Myeloproliferative neoplasms (MPNs) are caused by defects in blood cell production. This leads to an overproduction of mature cells, such as red blood cells or platelets. As a result, clinical symptoms and complications can develop. Circulatory disorders and resulting pain symptoms, such as headaches, are the most prominent. Furthermore, blood clotting disorders can occur, leading to vascular occlusions or bleeding. Over a longer period, bone marrow transformation into fibrous tissue or the development of acute leukemia can occur, resulting in even more serious complications.

In the vast majority of cases, MPNs are diagnosed in older adults. These diagnoses are extremely rare in children and adolescents. Therefore, clinical and genetic characteristics, treatment options, and outcomes in pediatric patients with MPNs are insufficiently described, and only limited data are available for standardizing diagnostic and therapeutic approaches for MPNs in childhood and adolescence. Recommendations and guidelines from the adult field, which have largely been adopted and applied to children and adolescents, do not adequately address the specific needs of patients in childhood and adolescence. To gain more insights into MPN during this early, vulnerable phase of life, we have established a nationwide registry in Germany that systematically collects data from children and adolescents with MPN.

The registry focuses particularly on the scientific analysis of the biological characteristics and differences of MPN in children and adolescents compared to adults.

Extractions from the original Registry Protocol; please see also https://www.kinderonkologie.uk-erlangen.de/forschung-und-lehre/mpn-childhood-registry/:

Classical MPN

Background

The classical myeloproliferative neoplasms (MPN) comprise the three BCR::ABL1-negative disease entities polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Serious complications associated with MPNs are thromboembolic events and disease progression of and to myelofibrosis and acute myeloid leukemia (AML) (1).

Like other myeloid diseases, e. g. myelodysplastic syndromes (MDS) and chronic myeloid leukemia (CML), MPNs are usually diagnosed in adulthood and the median age at diagnosis of the two more prevalent conditions, PV and ET, is over 60 years. In children and adolescents, however, MPNs are very rare and knowledge concerning the biological and clinical characteristics at diagnosis and in the further course of these diseases including the incidence of vascular and long-term complications remains limited. As a consequence, there is no standardization of diagnostic and therapeutic approaches in pediatric patients with MPN and in most instances, guidelines from adult patients are applied in children and adolescents. These include that the diagnosis of an MPN is based on the identification of a driver mutation and the assessment of a bone marrow trephine. Treatment should be adapted according to a stratification into low risk or high risk according to the patient's age and history of thrombosis or hemorrhage with the aim to reduce thrombotic complications (2-4). The significance of different therapeutic avenues including antiplatelet and/or cytoreductive treatment in the population of pediatric patients with MPN is largely unknown and information about the potential long-term sequelae of treatment is sparse.

Currently, there is no population-based registry on a national or international level for pediatric patients < 18 years with MPN. The main aims of the MPN Childhood Registry are to validate the epidemiology of MPN in childhood and adolescence, to improve and standardize the diagnostic approach by a centralized morphologic, histologic, cytogenetic and molecular review and to evaluate the different therapeutic modalities and tailor these to the specific needs of pediatric patients.

Epidemiology

A significant variability of data concerning in the incidence of MPN between countries was reported. The global incidence of MPN in children and adolescents has recently been estimated at around 0.82 per 100,000 per year (range 0.1 to 2.25), which is about 100 times lower than in adults (5-7). Thus, pediatric individuals represent only a small proportion of patients with MPN.

However, the more frequent use of routine blood counts in recent years has been associated with an increase in the diagnosis of MPNs in children and adolescents and therefore, the true incidence of these diseases might be underestimated.

The global incidences of PV, ET, and PMF were found to be variable around 0.18, 0.6, and 0.53 per 100,000 per year, respectively. Current studies showed a median age at diagnosis of 12 years for pediatric patients with PV and 9.3 years for pediatric patients with ET. The percentage of female cases in these analyses was 45% in PV and 57.6% in ET (6, 7).

Clinical presentation

There is a high variability of symptoms associated with MPN in children and adolescents. Recent analyses have shown that nearly half of the pediatric patients with MPN were asymptomatic at the time of diagnosis. Headaches, abdominal or bone pain were the most commonly reported symptoms. A small proportion of patients appears to be diagnosed following a thrombotic or hemorrhagic event. The frequency of these complications is lower in pediatric cohorts than in adults. The reason for the original consultation was unclear or unknown in most cases in these analyses.

The most frequent abnormal clinical finding is splenomegaly described in more than half of the cases with ET and a smaller subgroup of individuals with PV. There was no correlation of splenomegaly and abdominal symptoms or thrombosis (6-8).

Hematological characteristics

In a recent cumulative retrospective analysis, Ianotto et al. have assessed full blood counts of pediatric cases with MPN at diagnosis. For PV patients, the median leukocyte count was 13.2 G/L, the median hemoglobin 180 g/L (maximum level, 189 g/L), the maximum hematocrit was 72.5%, and the platelet count was 799 G/L. For ET patients, the median leukocyte count was 10.6 G/L, the median hemoglobin 131 g/L, and the median platelet count 1192 G/L (maximum 4500 G/L). Notably, in this and other retrospective analyses, the differentiation from hereditary and secondary erythrocytosis and thrombocytosis remained unclear and in a substantial number of cases, the authors rather generally stated that patients fulfilled the diagnostic criteria according to the current World Health Organization classification. However, bone marrow results were described for only about half of all cases comprising mostly short descriptions and general conclusions (6).

Molecular characteristics

As for other myeloid diseases like MDS (9), obvious differences concerning the frequency and the spectrum of genetic driver and non-driver variants between pediatric and adult patients with MPN have been described.

For PV, the percentage of pediatric cases positive for the classical Janus kinase 2 (JAK2) V617F driver mutation was between 37% and 24% and therefore significantly lower than in adult cases, whereas the rate of JAK2 exon 12 mutations appeared comparable. Accordingly, the percentage of pediatric individuals who did not harbor one of these two driver mutations was higher (10-12). In a larger analysis of pediatric ET cohorts including all driver mutations, the proportions of positivity were also lower than in adult cohorts and found to be 31% for JAK2V617F, 10% for CALR, and 2% for MPL. Consequently, a higher proportion of 57% of these pediatric cases were triple-negative for driver mutations (13-19).

In next-generation sequencing analyses, a significant proportion of 35% of patients did not carry any non-diver mutation (13, 15). High-risk mutations associated with an inferior prognosis in primary myelofibrosis in adult patients were uncommon and the clinical significance of non-driver mutations could not be assessed in these studies.

As already addressed, the exclusion of hereditary and secondary cases was critically discussed in these reports. The differences in the mutational landscape found in these analyses of pediatric patients with MPN compared to adult patients requires a prospective evaluation.

Systematic analyses concerning cytogenetic aberrations in pediatric MPN have not been performed so far.

Implications of diagnostic criteria in pediatric MPN

The diagnostic criteria for PV, ET, and PMF are shown in table 1 and 2, respectively. However, it needs to be emphasized that the World Health Organization (WHO) diagnostic criteria for MPNs are tailored to adults. The PV criteria, for example, do not consider pediatric age-adjusted normal ranges for hemoglobin (Hb) or hematocrit (Hct) (12). Moreover, as described earlier, a significant proportion of pediatric patients do not exhibit a driver mutation as a major diagnostic criterion for MPNs. Therefore, from the diagnostic point of view, it appears even more important that a bone marrow aspiration as well as a bone marrow biopsy assessing morphology, cellularity and reticulin fibrosis are routinely performed in all children and adolescents with suspected MPN.

Given the differences described in the disease biology, alternative criteria for PV and ET in children have been proposed, with PV criteria including Hb or RBC count above the 97.5th percentile for age, and ET criteria granting the absence of reactive causes of thrombocytosis equal weight as the identification of a known driver mutation (22).

Complications

Overall, complications in MPN, e. g. thrombotic or hemorrhagic events, disease progression and transformation and other malignancies or therapy-associated sequelae appear to be significantly less common in children and adolescents with MPN compared to adult individuals (23, 24). However, these observations should be interpreted with caution because of the limited median follow-up in the respective analyses.

The incidence of thrombosis at diagnosis in children and adolescents was 14.7% and 4% in patients with PV and ET, respectively, and decreased in cases with PV thereafter. A clear predominance of venous vs. arterial events (84.2%) has been described and the majority of events occurred in the splanchnic veins (75%) in particular as Budd-Chiari syndrome (62.5% of venous events) (6). The probability of recurrent thrombotic events in pediatric MPN remains unclear based on the available data.

Hemorrhagic events appeared to be very rare in children and adolescents with MPN (1% before and 4.8% after the diagnosis in ET patients and 4% before and after diagnosis in PV patients) and were not associated with the use of antithrombotic drugs (6).

Disease progression and transformation into secondary myelofibrosis and/or acute leukemia as the most serious complications in adult patients seem to occur rarely in pediatric MPN. Evolution into myelofibrosis was reported in only 2% of cases and transformation into acute myeloid leukemia was not described (6).

One previous study has found that a small proportion of pediatric cases with MPN might occur after previous treatment for acute leukemia or lymphoma (10). Data on the association of MPN and solid cancers is sparse and no systematic information on potential implications of previous chemotherapy or cytoreductive drugs on the occurrence of MPN or cancer is available. Similarly, there are no systematic analyses of the association of MPN with non-malignant disease entities or complications of pregnancy.

Treatment

In most analyses on pediatric MPN, it remained unclear, whether treatment decisions and initiation were made by pediatric or adult hematologists (6). However, the general impression is, that due to the rarity of MPN in childhood and adolescents and the associated lack of age-appropriate diagnostic and therapeutic guidelines, adult hematologists, who are much more familiar with these diseases, are regularly consulted by the pediatrician.

Antithrombotic drugs such as aspirin, vitamin K antagonists and low molecular weight heparin seem to be employed in more than half of the cases with PV and ET and irrespective of the lack of high-risk features, most patients received cytoreductive treatment (6).

In larger analyses, pediatric patients with PV were treated with phlebotomy (45.2%) or received hydroxycarbamide (25.8%) whereas interferon appears to be more rarely employed (6). Children and adolescents with ET were regularly treated with the non-chemotherapeutic agents anagrelide (20.9%) and interferon alpha (4.6%). Notably, ruxolitinib, the inhibitor of JAK1 and JAK2, which, since its approval, has become the standard-of-care treatment for adult patients with PMF and PV has so far been prescribed in single pediatric cases only (25).

Historically, a proportion of pediatric patients with MPN were treated with other conventional therapeutic approaches such as melphalan, busulfan, radiotherapy or allogeneic stem cell transplantation.

Outcome

The mortality rate of MPN in childhood and adolescence is low and the reported deaths were associated with vascular events such as Budd-Chiari syndrome (6).

However, it needs to be emphasized that the follow-up period of pediatric patients with MPN until transition to adult hematology is limited creating a reporting bias and the long-term outcome of MPN occurring early in life has not been systematically investigated yet.

Hypereosinophilic Syndrome

Background and classification

Hypereosinophilia and Hypereosinophilic Syndrome (HE/HES) belong to a heterogeneous group of myeloproliferative disorders characterized by an absolute eosinophil count (AEC) of ≥ 1.5 x G/L with associated end-organ involvement, extensive tissue hypereosinophilia or bone marrow hypereosinophilia of ≥ 20% with peripheral blood eosinophilia (26-30).

Hypereosinophilia and HES are also very rare in children and adolescents and data on the disease entity in these age groups is sparse. The incidence of pediatric HE/HES has been estimated with a rate of 3.5 per 100.000 children and adolescents per year (31). Due to variable clinical presentation, also HES might be underdiagnosed.

Based on the associated mechanism, HE/HES is classified as primary or secondary. For this registry, only children and adolescents with primary myeloid HE/HES (pHES) are eligible. However, primary HE/HES can be diagnosed only in a small minority of cases with HE/HES in adult and pediatric patients alike (8% and 11%, respectively [7]) caused by a malignant clonal myeloid or eosinophilic stem cell neoplasm. Underlying genetic events affect fusion genes or mutations involving tyrosine kinase pathways such as platelet-derived growth factor-alpha (PDGFR-α), platelet-derived growth factor-beta (PDGFR-β), fibroblast growth factor receptor 1 (FGFR1), and JAK2. Further causes of primary HE/HES comprise chronic eosinophilic leukemia, acute myeloid leukemia, systemic mastocytosis, MDS, classical MPNs (PV, ET and PMF) or MDS/MPN overlap disorders such as chronic myelomonocytic leukemia (CMML). The classical lymphocyte variant of primary HE/HES is associated with aberrant clonal T cells. Except for classical MPNs, these latter disease entities are not included in the registry.

Secondary HE/HES caused by defined underlying conditions are far more common than primary HE/HES. These cases are characterized by polyclonal expansion of eosinophils driven by increased production of cytokines, such as interleukin (IL) -3, IL-5 or granulocyte-macrophage colony-stimulating factor (GM-CSF). Secondary HE/HES are induced by a wide variety of conditions including allergies, infections, neoplasms, inflammatory syndromes, immunodeficiencies, drug hypersensitivities, and others.

Diagnosis of Pediatric HES

Hypereosinophilia/hypereosinophilic syndrome in children and adolescents with AEC ≥ 1.5 x G/L on more than 2 occasions more than 4 weeks apart with or without associate clinical symptoms should be further evaluated.

Owed to the potential severity of the disease, a primary hematological malignancy should be ruled out initially. Apart from a detailed history taking and physical examination including evaluation of fever, lymphadenopathy, organomegaly, pallor, and bleeding sings, the primary diagnostic approach includes the identification of potential additional organ involvement. The basic laboratory tests comprise blood count with differential, blood smear, lymphocyte subsets, serum-immunoglobulins with IgE, C-reactive protein, liver and renal function, urinalysis, lactate dehydrogenase, uric acid, serum tryptase, serum vitamin B12, and a basic metabolic panel.

Initial diagnostic imaging should include chest X-ray or chest/abdominal/pelvic CT or MRI.

Performing a bone marrow puncture for morphologic and cytogenetic/genetic analysis and a bone marrow biopsy for histological assessment should also be part of the diagnostic approach if hematological malignancy is suspected. Organ involvement should be addressed for example by targeted tissue biopsy, bronchoscopy including bronchoalveolar lavage, echocardiogram and electrocardiogram.

Further evaluation of secondary HE/HES comprises parasite serology with respect to possible exposure and diagnostics concerning immunodeficiency, autoinflammation and connective tissue disorders.

Pediatric patients with HE/HES may have a normal initial evaluation and should therefore be followed up including peripheral blood counts every two to six months.

Treatment of Pediatric HES

As for adults, first-line treatment in pediatric HE/HES is systemic high-dose steroid therapy. The usually applied dose is 1-2 mg/ kg body weight per day (29). Response to steroids is variable depending on the underling condition but usually occurs rapidly within a few days. In case response is lacking and the AEC and associated clinical symptoms do not improve, therapy should be extended.

Patients with underlying myeloid HES and FIP1L1- PDGFR-α fusion gene show a high response rate to imatinib (approved for pediatric CML and applied at a dose of 340 mg/m2). However, in cases without a PDGFR-α alteration, response is rare (32, 33).

To date, mepolizumab, a monoclonal antibody acting through IL-5 antagonism, is the only biologic therapeutic agent approved by the U. S. Food and Drug Administration, which has shown effectiveness in a phase 3 randomized placebo-controlled trial in adolescents ≥ 12 years and adults with HE/HES (34). Mepolizumab is applied subcutaneously every 4 weeks at a dose of 300 mg.

Additional therapies including hydroxyurea, interferon-alpha and benralizumab, a humanized anti-human IL5-Rα antibody, can be used off-label (29). Other non-steroid agents such as Janus kinase inhibitors and dexpramipexole are currently being studied in the context of HE/HES treatment (35, 36).

Generally, response to treatment is associated with the HE/HES subtype and the concomitant therapy of underlying conditions in secondary HE/HES. Like steroid therapy, IL-5 antagonism is presumably more efficient in non-myeloid HE/HES.

Objectives

Primary Objectives

• To determine the incidence and epidemiology of PV, ET, PMF and pHES in children and adolescents through systematic inclusion of these patients in a national population-based registry
• To systematically characterize clinical, hematologic, genetic and cytogenetic features of children and adolescents with PV, ET, PMF and pHES
• To identify pediatric patients with high risk of complications and disease progression and transformation into acute myeloid leukemia (AML)
• To improve the therapy for children and adolescents with MPN by discussing treatment options with the treating centers and tailor therapy to the specific and individual needs of pediatric patients

Secondary Objectives

• To prepare future international collaborative prospective studies focusing on the optimization and standardization of childhood MPN-diagnosis and treatment
• To develop a biobank system of pediatric patients with MPN Investigational Plan

Registry/Study Design

This is a German national multicenter, retro-, and prospective, non-randomized, non-interventional registry. A registry biobank will be established.

The total duration of the registry is not defined, patients can remain in the registry until adulthood.

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Inclusion Criteria:

• Newly diagnosed PV, ET, PMF or pHES
• Age < 18 years (up to 17 years and 365 days) at the day of diagnosis
• Patient treated in a participating center
• Written informed consent to registry participation

Exclusion Criteria:

o Secondary polycythemia, thrombocytosis, myelofibrosis or HES with underlying reasons other than PV, ET, PMF or pHES

Children and adolescents below the age of 18 years diagnosed with Myeloproliferative Neoplasms

Clinical and genetic data after deidentification

IPD after scientific publication of data Supporting information with start of registry

IPD medical professionals Supporting information public