Онкопедиатрия. 2014; 1: 23-33
Неходжкинские лимфомы у детей с первичными иммунодефицитами: клинические проявления, диагностика и лечение (А.С. Фёдорова, С.О. Шарапова, Т.М. Михалевская, С.Н. Алешкевич, М.В. Стеганцева, О.В. Алейникова)
Аннотация
Актуальность. Неходжкинские лимфомы (НХЛ) являются самыми частыми злокачественными новообразованиями, ассоциированными с первичными иммунодефицитами (ПИД). В настоящее время нет единого подхода к терапии НХЛ у детей с ПИД, и определение тактики лечения таких пациентов — по-прежнему актуальная и важная задача.
Цель. Анализ клинико-лабораторных данных и результатов лечения детей с ПИД, у которых развились НХЛ.
Пациенты и методы. За период 1996–2014 гг. проведен ретроспективный анализ диагностики и лечения 16 пациентов с ПИД- ассоциированными НХЛ с последующим сравнением с 277 случаями НХЛ у иммунокомпетентных детей. У 8 пациентов был комбинированный ПИД, у 5 — синдром Ниймеген, у 1 — синдром Блума, у 1 — Х-сцепленный лимфопролиферативный синдром.
Результаты. В 75% случаев диагноз ПИД был установлен после развития НХЛ. ПИД-ассоциированные НХЛ составили 5,7% всех НХЛ. Медиана возраста при диагностике НХЛ была меньше у детей с ПИД (6,3 против 10,0 лет; p < 0,05); при распределении по гистологическим вариантам превалировали крупноклеточные формы (68,8 против 24,5%; p < 0,001). У детей с комбинированными ПИД в раннем возрасте (медиана 1,3 года) развивалась ВЭБ-ассоциированная диффузная В-крупноклеточная лимфома с поражением легких. У 5 из 6 пациентов с синдромом хромосомной нестабильности развилась Т-НХЛ. Шестеро пациентов умерли от инфекционных осложнений, 2 — от опухолевой прогрессии, у 1 пациента был ранний рецидив, 2 умерли после развития второй НХЛ, 1 — после развития вторичного гемофагоцитарного синдрома. Всего живы 4 детей без признаков опухоли, время наблюдении — от 1,5 до 5,9 лет.
Заключение. ПИД необходимо диагностировать рано. Индивидуализированная химиотерапия, аккуратное сопроводительное лечение могут улучшить выживаемость детей с ПИД-ассоциированными НХЛ.
Список литературы
1. Chinen J., Anmuth D., Franklin A.R. et al. Long-term follow-up of patients with primary immunodeficiencies. J Allergy Clin Immunol. 2007; 120: 795–797.
2. De Miranda N.F., Björkman A., Pan-Hammarström Q. DNA repair: the link between primary immunodeficiency and cancer. Ann N Y Acad Sci. 2011 Dec; 1246: 50–63.
3. Tran H., Nourse J., Hall S. et al. Immunodeficiencyassociated lymphomas. Blood Rev. 2008; 22: 261–281.
4. Swerdlow S.H., Campo E., Harris N.L. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Pres, Lyon, France. 4th edition. 2008. Р. 312–316.
5. Murphy S.B. Classification, staging and end results of treatment in childhood non-Hodgkin’s lymphoma: dissimilarities from lymphomas in adults. Semin Oncol. 1980; 7: 332–339.
6. Самочатова Е.В., Шелихова Л.Н. Лечение неходжкинских лимфом и острых лейкозов из зрелых В-клеток у детей и подростков по данным региональных российских клиник. Онкогематология. 2011; 1: 30–34.
7. Sparano J.A., Lee J.Y., Kaplan L.D. et al. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood. 2011; 115: 3008–3016.
8. Al-Herz W., Bousfiha A., Casanova J.L. et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Front Immunology. 2014; 5: article 162.
9. Morra M., Howie D., Grande M.S. et al. X-linked lymphoproliferative disease: a progressive immunodeficiency. Ann Rev Immunol. 2001; 19: 657–82.
10. Booth C., Gilmour K.C., Veys P. et al. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood. 2011; 117: 53–62.
11. Seidemann K., Tiemann M., Henze G. et al. Therapy for Non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM Trials. Med Pediatr Oncol. 1999; 33: 536–544.
12. Sandoval C., Swift M. Treatment of lymphoid malignancies in patients with ataxia teleangiectasia. Med Pediatr Oncol. 1998; 31: 491–497.
13. Dembowska-Baginska B., Perek D., Brozyna A. et al. Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatr Blood Cancer. 2009; 52: 186–190.
14. Bienemann K., Burkhardt B., Modlich S. et al. Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey. Br J Haematol. 2011; 155: 468–476.
15. Sandlung J.T., Hudson M.M., Kennedy W. et al. Pilot study of modified LMB-based therapy for children with ataxiateleangiectasia and advanced stage high grade mature B-cell malignancies. Pediatr Blood Cancer. 2014; 61: 360–362.
16. Gladkowska-Dura M., Dzierzanowska-Fangrat K., Dura W.T. et al. Unique morphological spectrum of lymphomas in Nijmegen breakage syndrome (NBS) patients with high frequency of consecutive lymphoma formation. J Pathol. 2008; 216: 337–344.
17. Albert M.H., Gennery A.R., Greil J. et al. Successful SCT for Nijmegen breakage syndrome. Bone Marrow Transplant. 2010; 45: 622–626.
Oncopediatrics. 2014; 1: 23-33
Non-Hodgkin Lymphoma in Children with Primary Immunodeficiencies: Clinical Manifestations, Diagnosis and Management
Abstract
Introduction. Non-Hodgkin lymphoma (NHL) is the most frequent malignancy associated with primary immune deficiency disease (PID). There is no standard treatment approach for children with PID and NHL. Limited therapy tolerance, infectious status and immunodeficiency makes the choice of treatment challenging.
Aim. We aimed to present the clinical characteristics and outcomes of Belarusian children with PID who developed NHL.
Patients and Methods. We retrospectively reviewed 16 patients with PID and NHL and compared to 277 immunocompetent children with NHL, who were newly diagnosed from 1996 to 2014. Eight patients had combined PID, 5 — Nijmegen breakage syndrome, 1 — Bloom syndrome, 1 — Wiskott-Aldrich syndrome, 1 — Х-linked lymphoproliferative syndrome.
Results. In 75% cases PID was diagnosed simultaneously or after the NHL was confirmed. PID-associated NHL accounted for 5,7% of all NHL. Median age at NHL diagnosis was younger in children with PID (6,3 vs 10,0 years; p < 0,05) and distribution of histologic types was different with the prevalence of large-cell types (68,8 vs 24,5%; p < 0,001). Children with combined PID were the youngest with median age of 1,3 years, 5 of them developed EBV-associated diffuse large B-cell lymphoma with lung involvement. T-NHL progressed in 5 of 6 patients with chromosomal breakage syndrome. Six patients died of infections; two died after tumor progression; one child had early relapse; two died of second NHL and one of secondary hemophagocytic syndrome. Overall, 4 children are alive and disease free after a follow-up from 1 to 5 years.
Conclusions. PID needs to be diagnosed early. Individualized chemotherapy, comprehensive supportive treatment can reduce morbidity of children with PID and NHL.
References
1. Chinen J., Anmuth D., Franklin A.R. et al. Long-term follow-up of patients with primary immunodeficiencies. J Allergy Clin Immunol. 2007; 120: 795–797.
2. De Miranda N.F., Björkman A., Pan-Hammarström Q. DNA repair: the link between primary immunodeficiency and cancer. Ann N Y Acad Sci. 2011 Dec; 1246: 50–63.
3. Tran H., Nourse J., Hall S. et al. Immunodeficiencyassociated lymphomas. Blood Rev. 2008; 22: 261–281.
4. Swerdlow S.H., Campo E., Harris N.L. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Pres, Lyon, France. 4th edition. 2008. R. 312–316.
5. Murphy S.B. Classification, staging and end results of treatment in childhood non-Hodgkin’s lymphoma: dissimilarities from lymphomas in adults. Semin Oncol. 1980; 7: 332–339.
6. Samochatova E.V., Shelikhova L.N. Lechenie nekhodzhkinskikh limfom i ostrykh leikozov iz zrelykh V-kletok u detei i podrostkov po dannym regional'nykh rossiiskikh klinik. Onkogematologiya. 2011; 1: 30–34.
7. Sparano J.A., Lee J.Y., Kaplan L.D. et al. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood. 2011; 115: 3008–3016.
8. Al-Herz W., Bousfiha A., Casanova J.L. et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Front Immunology. 2014; 5: article 162.
9. Morra M., Howie D., Grande M.S. et al. X-linked lymphoproliferative disease: a progressive immunodeficiency. Ann Rev Immunol. 2001; 19: 657–82.
10. Booth C., Gilmour K.C., Veys P. et al. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood. 2011; 117: 53–62.
11. Seidemann K., Tiemann M., Henze G. et al. Therapy for Non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM Trials. Med Pediatr Oncol. 1999; 33: 536–544.
12. Sandoval C., Swift M. Treatment of lymphoid malignancies in patients with ataxia teleangiectasia. Med Pediatr Oncol. 1998; 31: 491–497.
13. Dembowska-Baginska B., Perek D., Brozyna A. et al. Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatr Blood Cancer. 2009; 52: 186–190.
14. Bienemann K., Burkhardt B., Modlich S. et al. Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey. Br J Haematol. 2011; 155: 468–476.
15. Sandlung J.T., Hudson M.M., Kennedy W. et al. Pilot study of modified LMB-based therapy for children with ataxiateleangiectasia and advanced stage high grade mature B-cell malignancies. Pediatr Blood Cancer. 2014; 61: 360–362.
16. Gladkowska-Dura M., Dzierzanowska-Fangrat K., Dura W.T. et al. Unique morphological spectrum of lymphomas in Nijmegen breakage syndrome (NBS) patients with high frequency of consecutive lymphoma formation. J Pathol. 2008; 216: 337–344.
17. Albert M.H., Gennery A.R., Greil J. et al. Successful SCT for Nijmegen breakage syndrome. Bone Marrow Transplant. 2010; 45: 622–626.
