification of a known driver mutation (given high rates of triple negative disease) [12]. It is important to recognize these differences when making a diagnosis in pediatric patients. Table 2 shows our process for working up a child for an MPN.

Table 2.

Proposed work-up for a child being evaluated for a classical MPN

Family history

Personal medical history

Review of systems

Physical exam

Labs:

• CBC with differential

• Hepatic function panel

• Erythropoietin level

• LDH

• Iron/Ferritin/TIBC

• von Willebrand panel and multimers*

Bone marrow:

• Aspirate for flow cytometry

• Biopsy

• assess iron stores

• assess cellularity

• assess morphology

• assess for fibrosis

Genetic testing:

JAK2

MPL**

CALR**

Can consider broader myeloid gene panel if triple negative

If a patient does not seem to clearly fit an MPN diagnosis, care must be taken to rule out other disorders that could lead to secondary polycythemia, thrombocytosis, or myelofibrosis (such as infectious, inflammatory, or congenital disorders)

CBC=complete blood count, LDH=lactate dehydrogenase, TIBC=total iron binding capacity

^*acquired von Willebrand’s disease generally occurs with extreme thrombocytosis, we generally perform this test in patients with platelet counts >1000×10⁹/L or with bleeding symptoms

^**If JAK2 mutation is identified, testing for CALR and MPL mutations in ET, PMF, or pre-PMF patients is not indicated.

Symptomatology and outcomes

Symptoms among children and adolescents with MPNs are rather variable. Some pediatric patients are completely asymptomatic, while others experience a variety of debilitating symptoms, and it is unclear whether they are always attributable to the MPN or to another underlying issue. Recent data showed that almost half of children with ET and PV were asymptomatic at the time of their diagnosis. Of children who do report symptoms, headaches, abdominal pain, and bone or limb pain are common [6]. Fatigue, erythromelalgia, and itching occur as well. Some children with MPNs have also experienced learning issues and challenges with concentration. Splenomegaly has been reported in all the classical MPNs in children [6,8].

Hemostatic complications and disease transformation are the most unwanted complications of MPNs. At the time of diagnosis, thrombosis occurred in 15% of PV and 4% of ET in pediatric patients, which is lower than rates in adults [13]. After diagnosis, 9% of children with PV and 4% with ET developed a thrombosis; rates of 3% in PV and 2% in ET are reported per patient-year in adults [13]. Budd-chiari syndrome was the most common thrombotic event reported in pediatric patients, and largely occurred in females [6]. Bleeding at diagnosis occurred in 1% of pediatric ET and 4% of pediatric PV patients, while 5% of ET and 4% of PV patients experienced serious bleeding after diagnosis [6]. Rates of bleeding at, and after, diagnosis in adults with MPNs is higher [13].

Disease progression is extremely rare in pediatrics. Around 2% and 3% of pediatric ET and PV respectively have been reported to transform to myelofibrosis [6], and as we learn more about the nuances of pediatric MPN diagnosis, we may find that some patients initially categorized as ET actually had pre-PMF at diagnosis, changing the meaning of transformation to overt PMF. Transformation to acute leukemia is exceedingly rare in pediatric MPNs. No leukemic transformation was identified in the review in PV or ET patients [6], or in one case series of pediatric PMF [8]. A recent abstract presentation reported 2 patients out of 47 (one with PV, one with ET) who developed leukemia, but no details were given (except that the PV patient developed leukemia 11 years after diagnosis, which might imply it occurred in young adulthood, given the median age reported) [14]. Another study showed surprisingly high rates of transformation in its PMF cohort, with almost half of the 14 patients transforming to AML. Interestingly, two-thirds of those who did develop AML were triple negative, and were also negative for mutations in genes associated with leukemic transformation, such as ASXL1, IDH2, and SRSF2 [4,15]. This is much higher than the transformation rate in adults during the first 10 years of disease [16], making this extremely unexpected, especially given their lack of identifiable genetic mutations, and it is not clear that this can be extrapolated to the broader pediatric MPN community.

Studies in the review reported no deaths in ET patients. Three children with PV died, all related to complications arising around vascular events [6]. In both PMF cohorts, death occurred in around 50% of patients (in one cohort, 4 of those children had undergone transplant, and in the other cohort, 6 of 7 children who died had transformed to AML) [8,9]. The question of whether someone who developed an MPN in childhood is more likely to develop AML as a young adult has not yet been answered and requires longer, prospective study.

Management

There are consensus guidelines for the management of MPNs in adults, utilizing risk stratifications and treatment algorithms. This is not the case for pediatrics, and there are no data that risk stratifications or scoring systems used in adults are applicable to children. There are very few papers discussing treatment of pediatric patients. In the limited available literature, most authors agree that children with MPNs who are fully asymptomatic should not receive cytoreductive medications, and our group does not prescribe cytoreduction to asymptomatic patients. On the opposite end of the spectrum, children who have had thrombosis or severe hemorrhage should receive cytoreductive agents [5,17,18]. Phlebotomy is regularly used in children with PV, although the blood count goals are not defined for children, and recommendations for both Hct < 45% and Hct < 48% have been proposed [5,17]. Low-dose aspirin is often used in children who do not have extreme thrombocytosis or acquired von Willebrand’s disease, and can be helpful for microvascular symptoms [16–18]. While avoiding cytoreduction in children is preferred if possible [5,17–19], when symptoms are persistent or severe and do not respond to initial therapies, cytoreduction is appropriate [17,18]. Certainly, for more severe cases, such as PMF, hematopoietic stem cell transplant has been recommended and successfully used to cure the disease [5,8]. Some challenging questions remain unanswered, including a) what cytoreductive agents are relatively safe and effective for use in children, b) given the importance of iron for normal development, how concerning is iron deficiency in young children with PV, and c) is there a platelet count threshold that is “too high” for children with ET.

There are no cytoreductive agents approved for use in pediatric MPNs, but there are reports of use of hydroxyurea (HU), interferon-α (IFN), anagrelide, and rarely, ruxolitinib, being used for treatment in pediatric MPN patients. HU and IFN are front-line agents in adult MPN patients, and pediatricians have more experience in general using HU because of its role in treating children with sickle cell disease. The question of the leukemogenicity of HU remains controversial, and some experts now suggest using IFN instead of HU as front-line therapy in younger patients [20,21], and there are no good data that using HU in children with MPNs increases risk of leukemic transformation. IFN has been shown to have significant disease modifying effects in adult studies, reducing mutation allele burden and possibly preventing or even reversing fibrosis, and this cannot be said about HU [22,23]. Major side effects of IFN include the potential to unmask autoimmune or psychiatric disease, and milder ones include flu-like symptoms. Limited data available on IFN use in children with other diseases implies good tolerability [24,25], and there are case reports in children with MPNs. In order to make more data available for treating physicians, a multi-center collaborative group described a small cohort of children with MPNs treated with pegylated-IFN (PEG). PEG seems generally well tolerated in pediatric patients, and has had beneficial results (stabilized or improved counts, and improved symptoms) in some patients [26]. If a child needs cytoreductive medication, it is appropriate to discuss both HU and PEG with the family and review potential risks and benefits of each. Based on clinical experiences, conversations with colleagues around the country, and the current available literature, our program generally recommends PEG upfront for children with PV, pre-PMF, PMF, and JAK2-mutated ET, and recommends both PEG and HU equally for CALR-mutated or triple negative ET. If one drug fails or the child is intolerant, other agents can be tried. Our group has not used anagrelide in young patients with ET, but cases have been reported [6]. Studies of ruxolitnib in children are extremely limited and have been focused on use in cancer, but initial studies showed that ruxolitnib was well tolerated in these patients [27], and further studies are ongoing and will hopefully include more children with MPNs.

Iron deficiency (ID) is an issue in most PV patients at baseline, and this can be exacerbated with phlebotomy; ID can cause symptoms in addition to anemia, such as fatigue and cognitive issues [28]. In children, iron is important for normal development, and deficiency has been linked to negative cognitive effects [29,30]. When children are found to be iron deficient, they are generally given guidelines for increasing iron in their diet or are prescribed supplements, yet iron replacement in PV patients is a controversial topic, and worsening of erythrocytosis can occur with iron supplementation in PV. It is sometimes difficult to distinguish if the symptoms experienced by children with PV are due to ID or their MPN, and it is not clear what effect long-term iron deficiency has on their growth and development. Cytoreduction to decrease phlebotomies and lower counts, ultimately reversing ID and its side effects, has been described in adults, and we have treated some young PV patients with cytoreduction for this reason.

The question of what platelet count is high enough to necessitate treatment is extremely challenging. Adults studies do not show a correlation between platelet count and thrombosis in PV and ET patients [5], and while we know extreme thrombocytosis is associated with bleeding, it is not clear if there is a platelet count threshold that makes bleeding risk “too high”. Some guidelines suggest cytoreduction is appropriate in adults with platelet counts >1500×10⁹/L [21], but there is no evidence that this can be extrapolated to children. In our practice, other factors are considered with platelet count, such as von Willebrand (vW) activity and multimer studies, symptoms, overall health and fitness, and, most importantly, activities that might increase risk of traumatic bleeding. If a child has increased bleeding or bruising and laboratory testing shows acquired vW disease, that is a good reason to start cytoreduction. Alternatively, we have followed a number of patients with platelet counts over 1500×10⁹/L who do not have significant reductions in vW activity, do not have bruising or bleeding, and are not interested in sports participation, who we did not start on cytoreduction. The most important thing to do is have a candid conversation with families about the risks and benefits of treatment and potential risks of extreme thrombocytosis, and discuss how each would affect the child’s lifestyle and make a treatment decision together. Counseling on avoidance of contact sports in the setting of untreated extreme thrombocytosis, maintaining good hydration, and healthy lifestyle, are important for all patients. There is not a clear trigger platelet count number for treatment, although our group has not had a patient with a platelet count above 3000× 10⁹/L who went untreated, and every specialist likely has their own comfort level based on their clinical experience, given the lack of data.

Young Adult MPN

Genetics and diagnosis

Most recent papers on young adult (YA) patients have included patients aged 16–40, with two groups including patients up to 45 years old. The YA patient groups represented 8–12% of total MPN patients seen at their respective centers [31,32]. In these cohorts, we see more genetic similarities to older patients than in pure pediatric cohorts. Unlike the pediatric literature, most PV patients described in these cohorts were JAK2-mutated [31–34]. In ET patients, 40–75% had JAK2V617F mutations [31–33,35], 1–2% had MPL mutations [32,35], and 24–35% had CALR mutation [32,35]. Among PMF patients, 35–60% were JAK2V617F-positive [31–33], one group reported 7% with MPL mutation and 48% with CALR mutations [32]. One cohort reported on pre-PMF patients, of which 40% were JAK2V617F-mutated, 35% had CALR mutations, and none had MPL mutations [35]. JAK2V617F mutant allele burden was significantly higher in older MPN patients with PV and PMF [31,34], and YA patients had significantly lower rates of cytogenetic abnormalities overall in one cohort [31]. Rates of triple negative disease are similar to older patients, and WHO diagnostic criteria seem appropriate to use. ET was the most common classical MPN seen in the younger cohorts.

Symptomatology and outcomes

Rates of splenomegaly varied in the cohorts, with 30–57% of PV patients, 6–28% of ET patients, and 42–68% of PMF patients having splenomegaly [31,32,34,35]. YA patients with PV and ET had higher median platelet counts than older patients in some cohorts, while hemoglobin was not different between groups [31,32,34]. PMF patients were less likely to have a white blood cell count ≥ 25 ×10⁹/L [31,32]. Rates of thrombosis at diagnosis occurred in 14–27% of PV, 6–13% of ET, and 14–16% of PMF patients in the YA cohorts [31,32]. Rates of arterial thrombosis were significantly lower in one cohort than the comparable older patients at that center, and overall thrombotic events after diagnosis were lower for their YA ET and PMF patients [32]. Splanchnic vein thrombosis was the most frequent venous event seen in one cohort [33], and was more common in a YA cohort with PV than in older adults [34]. Despite higher platelet counts in some YA PV and ET patients, rates of bleeding were not significantly different between older and younger adult MPN patients [31]. Fibrotic progression occurred in 0–22% of PV patients, and 0–16% of ET patients [31–34]. Leukemic transformation was rare in young adults. Rates of death varied, and occurred more frequenly in PMF [31–35]. YA patients had significantly higher median overall survival than older patients for all disease types in one group [32].

Management

Management of MPNs in YA patients is similar to that of older adults, and will not be discussed in detail in this review. Risk stratifications take younger age into account, and YA patients with PMF had lower risk scores than older cohorts [31,32]. One management paper recommended limiting cytoreductive therapy in YA patients with ET and PV to those who were high risk (defined as having had major thrombotic or hemorrhagic events) [5]. Interestingly, one study found that two-thirds of a YA cohort with ET received cytoreduction, with 71% of those subjects being treated for extreme thrombocytosis, 14% for hemorrhage or thrombosis, and 15% for microvascular symptoms that were refractory to aspirin [35]. Current guidelines do not have separate treatment recommendations for young adult patients, but utilize risk stratifications which can be applied to these patients. One note made in multiple guidelines is to cautiously use HU in young patients, and to consider IFN as frontline therapy [20,21]. This is especially relevant to think about in YA patients, as fertility and pregnancy are important issues in this age group. MPNs can be associated with higher rates of certain pregnancy complications, such as placental abruption and intrauterine growth restriction [36], and recent data suggests that use of aspirin or interferon might improve live birth rates in pregnant women with MPN [37]. HU is contraindicated during pregnancy and ruxolitinib has an unkown safety profile in this setting, so these are not appropriate treatments in pregnant patients requiring cytoreductive therapy. Switching from HU or Ruxolitinib to IFN before planned pregnancy may help minimize the potential teratogenic effects of these medications.

Conclusions and Future Directions

MPNs are being diagnosed more frequently in younger patients than in the past, yet they are still seen as rare diseases. Available data on diagnosis and treatment of these disorders is largely based on years of experience in older patients, and this makes caring for younger patients more challenging. Studies on pediatric and young adult MPNs are largely retrospective in nature, and some include short periods of evaluation. Cohorts with much longer-term follow-up are needed to better understand symptom burden, true incidence of hemostatic complications and disease transformation, and effects on other aspects of life in young patients. Concerns about very long-term use of cytoreductive medications, long-term effects of abnormal blood counts on vasculature, potential for development of cancer earlier in adulthood, changing rates of cardiovascular risk factors in the general population, and worries about fertility and pregnancy complications, are all issues to think about in young MPN patients. This is information that may not be in the forefront of a practitioner’s mind who is largely caring for older patients, yet is of great importance to families and young patients with MPNs. Challenges with transitioning from pediatric to adult clinics, lapses in insurance as young adults age out of parental insurance plans, and issues with medication adherence and compliance when faced with life-long therapies starting at a young age, are important issues for this patient population. As practitioners start seeing younger MPN patients with increasing frequency, reframing the conversations around these disorders will be important.

Over the coming years, it will be extremely important to expand collaborative trials studying these diseases in younger patients to allow for sufficient patient recruitment to make meaningful conclusions. More data is needed on long-term outcomes, and identification of the safest therapies for prolonged use is crucial. Identifying appropriate diagnostic standards and determining appropriate treatment parameters for these young patients is necessary to properly counsel families and young adults, and guide them in making informed decisions about care. Our program is very candid with families about the lack of hard data when discussing treatment recommendations for a child with an MPN, and we recognize how frustrating this is for them. Being diagnosed with a chronic disease at the age of 65 has a very different meaning than being diagnosed at 5 years or 25 years, and the effects of this need to be studied carefully. However, the outcomes data currently available in our pediatric and young adult populations is reassuring, and the dedication of researchers and families towards developing a better understanding of MPNs in young patients is truly encouraging.