POLYCYTHEMIA VERA IN CHILDREN AND ADOLESCENTS (ANALYSIS OF SEVEN CASES)

Myeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic disorders of stem cells characterized by aberrant proliferation of one or more myeloid lines. MPNs are extremely rare in patients younger than 20 years old, for example, polycythemia vera (PV) is about 2 cases per 10 million people per year. The true prevalence of PV and treatment standards for pediatric patients are not defined. The goal is to analyze the identified cases of polycythemia vera (PV) in patients younger than 20 years and create an algorithm for the choice of therapy.

Materials and methods. The analysis of 7  patients with PV at the age under 18 years (3 months — 14 years), 6 of them are boys and 1 is girl. The patients underwent general clinical studies, morphological, histological, cytogenetic, molecular genetic studies of the bone marrow, ultrasound studies of the abdominal organs and vessels. Cytoreductive therapy was performed with pegylated interferon, and in the absence of a response — ruxolitinib.

Results. In the debut of the disease, splenomegaly of various degrees was detected in all patients, the total number of leukocytes (WBC) > 10.0  × 109/L, the number of neutrophils 6.2—13.5  × 109/L, the number of red blood cells (RBC) 5.6—8.9 × 1012/L, in 4 patients — platelet count (PLT) > 1000 ×109/L (1103—3000 × 109/L). No cases of throm bosis or bleeding were noted. In 100% of cases, a mutation was detected in the JAK2 gene (6 patients with the mutation JAK2V617F, 1 patient with a mutation in exon 12 of the JAK2 gene p.1613_1616delACAAinsT). The allelic load in the debut of the disease was 14—33% (n = 4) and 35—66% (n = 3). With pegylated interferon α2 (peg-INF α-2a) therapy, a full response to therapy was obtained in 2 cases, a partial response — in 2 cases, in one of them the therapy was discontinued due to pronounced toxicity. Second-line therapy (ruxolitinib) was performed in 3 patients and after 6 months partial remission was achieved in the form of a hematocrit decrease of less than 45% without bloodletting. The tolerability of ruxolitinib is satisfactory; no adverse events requiring dose reduction or complete withdrawal were noted.

Conclusion. Considering the extremely rare occurrence of PV in patients younger than 18  years of age, as well as the results of long-term follow-up (disease outcomes: frequency of progression in acute myeloid leukemia or myelofibrosis), it is necessary to continue collecting information on patients with debut of the disease earlier than 18 years. For patients younger than 18 years old, it is advisable to use peg-INF α-2a as the first line of cytoreductive therapy, in the absence of response and/or in case of intolerance to peg-INF α-2a, switch to the second line of therapy, ruxolitinib, in the absence of response or progression of bone marrow fibrosis (MF2 and more) it is necessary to consider the transplantation of allogeneic hematopoietic stem cells as the only curative method.

1. Меликян АЛ, Суборцева ИН. Биология миелопролиферативных новообразований Клиническая онкогематология. Фундаментальные исследования и клиническая практика. 2016;9:314—25.

2. Меликян АЛ, Туркина АГ, Ковригина АМ, Суборцева ИН, Судариков АБ, Соколова МА и др. Клинические рекомендации по диагностике и терапии Ph-негативных миелопролиферативных заболеваний (истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз) (редакция 2016 г.). Гематология и трансфузиология. 2017;62:25—60.

3. Суборцева ИН, Колошейнова ТИ, Пустовая ЕИ, Егорова ЕК, Ковригина АМ, Плискунова ЮВ и др. Истинная полицитемия: обзор литературы и собственные данные. Клиническая онкогематология. Фундаментальные исследования и клиническая практика. 2015;8:397—412.

4. Остальные источники см. в References.

5. References

6. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point of-care diagnostic algorithms. Leukemia. 2008;22:14—22.

7. Melikyan AL, Subortseva IN. Biology of Myeloproliferative Malignancies. Clinical Oncohematology (Klinicheskaya Gematologia). 2016;9:326—35. (In Russian)

8. Melikyan AL, Turkina AG, Kovrigina AM, Subortseva IN, Sudarikov AB, Sokolova MA et al. Clinical recommendations for diagnoses and therapy of Ph-negative myeloproliferative neoplasms (polycythaemia vera, essential trombocythemia, primary myelofibrosis) (edition 2016). Hematology and Transfusiology (Gematologiya i Transfuziologiya). 2017;62:25—60. (In Russian)

9. Grinfeld J, Nangalia J, Green AR. Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms. Haematologica. 2017;102:2—12.

10. Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24:1128—38.

11. McNally RJ, Rowland D, Roman E, Cartwright RA. Age and sex distributions of hematological malignancies in the U.K. Hematological oncology. 1997;15:173—89.

12. Giona F, Teofili L, Moleti ML, Martini M, Palumbo G, Amendola A et al. Thrombocythemia and polycythemia in patients younger than 20 years at diagnosis: clinical and biologic features, treatment, and long-term outcome. Blood. 2012;119:2219—27.

13. Hofmann I. Myeloproliferative Neoplasms in Children. J Hematop. 2015;8:143—57.

14. Teofili L, Giona F, Martini M, Cenci T, Guidi F, Torti L et al. Markers of myeloproliferative diseases in childhood polycythemia vera and essential thrombocythemia. J Clin Oncol. 2007;25:1048—53.

15. Cario H, Schwarz K, Herter JM, Komrska V, McMullin MF, Minkov M et al. Clinical and molecular characterisation of a prospectively collected cohort of children and adolescents with polycythemia vera. Br J Haematol. 2008;142:622—6.

16. Michiels JJ, Juvonen E. Proposal for revised diagnostic criteria of essential thrombocythemia and polycythemia vera by the Thrombocythemia Vera Study Group. Seminars in thrombosis and hemostasis. 1997;23:339—47.

17. Barbui T, Thiele J, Gisslinger H, Kvasnicka HM, Vannucchi AM, Guglielmelli P et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8:15.

18. Finazzi G, Barbui T. How I treat patients with polycythemia vera. Blood. 2007;109:5104—11.

19. Berlin NI. Polycythemia vera: diagnosis and treatment 2002. Expert review of anticancer therapy. 2002;2:330—6.

20. Kiladjian JJ, Cassinat B, Turlure P, Cambier N, Roussel M, Bellucci S et al. High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. Blood. 2006;108:2037—40.

21. Kiladjian JJ, Cassinat B, Chevret S, Turlure P, Cambier N, Roussel M et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112:3065—72.

22. Masarova L, Patel KP, Newberry KJ, Cortes J, Borthakur G, Konopleva M et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017;4:e165—75.

23. Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372:426—35.

24. Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC et al. Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. Blood. 2009;113:4829—33.

25. Czepulkowski B, Bhatt B, Rooney D. Malignancy and acquired abnormalities. Vol. 2. Oxford University Press. New York. 1992. Analysis of chromosomes from bone marrow and leukaemic blood. In: Human cytogenetics. A practical approach; pp. 1—25.

26. Jaradat SA, Khasawneh R, Kamal N, Matalka I, Al-Bishtawi M, AlSweedan S et al. Analysis of JAK2V617F mutation in Jordanian patients with myeloproliferative neoplasms. Hematol Oncol Stem Cell Ther. 2015;8:160—6.

27. Jones AV, Cross NCP, White HE, Green AR, Scott LM. Rapid identification of JAK2 exon 12 mutations using high resolution melting analysis. Haematologica. 2008;93:1560—4.

28. Subortseva IN, Kolosheinova TI, Pustovaya EI, Egorova EK, Kovrigina AM, Pliskunova YuV et al. Polycythemia vera: literature review and own data. Clinical Oncohematology (Klinicheskaya Gematologia). 2015;8:397—412. (In Russian)

29. Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono C et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23:2224—32.

30. Coucelo M, Caetano G, Sevivas T, Santos SA, Fidalgo T, Bento C et al. JAK2V617F allele burden is associated with thrombotic mechanisms activation in polycythemia vera and essential thrombocythemia patients. Int J Hematol. 2014;99:32—40.

31. Michiels JJ. Myeloproliferative and thrombotic burden and treatment outcome of thrombocythemia and polycythemia patients. World J Crit Care Med. 2015;4:230—9.

32. Kelly K, McMahon C, Langabeer S, Eliwan H, O’Marcaigh A, Smith OP. Congenital JAK2V617F polycythemia vera: where does the genotypephenotype diversity end? Blood. 2008;112:4356—7.