Acute lymphoblastic leukemia in children with Down syndrome: “Moscow–Berlin” experience

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Abstract

Down syndrome (DS) is one of the most common chromosomal abnormalities. Children with DS are more likely to develop acute lymphoblastic leukemia (ALL). Standard therapy is usually used to treat DS-ALL, but children with DS-ALL have an inferior outcome compared to non-DS patients, mainly due to increased therapy toxicity. The purpose of the study: in this study we aimed to analyze our experience of treating DS-ALL according to original protocol “Moscow–Berlin”. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The analysis included primary ALL patients, aged 1 to 18 years, who received therapy in Russian and Belarusian clinics participating in the “Moscow–Berlin” study from January 2008 to December 2020. To analyze the treatment results of SD-ALL patients, a comparison group was formed from all patients with ALL registered in the database, using the matched-pair method. A total of 8296 ALL patients were registered in the database, of which 135 (1.63%) were patients with DS-ALL. The predominant age group of DS-ALL patients is 3–10 years. Among them there was no T-cell ALL patient, and both favorable and unfavorable genetic abnormalities were significantly less common. There were no differences in early response between DS-ALL and non-DS-ALL patients. The event-free (61 ± 6%) and overall survival (74 ± 4%) of DS-ALL patients was significantly lower than in the comparison group (84 ± 3% and 89 ± 3% respectively; p < 0.001). No differences were found in relapse rate, while the treatment-related mortality (TRM) was higher in DS-ALL group (19.3 ± 3.5% versus 3.9 ± 1.2%; p˂0.001) in all treatment phase. The treatment results for DS-ALL patients remain unsatisfactory; therefore, new approaches to optimizing therapy are needed. High toxicity and associated TRM are the main problem. Future strategies to improve outcome in DS-ALL should include improved supportive care, the use of targeted drugs and immunotherapy, as well as the identification of new molecular genetic features. 

About the authors

R. N. Suprun

Regional Children Clinical Hospital

Krasnodar

Russian Federation

Yu. V. Roumiantseva

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology;
Pirogov Russian National Research Medical University

ORCID iD: 0000-0001-9670-3728

Moscow

Russian Federation

O. I. Bydanov

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology;
Belarusian Research Center for Pediatric Oncology, Hematology and Immunology

Moscow;

Minsk region, Borovlyany

Belarus

L. I. Zharikova

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology;
Pirogov Russian National Research Medical University

ORCID iD: 0000-0002-1105-8676

Moscow

Russian Federation

S. N. Lagoiko

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

ORCID iD: 0000-0002-3793-104X

Moscow

Russian Federation

V. V. Lebedev

Regional Children Clinical Hospital

Krasnodar

Russian Federation

K. L. Kondratchik

Pirogov Russian National Research Medical University;
Morozov Children City Clinical Hospital

Moscow

Russian Federation

K. S. Aslanyan

Regional Children Clinical Hospital

Rostov-on-Don

Russian Federation

O. V. Aleynikova

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

ORCID iD: 0000-0003-0143-1921

Moscow

Russian Federation

L. G. Fechina

Regional Children Clinical Hospital

Yekaterinburg

Russian Federation

G. V. Bykova

Regional Children Clinical Hospital

Stavropol

Russian Federation

N. I. Ponomareva

Pirogov Russian National Research Medical University

Moscow

Russian Federation

N. V. Myakova

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

ORCID iD: 0000-0002-4779-1896

Moscow

Russian Federation

A. M. Popov

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

ORCID iD: 0000-0002-0889-6986

Moscow

Russian Federation

Yu. V. Olshanskaya

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

ORCID iD: 0000-0002-2352-7716

Moscow

Russian Federation

A. N. Kazakova

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Moscow

Russian Federation

A. A. Maschan

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology;
Pirogov Russian National Research Medical University

ORCID iD: 0000-0002-0016-6698

Moscow

Russian Federation

G. A. Novichkova

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

ORCID iD: 0000-0002-2322-5734

Moscow

Russian Federation

A. I. Karachunskiy

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology;
Pirogov Russian National Research Medical University

Author for correspondence.
Email: alexandr.karachunski@fccho-moscow.ru

Moscow

Russian Federation

References

  1. Seewald L., Taub J.W., Maloney K.W., McCabe E.R.B. Acute leukemias in children with Down syndrome. Mol Genet Metab 2012; 107 (1–2): 25–30. doi: 10.1016/j.ymgme.2012.07.011. PMID: 22867885
  2. Ross J.A., Spector L.G., Robison L.L., Olshan A.F. Epidemiology of leukemia in children with Down syndrome. Pediatr Blood Cancer 2005; 44 (1): 8–12. doi: 10.1002/pbc.20165. PMID: 15390275
  3. Vis J.C., Duff els M.G., Winter M.M., Weijerman M.E., Cobben J.M., Huisman S.A., et al. Down syndrome: a cardiovascular perspective. J Intellect Disabil Res 2009; 53 (5): 419– 25. doi: 10.1111/j.1365-2788.2009.01158.x. PMID: 19228275
  4. Watt T., Robertson K., Jacobs R.J. Refractive error, binocular vision and accommodation of children with Down syndrome. Clin Exp Optom 2015; 98 (1): 3–11. doi: 10.1111/cxo.12232. PMID: 25395109
  5. Ferreira-Vasques A.T., Lamônica D.A.C. Motor, linguistic, personal and social aspects of children with Down syndrome. J Appl Oral Sci 2015; 23 (4): 424–30. doi: 10.1590/1678-775720150102. PMID: 26398516
  6. Lange B. The management of neoplastic disorders of haematopoiesis in children with Down's syndrome. Br J Haematol 2000; 110 (3): 512–24. doi: 10.1046/j.1365-2141.2000.02027.x. PMID: 10997960
  7. Hasle H., Clemmensen I.H., Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 2000; 355 (9199): 165–9. doi: 10.1016/S0140-6736(99)05264-2. PMID: 10675114
  8. Yang Q., Rasmussen S.A., Friedman J.M. Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study. Lancet 2002; 359 (9311): 1019–25. doi: 10.1016/s0140-6736(02)08092-3. PMID: 11937181
  9. Langebrake C., Creutzig U., Reinhardt D. Immunophenotype of Down syndrome acute myeloid leukemia and transient myeloproliferative disease differs significantly from other diseases with morphologically identical or similar blasts. Klin Padiatr 2005; 217 (3): 126–34. doi: 10.1055/s-2005-836510. PMID: 15858703
  10. Wechsler J., Greene M., McDevitt M.A., Anastasi J., Karp J.E., Le Beau M.M., et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 2002; 32 (1): 148–52. doi: 10.1038/ng955.; PMID: 12172547
  11. Caldwell J.T., Ge Y., Taub J.W. Prognosis and management of acute myeloid leukemia in patients with Down syndrome. Expert Rev Hematol 2014; 7 (6): 831–40. doi: 10.1586/17474086.2014.959923. PMID: 25231553
  12. Creutzig U., van den Heuvel-Eibrink M.M., Gibson B., Dworzak M.N., Adachi S., de Bont E., et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood 2012; 120 (16): 3187–205. doi: 10.1182/blood2012-03-362608. PMID: 22879540
  13. Taga T., Watanabe T., Tomizawa D., Kudo K., Terui K., Moritake H., et al. Preserved High Probability of Overall Survival with Significant Reduction of Chemotherapy for Myeloid Leukemia in Down Syndrome: A Nationwide Prospective Study in Japan. Pediatr Blood Cancer 2016; 63 (2): 248–54. doi: 10.1002/pbc.25789. PMID: 26481183
  14. Ge Y., Stout M.L., Tatman D.A., Jensen T.L., Buck S., Thomas R.L., et al. GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst 2005; 97 (3): 226–31. doi: 10.1093/jnci/dji026. PMID: 15687366
  15. Maloney K.W., Carroll W.L., Carroll A.J., Devidas M., Borowitz M.J., Martin P.L., et al. Down syndrome childhood acute lymphoblastic leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome: a report from the Children's Oncology Group. Blood 2010; 116 (7): 1045–50. doi: 10.1182/blood-2009-07-235291. PMID: 20442364
  16. Zeller B., Gustafsson G., Forestier E., Abrahamsson J., Clausen N., Heldrup J., et al. Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 2005; 128 (6): 797–804. doi: 10.1111/j.1365-2141.2005.05398.x. PMID: 15755283
  17. Buitenkamp T.D., Izraeli S., Zimmermann M., Forestier E., Heerema N.A., van den Heuvel-Eibrink M.M., et al. Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood 2014; 123 (1): 70–7. doi: 10.1182/blood-2013-06-509463. PMID: 24222333
  18. Arico M., Ziino O., Valsecchi M.G., Cazzaniga G., Baronci C., Messina C., et al. Acute lymphoblastic leukemia and Down syndrome: presenting features and treatment outcome in the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Cancer 2008; 113 (3): 515–21. doi: 10.1002/cncr.23587. PMID: 18521927
  19. Zwaan C.M., Kaspers G.J., Pieters R., Hahlen K., Janka-Schaub G.E., van Zantwijk C.H., et al. Diff erent drug sensitivity profi les of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood 2002; 99 (1): 245–51. doi: 10.1002/cncr.23587. PMID: 11756178
  20. Maloney K.W., Wood B., Whitlock J.A., Loh M., Raetz E.A., Winick N., et al. Event free (EFS) and overall survival (OS) for children with Down syndrome (DS) and B-lymhoblastic leukemia in Children's Oncology Group (COG) trials AALL0232 and AALL0331. Pediatric Blood Cancer 2014; 61 (S1): S4, abstract #4009.
  21. Buitenkamp T.D., Mathot R.A., de Haas V., Pieters R., Zwaan C.M. Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia. Haematologica 2010; 95 (7): 1106– 13. doi: 10.3324/haematol.2009.019778. PMID: 20418240
  22. Bene M., Castoldi G., Knapp W., Ludwig W.D., Matutes E., Orfao A., et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995; 9 (10): 1783‒6. PMID: 7564526
  23. Новикова И.А., Вержбицкая Т.Ю., Мовчан Л.В., Цаур Г.А., Белевцев М.В., Попов А.М. Стандарт российско-белорусской кооперативной группы по иммунофенотипированию острого лимфобластного лейкоза у детей. Онкогематология 2018; 13 (1): 73–82. doi: 10.17650/1818-8346-2018-13-1-73-82
  24. Kaplan E.L., Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81.
  25. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50 (3): 163‒70. PMID: 5910392
  26. Kalbfleisch J., Prentice R. The Statistical Analysis of Failure Time Data. Wiley, New York; 2002.
  27. Cortese G., Andersen P.K. Competing risks and time-dependent covariates. Biom J 2010; 52 (1): 138‒58. doi: 10.1002/bimj.200900076. PMID: 20029852
  28. Dordelmann M., Schrappe M., Reiter A., Zimmermann M., Graf N., Schott G., et al. Down's syndrome in childhood acute lymphoblastic leukemia: clinical characteristics and treatment outcome in four consecutive BFM trials. Berlin–Frankfurt–Munster Group. Leukemia 1998; 12 (5): 645‒51. doi: 10.1038/sj.leu.2400989. PMID: 9593260
  29. Chessells J.M., Harrison G., Richards S.M., Bailey C.C., Hill F.G., Gibson B.E., et al. Down’s syndrome and acute lymphoblastic leukaemia: clinical features and response to treatment. Arch Dis Child 2001; 85 (4): 321–5. doi: 10.1136/adc.85.4.321. PMID: 11567943
  30. Whitlock J.A., Sather H.N., Gaynon P., Robison L.L., Wells R.J., Trigg M., et al. Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood 2005; 106 (13): 4043–9. doi: 10.1182/blood-2003-10-3446. PMID: 16109782
  31. Conter V., Arico M., Valsecchi M.G., Basso G., Biondi A., Madon E., et al. Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) acute lymphoblastic leukemia studies, 1982– 1995. Leukemia 2000; 14 (12): 2196–204. doi: 10.1038/sj.leu.2401963. PMID: 11187911
  32. Lejeune J., Rethore M.O., de Blois M.C., Maunoury-Burolla C., Mir M., Nicolle L., et al. Metabolism of monocarbons and trisomy 21: sensitivity to methotrexate. Ann Genet 1986; 29 (1): 16‒9. PMID: 2940958
  33. Garre M.L., Relling M.V., Kalwinsky D., Dodge R., Crom W.R., Abromowitch M., et al. Pharmacokinetics and toxicity of methotrexate in children with Down syndrome and acute lymphocytic leukemia. J Pediatr 1987; 111 (4): 606‒12. doi: 10.1016/s0022- 3476(87)80131-2. PMID: 2958611
  34. Ueland P.M., Refsum H., Christensen B. Methotrexate sensitivity in Down’s syndrome: a hypothesis. Cancer Chemother Pharmacol 1990; 25 (5): 384‒6. doi: 10.1007/BF00686245. PMID: 2137726
  35. Belkov V.M., Krynetski E.Y., Scheutz J.D., Yanishevski Y., Masson E., Matthew S., et al. Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation. Blood 1999; 93 (5): 1643‒50. PMID: 10029593

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Copyright (c) 2021 Suprun R.N., Roumiantseva Y.V., Bydanov O.I., Zharikova L.I., Lagoiko S.N., Lebedev V.V., Kondratchik K.L., Aslanyan K.S., Aleynikova O.V., Fechina L.G., Bykova G.V., Ponomareva N.I., Myakova N.V., Popov A.M., Olshanskaya Y.V., Kazakova A.N., Maschan A.A., Novichkova G.A., Karachunskiy A.I.

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