All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the MPN Advocates Network.

The MPN Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

Special populations in MPN: pediatric, adolescent, and young adults with MPN

Oct 7, 2021
Share:

Triple negative mutations i.e., the absence of driver mutations in JAK2, MPN and CALR are reported in many young patients with myeloproliferative neoplasms (MPN).

Surprisingly, in a large cohort study of young patients <20 years of age, 73% of patients with polycythemia vera (PV) and 57% of patients with essential thrombocytosis had triple negative mutations. It is unusual to have such a high number of PV patients without JAK2 mutations and is in contrast to observations made in adult patients.1

At the Texas Virtual MPN Workshop (TMW) 2021: Second Annual Workshop and Meeting, Kucine2 provided an overview of special considerations for pediatric, adolescent, and young adult patients with MPN. She focussed on genetic mutations, thrombosis, and disease progression as well as the management of pregnant patients with MPN.

Genetic mutations, thrombosis, and disease progression in pediatric/AYA patients with MPN

The Cornell pediatric MPN study was a prospective observational study with 43 patients enrolled, representing 19 states in the US (age range 3–21, years).

Mutations

The mutation profile of all patients in the study is given in Table 1. The rate of triple negative mutations was lower in the study cohort compared to previous literature reports, and all patients with PV had JAK2 mutations.

Secondary mutations were infrequent, based on the gene sequencing results of a sub-population of patients (n = 33). Only three patients had secondary mutations in TET2, two of which co-occurred with JAK2. There were no signs of mutation in genes such as ASXL1, EZH2, and IFH1/2. Since mutations in these genes are frequently identified in adults with MPN, these results suggest that the mutation profile may change over time and mutations may be acquired with age.

Table 1. Patient demographic characteristics/ mutation profile*

Characteristic, % (unless otherwise stated)

All patients (n = 43)

Age range, years

3–21

Triple negative

35

MPL

2

CALR

14

JAK2 exon 12

5

JAK2 V617F

44

CALR, Calreticulin gene; JAK2, Janus kinase 2 gene; MPL, myeloproliferative leukemia protein gene; NP, not present.
*Adapted from Kucine2

Thrombosis

Six out of 43 (14%) patients had a thrombotic event, five of whom were female. JAK2V617F mutations were found in four of these female patients and only one female patient had triple negative mutation. The only one male patient with thrombosis had a JAK2 mutation.

The disease features and thrombosis type in pediatric MPN patients are presented in Table 2. Five out of six patients with thrombosis had either PV or presumed PV. All patients who were diagnosed with budd chiari syndrome (n = 4) were females and JAK2 positive, consitent with what is observed in the literature for adult patients with MPN. None of the patients had extreme thrombocytosis at the time of their thrombotic event, supporting the notion that platelet count does not directly correlate with thrombotic risk.

Table 2. Disease features and thrombosis type in pediatric patients with MPN*

Disease features and Thrombosis type, n           

N = 6

MPN subtype

 

              PV

2

              Presumed PV

3

              ET

1

Type of thrombosis

              Arterial ischemic stroke

1

              CVST + PE

1

              Budd chiari syndrome

4

Blood count at the time of thrombotic event

              Thrombocytosis (>450 × 109/L)

5

              Extreme thrombocytosis (>1000 × 109/L)

0

              Polycythemia (based on age/ sex norms)

3

              Leukocytosis (>10 × 109/L)

4

CVST, cerebral venous sinus thrombosis; ET, essential thrombocytosis; MPN, myeloproliferative neoplasms; PE, pulmonary embolism; PV, polycythemia vera.
*Adapted from Kucine2

The rate of fibrotic and leukemic transformation in the current study was low which is in line with published studies. Only three patients transformed to myelofibrosis since enrolment, two of those patients had a CALR mutation, one patient had an MPL mutation, and no patients had transformed to acute leukemia.  

Case study

The case of an asymptomatic 17 year-old male was discussed. This patient’s routine complete blood count test showed extreme thrombocytosis but with normal blood count and hemoglobin. He had mild splenomegaly and mildly elevated LDH. Genetic testing revealed a novel CALR exon 9 mutation. Cytogenetics was normal at diagnosis and the patient was diagnosed with MPN-unclassified.

Over time, although asymptomatic with no bleeding or thrombosis, the patient developed a mild decrease in hemoglobin, increase in LDH, and increased spleen size which prompted a bone marrow biopsy for possible disease progression. A 5q deletion was detected in 5% of cells, and the patient met the diagnostic criteria for overt myelofibrosis Grade 2.  

This was a young, asymptomatic patient. Despite the presence of consistent thrombocytosis, there were no complications associated with acquired Von Willebrand’s disease and no additional risk factors were observed, he was otherwise healthy. In this case, PEG interferon alpha 2a was used to prevent further disease progression and the patient was later referred for transplant evaluation.

With this case in mind, Kucine asked whether we should be minimizing cytoreduction in young patients, reserving use for severe symptomatic disease considering that cytoreductive medications are not completely benign, or aiming to prevent disease progression. Since there is good data supporting the use of interferon in PV to prevent disease progression, this approach is worth considering, but there is no right answer and the debate is ongoing. 

Impact of MPN on fertility

Fertility and pregnancy concerns are important to many young patients with MPN, including the impact of cytoreductive medications on future fertility and risks to both mother and fetus during pregnancy.

In a systematic review of 1,210 pregnancies in women with MPN, there was a 71% live birth rate and moderate quality evidence showed that use of aspirin and interferon was associated with an increased rate of live births.3

A comprehensive team-based approach, partnering with maternal and fetal medicine, is considered the best way to manage different stages of pregnancy in patients with MPN, as presented in Table 3.

Table 3. A comprehensive approach to pregnancy in MPN*

Stage/Condition

Treatment approach

Preconception

Counsel

Risk assessment

Optimise haematocrit and platelet count

Address cardiovascular risk factors

Pre-existing indication cytoreduction: switch to interferon alpha

Pregnancy all

Offer low dose aspirin

Venesection (PV)

Offer LMW heparin in the presence of one additional thrombosis risk factor

Anomaly scan and uterine artery doppler 20/40

Serial growth scans

Avoid dehydration and immobility (hyperemesis and labour)

Pregnancy high risk

Offer interferon alpha

Offer LMW heparin if prior thrombosis

Consider LMW heparin if prior poor pregnancy outcome

Increased fetal monitoring

Post delivery

LMW heparin for 6 weeks

Continue aspirin according to management MPN prior to pregnancy

Individual breast-feeding plan

Discuss contraception option

LMW, low molecular weight; PV, polycythaemia vera.
*Adapted from Kucine2

Conclusion

Information about the optimal care for pediatric, adolescent, and young adult patients with MPN is scarce, leading these patients to face unique challenges that may not be present in an older adult patient population.

This article highlights atypical genetic mutations in younger patients, compared with adult patients, and an open question remains as to whether toxic cytoreductive treatment should be minimized or prevention of disease progression should be the goal in young, asymptomatic patients. A comprehensive, multidisciplinary approach is necessary for the management of pregnant patients with MPN.

Overall, it is important to address specific concerns of pediatric, adolescent and young adult patients and their families. There is a need for continued research and collaboration to best learn about this unique patient population.

  1. Lanotto JC, Curto Garcia N, Lauermanova M, et al. Characteristics and outcomes of patients with essential thrombocythemia or polycythemia vera diagnosed before 20 years of age: a systematic review. Hematologica. 2019;104(8):1580-1588. DOI: 3324/haematol.2018.200832
  2. Kucine N. Special population in MPN: pediatric AYA/MPN. Oral abstract. Texas Virtual MPN Workshop 2021: Second Annual Workshop and Meeting. Aug 19-20, 2021; Virtual.
  3. Maze D, Kazi S, Gupta V, et al. Association of treatments for myeloproliferative neoplasms during pregnancy with birth rates and maternal outcomes: a systematic review and meta-analysis. JAMA Netw Open. 2019;2(10):e1912666. DOI: 1001/jamanetworkopen.2019.12666

Share: