Use of Pegylated Interferon in Young Patients With Polycythemia Vera and Essential Thrombocythemia

Abstract

Myeloproliferative neoplasms are rare disorders in young patients, and because of this, standardized treatment recommendations are not available. Pediatric patients are more frequently treated with hydroxyurea than interferon, yet there is no data suggesting this is the best practice. Current treatment guidelines for adults suggest using interferon as upfront therapy in young patients. We reviewed the cases of 13 young patients, with polycythemia vera or essential thrombocythemia, who were treated with interferon. Extreme thrombocytosis was well controlled and the medication was tolerated by many. Our work shows the need for prospective studies evaluating interferon in our youngest MPN patients.

Introduction:

Polycythemia vera (PV) and essential thrombocythemia (ET), two classical myeloproliferative neoplasms (MPNs), are clonal disorders associated with marrow hyperplasia and driver mutations involving JAK2, CALR, or MPL^1,2. The World Health Organization’s (WHO) diagnostic criteria were based on features identified in adult patients², and alternative pediatric diagnostic criteria have been proposed³. In addition, risk stratification schema and treatment guidelines have been developed for adult patients^4,5. Various cytoreductive treatments are available for adult patients and novel clinical trials generally exclude children.

Hydroxyurea is commonly used to treat children with MPNs, likely because of experience using it in sickle cell anemia. Young patients with PV or ET (PV/ET) have been treated with hydroxyurea⁶, although its use is controversial because of the potential concern for leukemogenicity and fertility effects⁷. Recent adult guidelines recommend using hydroxyurea cautiously in younger patients^4,5. Interferon has been used in adults with MPNs for decades, and pegylated forms (PEG) have led to increased tolerability⁸. Furthermore, enthusiasm for interferon has increased with hematologic and molecular responses in adults^9,10. With improved tolerability and potential benefits, PEG may be an appropriate treatment for young patients with PV/ET. Given the limited experience in this population, we sought to review a multi-institutional cohort of young PV/ET patients treated with PEG.

Methods:

We reviewed charts starting from 2005 of young patients who were diagnosed with PV/ET (based on WHO criteria) before 21 years of age, who received PEG at any point after diagnosis. Subject data were deidentified prior to pooling and secure storage. Details regarding treatment, demographic information, toxicities, and responses were obtained from chart reviews. Local Institutional Review Boards approved this study.

Results:

Thirteen young patients with PV (n=7) or ET (n=6) treated with PEG were identified from records at six institutions (Table 1). Age at diagnosis and start of PEG treatment was 2–18 and 3–22 years, respectively. Eight subjects were female. Five subjects with PV were JAK2V617F+, and two were JAK2-Exon-12+. One subject with ET was JAK2V617F+, one was CALR+, and four lacked a driver mutation (triple-negative). Four PV and five ET patients had extreme thrombocytosis, with platelet counts >1000×10⁹/L. Six children had splenomegaly (above the umbilicus), and one had splanchnic vein thrombosis at diagnosis.

Table I.

Young MPN Subjects Treated With PEG

	Total	ET	PV
Subjects (n)	13	6	7
Age at diagnosis, years - median (IQR)	11 (5.5–14.5)	12.5 (10–14)	10 (2–16)
Age at starting PEG, years - median (IQR)	14 (9.5–16)	14 (11–15)	10 (9–19)
Gender (n)
Male	5	2	3
Female	8	4	4
Mutational Status (n)
JAK2V617F	6	1	5
JAK2-Exon-12	2	0	2
CALR	1	1	0
Triple negative	4	4	0

IQR = interquartile range

Cytoreductive therapy was started for various indications, including acquired von Willebrand’s disease (avWD) and extreme thrombocytosis, severe iron deficiency, and systemic symptoms. Seven subjects were treated with hydroxyurea before PEG, and three received a combination of PEG and hydroxyurea for disease management. Reasons for starting PEG included concern for risk of hydroxyurea-associated malignancies or fertility effects, potential for disease-modifying therapy, and side effects of hydroxyurea.

Most patients received 45, 60, or 90 micrograms of PEG, with some patients requiring higher doses (Table 2). Patients received PEG for a median of 24 months (range 10–168). In eight of nine subjects with extreme thrombocytosis, platelet counts decreased below 1000×10⁹/L, with one subject normalizing their count below 450×10⁹/L. The two patients with JAK2-Exon-12-mutated PV did not show improvement in degree of iron deficiency despite decreased phlebotomy.

Table II.

Features of PEG treatment in Pediatric and Young Adult Cohort

Prior Treatment with Hydroxyurea (n)	7
Duration of Therapy, months – median (range)	24 (10–168)
Dose range (mcg)	45–153
Dose frequency (weeks)	1–4
Thrombotic events while on PEG (n)	2
Bleeding events while on PEG (n)	1
Interferon discontinued (n)	5
Currently still on interferon (n)	8

mcg=micrograms

One patient had a gastrointestinal bleeding event attributed to gastritis from non-steroidal anti-inflammatory agent use for an injury (platelet count was 610×10⁹/L) that did not require PEG discontinuation. Two teenagers had venous thromboses after 10.5 and 3 years, respectively. The first (PV, JAK2V617F+) had a pulmonary embolism; the second (ET, triple-negative) had a pulmonary embolism and cerebral sinovenous thrombosis. Both had normal blood counts at the time of thrombosis and were ultimately taken off PEG (the first for development of antiphospholipid antibody syndrome.) Two patients had PEG discontinued for depression and anxiety (with no suicidal ideation). One patient had PEG discontinued for persistent transaminitis post-liver transplant (which resolved off PEG). Intermittent side effects reported by subjects included dizziness, malaise, and injection site reactions, but none required discontinuing medication.

Serial allele burdens were not available for the majority of this cohort, but three patients showed improvement in their JAK2V617F allele burden. One had a decrease from 49% to 32.7% after 3 years, one from 53% to 25% after 2 years, and one from 26% to 21% after 1 year. Testing for secondary mutations was not routinely performed. Eight patients currently remain on PEG therapy. No subjects have had disease transformation.

Discussion:

The appropriate use of cytoreductive medications in young patients with PV/ET remains undefined. It is not clear if laboratory values, symptoms, hemorrhage or thrombosis, or disease progression should drive treatment decisions. Even though extreme thrombocytosis is not correlated with thrombosis risk¹¹, elevated counts are associated with avWD¹². Younger patients may exhibit higher risk behaviors (e.g. participation in contact sports), in which avWD could restrict activity and impact quality of life. Some practitioners therefore use avWD as an indication to treat young patients. Phlebotomy is useful for PV patients, but the appropriate target hematocrit in young patients is unknown, and often leads to symptomatic iron deficiency. This complication may matter most for younger patients, in whom iron is essential for growth and development. The subjects with severe iron deficiency and highest red blood cell counts were those with JAK2-Exon-12-mutant PV. This may be due to altered iron metabolism as reported in JAK2-Exon-12 MPN animal models¹³. The long-term consequences of severe iron deficiency in young PV patients remain unknown.

Definitions for hematologic remission for adult PV/ET patients include resolution of symptoms, gender-specific normalization of counts, and normalization of marrow¹⁴. Symptom burden is variable in young patients. Normal hematocrit values are age-dependent in children, underscoring the need for age-specific targets. Marrow examinations are not always repeated in children, as they require sedation. The lack of remission criteria relevant to children further adds to the challenge of identifying appropriate therapeutic targets. Many physicians adjust cytoreductive medications to doses that relieve symptoms, resolve extreme thrombocytosis, or correct avWD, while tolerating abnormal blood counts. This approach may favor lower doses of medications, thus minimizing side effects.

In this cohort of young PV/ET patients, PEG treatment resulted in resolution of extreme thrombocytosis in eight of nine patients (89%). Despite toxicities such as depression and transaminitis, 62% remain on PEG therapy. Two patients developed thrombotic events after years of PEG therapy, at times when they had normal blood counts, further emphasizing the importance of defining an effective therapeutic target. This also raises the question of whether thromboses occur independently of normalization of blood counts. Reassuringly, no patients have had fibrotic transformation, which has been reported in up to 2% of young patients with PV/ET¹⁵. In adults, JAK2V617F-mutated-PV is associated with splanchnic vein thrombosis, which was seen in one of our patients at diagnosis, and CALR mutations have a lower rate of thrombosis¹⁶. Younger patients in general seem to have lower rates of transformation than older adults¹⁷. The role of driver mutations, whether somatic or germline, in pediatric patients remains unclear.

In a recent systematic review, more young patients received hydroxyurea than interferon¹⁵, yet there is no data showing one treatment is safer or superior to the other in children. PEG has established efficacy in young patients, and can be well tolerated. Therefore, we feel that PEG should be included in discussions of first-line therapy options with patients’ families. Given the limited treatment options available to younger patients, our study highlights the need for larger studies of PEG for treatment of young patients.

Abbreviation table:

PV

Polycythemia Vera

ET

Essential Thrombocythemia

MPN

Myeloproliferative Neoplasms

WHO

World Health Organization

PV/ET

Polycythemia Vera or Essential Thrombocythemia

PEG

Pegylated Interferon

aVWD

Acquired von Willebrand’s disease