The results of a registry study on acute myeloid leukemia in Russian children

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Abstract

We conducted a prospective observational registry study at the Dmitry Rogachev National Medical Research Center aiming to evaluate acute myeloid leukemia (AML) treatment and its outcomes in children in regional oncology/hematology centers of Russia as well as to report the results. The study was approved by the Independent Ethics Committee and the Scientific Council of the The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. We enrolled a total of 380 patients (205 boys and 175 girls) with newly diagnosed AML with the median age of 6.6 years (52 days to 18 years) and the median white blood cell count at disease onset equaling 17.7 (0–540) × 109/L. Fifty-two patients (13.6%) had WBC count greater than 100 × 109/L (hyperleukocytosis), 55 patients (14%) presented with neuroleukemia, and 60 (16%) had extramedullary lesions. The enrolled patients were stratified into a standard risk (92 patients), intermediate risk (99) or high risk (189) group. The first clinical and hematological remission (CR1) was achieved in 324 patients (85%), with early mortality rate reaching 8.4%. The median follow-up of the survivors was 8.3 years (1.5 months to 11.5 years). The 5-year overall survival (OS) in the entire cohort was 0.60 ± 0.025, the 5-year event-free survival (EFS) – 0.42 ± 0.025, and the cumulative incidence of relapse (CIR) – 0.37 ± 0.027. Initial extramedullary lesions (OS 0.47 ± 0.06 and EFS 0,37 ± 0.06) and hyperleukocytosis (OS 0.47 ± 0.07 and EFS 0.25 ± 0.06) led to a poorer prognosis in the AML patients, but CIR was not affected by these factors. The lowest OS rate was observed in the patients with monosomy 7 and with t(10;11)(p11-15;q21)/PICALM::MLLT10, totaling 0.2 ± 0.2 and 0.14 ± 0.1, respectively. Hematologic stem cell transplantation (HSCT) performed in CR1 significantly improved OS (0.84 ± 0.05), EFS (0.77 ± 0.06) and CIR (0.18 ± 0.05) in the high-risk patients. The majority of allogeneic HSCTs were performed using cells from haploidentical (51%), unrelated (25%) and genoidentical donors (18%). In the 50 patients treated with HSCT while in active disease, the OS was 50%. Out of 189 high-risk patients, only 67 (35%) underwent HSCT in CR1. The OS and EFS of the patients from regions were 0.51 ± 0.033 and 0.38 ± 0.032, respectively. The CIR was 0.36 ± 0,04. Relapses were reported in 37% of the patients who had achieved СR1. A total of 157 (41%) patients died during the study, out of which 112 patients had been treated at regional hospitals. The OS in the AML pediatric patients in Russia was 60%. The main treatment failures were toxic deaths (16%) and relapses (37%). In 2018, healthcare professionals of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology developed the AMLMRD-2018 protocol that could also be implemented in regional clinics, aiming to reduce toxic (infectious) death rates and thus increase the OS by at least 10% as well as to ensure HSCT accessibility for all high-risk patients.

About the authors

I. I. Kalinina

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

Email: burbir@mail.ru
ORCID iD: 0000-0002-0813-5626

Irina I. Kalinina - Cand. Med. Sci., a hematologist at the Department of Pediatric Hematology/ Oncology.

117 bldg. 1, Leninsky prospekt, 119571, Moscow

Russian Federation

D. A. Venyov

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0002-0183-1530

Moscow

Russian Federation

M. N. Sadovskaya

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0002-7918-680X

Moscow

Russian Federation

Yu. V. Starichkova

MIREA – Russian Technological University

ORCID iD: 0000-0003-1804-9761

Moscow

Russian Federation

K. A. Voronin

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0001-7578-9657

Moscow

Russian Federation

Yu. V. Olshanskaya

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0002-2352-7716

Moscow

Russian Federation

E. A. Zerkalenkova

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0001-9634-5828

Moscow

Russian Federation

M. V. Gaskova

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0002-3277-9018

Moscow

Russian Federation

A. M. Popov

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0002-0889-6986

Moscow

Russian Federation

M. E. Dubrovina

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0001-8228-4876

Moscow

Russian Federation

A. I. Mandzhieva

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0003-4039-430X

Moscow

Russian Federation

V. V. Lebedev

Regional Children’s Clinical Hospital of Ministry of Healthcare of the Krasnodar Region

ORCID iD: 0000-0001-8797-4956

Krasnodar

Russian Federation

R. N. Suprun

Regional Children’s Clinical Hospital of Ministry of Healthcare of the Krasnodar Region

ORCID iD: 0000-0001-6966-5180

Krasnodar

Russian Federation

A. P. Shapochnik

Regional Children’s Clinical Hospital

ORCID iD: 0000-0003-0630-9618

Orenburg

Russian Federation

V. Yu. Shapiro

The Republican Children’s Hospital of Ministry of Healthcare of the Republic of Tatarstan

ORCID iD: 0009-0000-6318-1003

Kazan

Russian Federation

T. G. Kadricheva

Krasnoyarsk Regional Clinical Centre for Maternal and Child Health

ORCID iD: 0000-0001-9697-806X

Krasnoyarsk

Russian Federation

E. V. Iakupova

The Republican Children’s Clinical Hospital

ORCID iD: 0009-0000-8940-2177

Ufa

Russian Federation

L. V. Moiseeva

Chelyabinsk Regional Children’s Clinical Hospital

Author for correspondence.

Chelyabinsk

Russian Federation

G. A. Novichkova

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0002-2322-5734

Moscow

Russian Federation

A. A. Maschan

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0002-0016-6698

Moscow

Russian Federation

M. A. Maschan

The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0003-1735-0093

Moscow

Russian Federation

References

  1. Bennett J.M., Catovsky D., Daniel M.T., Flandrin G., Galton D.A., Gralnick H.R., Sultan C. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976; 33 (4): 451–8.
  2. Alexenko M.Yu., Illario- nova O.I., Verzhbitskaya N.Yu., Zerkalenkova E.A., Novikova I.A., Panfe- rova A.V., et al. Immunophenotypic characterization of acute megakaryoblastic leukaemia in children. Pediatric Hematology/Oncology and Immunopathology 2019; 18 (3): 35–40. (In Russ.).
  3. Novikova I.A., Verzhbitskaya T.Yu., Movchan L.V., Tsaur G.A., Belevtsev M.V., Popov A.M. Russian-belarusian multicenter group standard guidelines for childhood acute lymphoblastic leukemia flow cytometric diagnostics. Oncohematology 2018; 13 (1): 73–82. (In Russ.).
  4. [Electronic resource]. URL: https://www.mediasphera.ru/issues/laboratornaya-sluzhba/2020/1/1230521982020011090 (accessed 20.07.2021).
  5. Dworzak M.N., Buldini B., Gaipa G., Ratei R., Hrusak O., Luria D., et al. AIEOP-BFM Consensus Guidelines 2016 for Flow Cytometric Immunophenotyping of Pediatric Acute Lymphoblastic Leukemia. Cytom Part B Clin 2018; 94 (1): 82–93.
  6. Human cytogenetics : a practical approach. Ed. by D.E. Rooney, B.H. Czepulkowski. IRL Press; 1992.
  7. [Electronic resource]. URL: https://www.amazon.com/ISCN-2016-International-Cytogenomic-Nomenclature-dp-3318058572/dp/3318058572/ref=mt_other?_encoding=UTF8&me=&qid= (accessed: 20.07.2021).
  8. Dolz S., Barragán E., Fuster Ó.,Llop M., Cervera J., Such E., et al. Novel real-time polymerase chain reaction assay for simultaneous detection of recurrent fusion genes in acute myeloid leukemia. J Mol Diagn 2013; 15 (5): 678–86.
  9. Jansen M., van der Velden V., van Dongen J. Efficient and easy detection of MLL-AF4, MLL-AF9 and MLL-ENL fusion gene transcripts by multiplex real-time quantitative RT-PCR in TaqMan and LightCycler. Leukemia 2005; 19 (11): 2016–8.
  10. Zerkalenkova E., Lebedeva S., Kazakova A., Tsaur G., Starichkova Y., Timofeeva N., et al. Acute myeloid leukemia with t(10;11)(p1112;q23.3): Results of Russian Pediatric AML registration study. Int J Lab Hematol 2019; 41 (2): 287–92.
  11. Ben Abdelali R., Asnafi V., Petit A.,Micol J.B., Callens C., Villarese P., et al. The prognosis of CALM-AF10-positive adult T-cell acute lymphoblastic leukemias depends on the stage of maturation arrest. Haematologica 2013; 98 (11): 1711–7.
  12. Starichkova Yu.V., Kalinina I.I., Pavlyuk A.V., Zerkalenkova E.A., Danilkin Yu.A., Fominykh А.M., Maschan M.A., Novichkova G.A. The effectiveness of the information system for managing data from a registration study of acute myeloid leukemia in children. Pediatric Hematology/Oncology and Immunopathology. 2019; 18 (1): 144–51. (In Russ.). doi: 10.24287/1726-1708-201918-1-144-151
  13. Salimova T.Yu., Kalinina I.I., Goronkova O.V., Pavlyuk A.V., Starichkova Yu.V., Olshanskaya Yu.V. et al. The management of epidemiological and clinical data in a multicenter study on acute myeloid leukemia in children. Patent RU 2015662790; 01.12.2015. Application submitted on 09.10.2015. (In Russ.)]
  14. Döhner H., Estey E., Grimwade D., Amadori S., Appelbaum F.R., Büchner T., et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129 (4): 424–47.
  15. Kalinina I.I., Venyov D.A., Olshanskaya Yu.V., Sadovskaya M.N., Goronkova O.V., Salimova T.Yu., et al. The outcomes of children with acute myeloid leukemia treated in accordance with the AML–MM-2006 protocol. Pediatric Hematology/Oncology and Immunopathology. 2022; 21 (1): 20–35. (In Russ.). doi: 10.24287/1726-1708-2022-211-20-35
  16. Nemirovchenko V.S., Shervashidze M.A., Valiev T.T., Kondratchik K.L. Treatment results of pediatric acute myeloid leukemia with epigenetic drugs addition. Onkogematologiya = Oncohematology 2020;15(2):19–28. (In Russ.). doi: 10.17650/1818-8346-2020-15-219-28
  17. Popa A.V., Gorokhova E.S., Flejshman E.V., Sokova O.I., Serebrya- kova I.N., Nemirovchenko V.S. Epigenetic therapy is an important component in treating children with acute myeloid leukemia. Clinical oncohematology 2011; 4 (1): 20–6. (In Russ.).
  18. Creutzig U., Zimmermann M., Bourquin J.-P., Dworzak M.N., Fleischhack G., Graf N., et al. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: Results from study AML-BFM 2004. Blood 2013; 122 (1): 37–43.
  19. Rasche M., Zimmermann M., Borschel L., Bourquin J.-P., Dworzak M., Klingebiel T., et al. Successes and challenges in the treatment of pediatric acute myeloid leukemia: a retrospective analysis of the AML-BFM trials from 1987 to 2012. Leukemia 2018; 32 (10): 2167–77.
  20. Kalinina I.I., Shneider M.M., Kirsanova N.P., Baydildina D.D., Suntsova E.V., Goronkova O.V. et al. Clinical and genetic features of acute myeloid leukemia with t(8;21) in children and outcomes of treatment according to the AML-MM-2000 protocol. Oncohematology 2011; (1): 11–9. (In Russ.).
  21. Kalinina I.I., Maschan A.A., Olshanskaya Yu.V. et al. The diagnosis and treatment of acute myeloid leukemia in children. М.; 2021. 104 p. (In Russ.).
  22. Morgan C.J. Landmark analysis: A primer. J Nucl Cardiol 2019; 26 (2): 391–3.
  23. Pession A., Masetti R., Rizzari C., Putti M.C., Casale F., Fagioli F., et al. Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia. Blood 2013; 122 (2): 170–8.
  24. Tsukimoto I., Tawa A., Horibe K., Tabuchi K., Kigasawa H., Tsuchida M., et al. Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: The AML99 trial from the Japanese childhood AML cooperative study group. J Clin Oncol 2009; 27 (24): 4007–13.
  25. Imamura T., Iwamoto S., Kanai R., Shimada A., Terui K., Osugi Y., et al. Outcome in 146 patients with paediatric acute myeloid leukaemia treated according to the AML99 protocol in the period 2003-06 from the Japan Association of Childhood Leukaemia Study. Br J Haematol 2012; 159 (2): 204–10.
  26. Gibson B.E.S., Webb D.K.H., Howman A.J., De Graaf S.S.N., Harrison C.J., Wheatley K.; United Kingdom Childhood Leukaemia Working Group and the Dutch Childhood Oncology Group. Results of a randomized trial in children with Acute Myeloid Leukaemia: Medical Research Council AML12 trial. Br J Haematol 2011; 155 (3): 366–76.
  27. Abrahamsson J., Forestier E., Heldrup J., Jahnukainen K., Jóns- son O.G., Lausen B., et al. Responseguided induction therapy in pediatric acute myeloid leukemia with excellent remission rate. J Clin Oncol 2011; 29 (3): 310–5.
  28. Tierens A., Bjørklund E., Siitonen S., Vibeke Marquart H., Wulff-Juergensen G., Pelli- niemi T.-T., et al. Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study. Br J Haematol 2016; 174 (4): 600–9.
  29. Rubnitz J.E., Inaba H., Dahl G., Ribeiro R.C., Bowman W.P., Taub J., et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: Results of the AML02 multicentre trial. Lancet Oncol 2010; 11 (6): 543–52.

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Copyright (c) 2025 Kalinina I.I., Venyov D.A., Sadovskaya M.N., Starichkova Y.V., Voronin K.A., Olshanskaya Y.V., Zerkalenkova E.A., Gaskova M.V., Popov A.M., Dubrovina M.E., Mandzhieva A.I., Lebedev V.V., Suprun R.N., Shapochnik A.P., Shapiro V.Y., Kadricheva T.G., Iakupova E.V., Moiseeva L.V., Novichkova G.A., Maschan A.A., Maschan M.A.

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