Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2025; 24: 66-77
Прогностическое значение внутренних тандемных дупликаций в гене FLT3 в различных цитогенетических и молекулярно-генетических подгруппах острого миелоидного лейкоза у детей
https://doi.org/10.24287/1726-1708-2025-24-1-66-77Аннотация
Внутренние тандемные дупликации в гене FLT3 (FLT3-ITD) часто встречаются при остром миелоидном лейкозе (ОМЛ) у взрослых (25–35%), реже у детей (15–17%) и при отсутствии терапии специфическими ингибиторами являются предикторами неблагоприятного прогноза. Однако это неблагоприятное влияние было продемонстрировано в основном при ОМЛ с нормальным кариотипом при отсутствии мутаций в гене NPM1 или при сочетании мутаций в гене NPM1 и FLT3-ITD с высокой аллельной нагрузкой (> 0,5). Наше исследование показывает высокую генетическую гетерогенность пациентов с FLT3-ITD и ее неблагоприятное прогностическое влияние во всех подгруппах ОМЛ. Наличие FLT3-ITD ухудшает исход заболевания в группе пациентов с нормальным кариотипом (2-летняя бессобытийная выживаемость (БСВ) – 32%, общая выживаемость (ОВ) – 55%) независимо от соотношения мутированного и интактного аллелей и наличия мутаций в гене NPM1. В группе с маркерами благоприятного прогноза наличие FLT3-ITD по сравнению с таковыми без FLT3-ITD ассоциировано со сниженными показателями 2-летней БСВ – 45% (95% доверительный интервал 26–78) и ОВ – 43% (95% доверительный интервал 22–83), а также с резистентностью к FLT3-ингибиторам при проведении противорецидивной терапии. В группах с маркерами промежуточного и неблагоприятного риска наличие FLT3-ITD ассоциировано с высокой резистентностью к индукционной терапии (57,9% и 55% соответственно). Однако добавление ингибиторов FLT3-киназы к «терапии спасения» и высокий процент проведения в этих группах трансплантации гемопоэтических стволовых клеток в первой линии в комбинации с FLT3-ингибиторами в качестве поддерживающей терапии значительно улучшили показатели 2-летней ОВ (68% против 62%). Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России.
Список литературы
1. Ley T.J., Miller C., Ding L.,Raphael B.J., Mungall A.J., Robertson A., et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368 (22): 2059–74. DOI: 10.1056/NEJMoa1301689. Erratum in: N Engl J Med 2013; 369 (1): 98.
2. Hou H.A., Tien H.F. Genomic landscape in acute myeloid leukemia and its implications in risk classification and targeted therapies. J Biomed Sci 2020; 27 (1): 81. DOI: 10.1186/s12929-020-00674-7
3. Stirewalt D.L., Kopecky K.J., Meshinchi S., Appelbaum F.R., Slovak M.L., Willman C.L., et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 2001; 97 (11): 3589– 95. DOI: 10.1182/blood.v97.11.3589. Erratum in: Blood 2001; 98 (4): 924.
4. Czogała M., Czogała W., Pawińska-Wąsikowska K., Książek T., Bukowska-Strakova K., Sikorska-Fic B., et al. Characteristics and Outcome of FLT3-ITD-Positive Pediatric Acute Myeloid Leukemia-Experience of Polish Pediatric Leukemia and Lymphoma Study Group from 2005 to 2022. Cancers (Basel) 2023; 15 (18): 4557. DOI: 10.3390/cancers15184557
5. Sharma N., Liesveld J.L. NPM1 Mutations in AML-The Landscape in 2023. Cancers (Basel) 2023; 15 (4): 1177. DOI: 10.3390/cancers15041177
6. Jan M., Snyder T.M., Corces-Zimmerman M.R., Vyas P., Weissman I.L., Quake S.R., Majeti R. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med 2012; 4 (149): 149ra118. DOI: 10.1126/scitranslmed.3004315
7. Meshinchi S., Appelbaum F.R. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res 2009; 15 (13): 4263–9. DOI: 10.1158/1078-0432.CCR-081123
8. Zwaan C.M., Meshinchi S., Radich J.P., Veerman A.J., Huismans D.R., Munske L., et al. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood 2003; 102 (7): 2387–94. DOI: 10.1182/blood-2002-12-3627
9. Meshinchi S., Alonzo T.A., Stirewalt D.L., Zwaan M., Zimmerman M., Reinhardt D., et al. Clinical implications of FLT3 mutations in pediatric AML. Blood 2006; 108 (12): 3654–61. DOI: 10.1182/blood-2006-03-009233
10. Döhner H., Wei A.H., Appelbaum F.R., Craddock C., DiNardo C.D., Dombret H., et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022; 140 (12): 1345–77. DOI: 10.1182/blood.2022016867
11. Fröhling S., Schlenk R.F., Breitruck J., Benner A., Kreitmeier S., Tobis K., et al; AML Study Group Ulm. Acute myeloid leukemia. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100 (13): 4372–80. DOI: 10.1182/blood-2002-05-1440
12. Tarlock K., Gerbing R.B., Ries R.E., Smith J.L., Leonti A., Huang B.J., et al. Prognostic impact of cooccurring mutations in FLT3-ITD pediatric acute myeloid leukemia. Blood Adv 2024; 8 (9): 2094–103. DOI: 10.1182/bloodadvances.2023011980
13. Kayser S., Kramer M., Martínez-Cuadrón D., Grenet J., Metzeler K.H., Sustkova Z., et al. Characteristics and outcome of patients with core-binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. Haematologica 2022; 107 (4): 836–43. DOI: 10.3324/haematol.2021.278645
14. Sakaguchi M., Yamaguchi H., Najima Y.,Usuki K., Ueki T., Oh I., et al. Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia. Blood Adv 2018; 2 (20): 2744–54. DOI: 10.1182/bloodadvances.2018020305
15. Den Nijs J.I., Gonggrijp H.S., Augustinus E., Leeksma C.H. Hot bands: A simple G-banding method for leukemic metaphases. Cancer Genet Cytogenet 1985; 15: 373–4.
16. ISCN 2020: An International System for Human Cytogenomic Nomenclature (2020). ISCN 2020, 2020.
17. Kaplan E.L., Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81.
18. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–70.
19. Herlin M.K., Yones S.A., Kjeldsen E., Holmfeldt L., Hasle H. What Is Abnormal in Normal Karyotype Acute Myeloid Leukemia in Children? Analysis of the Mutational Landscape and Prognosis of the TARGET-AML Cohort. Genes (Basel) 2021; 12 (6): 792. DOI: 10.3390/genes12060792
20. Sharma N., Liesveld J.L. NPM1 Mutations in AML-The Landscape in 2023. Cancers (Basel) 2023; 15 (4): 1177. DOI: 10.3390/cancers15041177
21. Matsukawa T., Yin M., Nigam N., et al. NUP98::Nsd1 and FLT3-ITD collaborate to generate acute myeloid leukemia. Leukemia 2023; 37: 1545–8. DOI: 10.1038/s41375-023-01913-0
22. Potluri S., Kellaway S.G., Coleman D.J.L., Keane P., Imperato M.R., Assi S.A., et al. Gene regulation in t(6;9) DEK::NUP214 Acute Myeloid Leukemia resembles that of FLT3ITD/NPM1 Acute Myeloid Leukemia but with an altered HOX/MEIS axis. Leukemia 2024; 38 (2): 403–7. DOI: 10.1038/s41375-023-02118-1
23. Liu J., Han W., Cai X., Wang Z., Cao L., Hua H., et al. Molecular genetic and clinical characterization of acute myeloid leukemia with trisomy 8 as the sole chromosome abnormality. Hematology 2022; 27 (1): 565–74. DOI: 10.1080/16078454.2022.2071799
24. Bhatnagar B., Kohlschmidt J.,Orwick S.J., Buelow D.R., Fobare S., Oakes C.C., et al. Framework of clonal mutations concurrent with WT1 mutations in adults with acute myeloid leukemia: Alliance for Clinical Trials in Oncology study. Blood Adv 2023; 7 (16): 4671–5. DOI: 10.1182/bloodadvances.2023010482
25. Stone R.M., Mandrekar S.J., Sanford B.L., Laumann K., Geyer S., Bloomfield C.D., et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017; 377: 454–64. DOI: 10.1056/NEJMoa1614359
26. Maziarz R.T.T., Patnaik M.M., Scott B.L., Mohan R.S., Deol A., Rowley S.D., et al. Radius: A phase 2 randomized trial investigating standard of care ± midostaurin after allogeneic stem cell transplant in FLT3ITD-Mutated AML. Blood 2018; 132 (S1): 662. DOI: 10.1182/blood-201899-113582 29954750
27. Alotaibi A.S., Yilmaz M., Kanagal-Shamanna R., Loghavi S., Kadia T.M., DiNardo C.D., et al. Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 inhibitors. Blood Cancer Discov 2021; 2 (2): 125–34. DOI: 10.1158/2643-3230.BCD-20-0143
Pediatric Hematology/Oncology and Immunopathology. 2025; 24: 66-77
The prognostic value of FLT3-ITD in different cytogenetic and molecular genetic subgroups of pediatric acute myeloid leukemia
https://doi.org/10.24287/1726-1708-2025-24-1-66-77Abstract
Internal tandem duplications in the FLT3 gene (FLT3-ITD) are common in acute myeloid leukemia (AML) in adults (25–35%) and less common in children (15–17%) and, in the absence of therapy with specific inhibitors, are predictors of a poor prognosis. However, this unfavorable impact has been demonstrated mainly in AML with a normal karyotype in the absence of mutations in the NPM1 gene, or in the presence of a combination of mutations in the NPM1 gene and FLT3-ITD with a high allele ratio (> 0.5). Our study shows a high genetic heterogeneity in the patients with FLT3-ITD and its unfavorable prognostic impact in all the AML subgroups. The presence of FLT3-ITD worsens disease outcomes in the group of patients with a normal karyotype (the 2-year event-free survival (EFS) – 32%, overall survival (OS) – 55%), irrespective of the ratio of mutated to wild-type allele and the presence of mutations in the NPM1 gene. In the group of patients with markers of a favorable prognosis, the presence of FLT3ITD was associated with reduced rates of the 2-year EFS (45%; 95% CI 26–78%) and OS (43%; 95%CI 22–83%), as well as with the resistance to FLT3 inhibitors during relapse therapy. In the groups of patients with intermediate and unfavorable risk markers, the presence of FLT3-ITD was associated with a high resistance to induction therapy (57.9% and 55%, respectively). However, the addition of FLT3 kinase inhibitors to salvage therapy and a high rate of first-line hematopoietic stem cell transplantation in combination with FLT3 inhibitors as maintenance therapy in these groups significantly improved the 2-year OS rate (68% vs 62%, respectively). The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation.
References
1. Ley T.J., Miller C., Ding L.,Raphael B.J., Mungall A.J., Robertson A., et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368 (22): 2059–74. DOI: 10.1056/NEJMoa1301689. Erratum in: N Engl J Med 2013; 369 (1): 98.
2. Hou H.A., Tien H.F. Genomic landscape in acute myeloid leukemia and its implications in risk classification and targeted therapies. J Biomed Sci 2020; 27 (1): 81. DOI: 10.1186/s12929-020-00674-7
3. Stirewalt D.L., Kopecky K.J., Meshinchi S., Appelbaum F.R., Slovak M.L., Willman C.L., et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 2001; 97 (11): 3589– 95. DOI: 10.1182/blood.v97.11.3589. Erratum in: Blood 2001; 98 (4): 924.
4. Czogała M., Czogała W., Pawińska-Wąsikowska K., Książek T., Bukowska-Strakova K., Sikorska-Fic B., et al. Characteristics and Outcome of FLT3-ITD-Positive Pediatric Acute Myeloid Leukemia-Experience of Polish Pediatric Leukemia and Lymphoma Study Group from 2005 to 2022. Cancers (Basel) 2023; 15 (18): 4557. DOI: 10.3390/cancers15184557
5. Sharma N., Liesveld J.L. NPM1 Mutations in AML-The Landscape in 2023. Cancers (Basel) 2023; 15 (4): 1177. DOI: 10.3390/cancers15041177
6. Jan M., Snyder T.M., Corces-Zimmerman M.R., Vyas P., Weissman I.L., Quake S.R., Majeti R. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med 2012; 4 (149): 149ra118. DOI: 10.1126/scitranslmed.3004315
7. Meshinchi S., Appelbaum F.R. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res 2009; 15 (13): 4263–9. DOI: 10.1158/1078-0432.CCR-081123
8. Zwaan C.M., Meshinchi S., Radich J.P., Veerman A.J., Huismans D.R., Munske L., et al. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood 2003; 102 (7): 2387–94. DOI: 10.1182/blood-2002-12-3627
9. Meshinchi S., Alonzo T.A., Stirewalt D.L., Zwaan M., Zimmerman M., Reinhardt D., et al. Clinical implications of FLT3 mutations in pediatric AML. Blood 2006; 108 (12): 3654–61. DOI: 10.1182/blood-2006-03-009233
10. Döhner H., Wei A.H., Appelbaum F.R., Craddock C., DiNardo C.D., Dombret H., et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022; 140 (12): 1345–77. DOI: 10.1182/blood.2022016867
11. Fröhling S., Schlenk R.F., Breitruck J., Benner A., Kreitmeier S., Tobis K., et al; AML Study Group Ulm. Acute myeloid leukemia. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100 (13): 4372–80. DOI: 10.1182/blood-2002-05-1440
12. Tarlock K., Gerbing R.B., Ries R.E., Smith J.L., Leonti A., Huang B.J., et al. Prognostic impact of cooccurring mutations in FLT3-ITD pediatric acute myeloid leukemia. Blood Adv 2024; 8 (9): 2094–103. DOI: 10.1182/bloodadvances.2023011980
13. Kayser S., Kramer M., Martínez-Cuadrón D., Grenet J., Metzeler K.H., Sustkova Z., et al. Characteristics and outcome of patients with core-binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. Haematologica 2022; 107 (4): 836–43. DOI: 10.3324/haematol.2021.278645
14. Sakaguchi M., Yamaguchi H., Najima Y.,Usuki K., Ueki T., Oh I., et al. Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia. Blood Adv 2018; 2 (20): 2744–54. DOI: 10.1182/bloodadvances.2018020305
15. Den Nijs J.I., Gonggrijp H.S., Augustinus E., Leeksma C.H. Hot bands: A simple G-banding method for leukemic metaphases. Cancer Genet Cytogenet 1985; 15: 373–4.
16. ISCN 2020: An International System for Human Cytogenomic Nomenclature (2020). ISCN 2020, 2020.
17. Kaplan E.L., Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81.
18. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–70.
19. Herlin M.K., Yones S.A., Kjeldsen E., Holmfeldt L., Hasle H. What Is Abnormal in Normal Karyotype Acute Myeloid Leukemia in Children? Analysis of the Mutational Landscape and Prognosis of the TARGET-AML Cohort. Genes (Basel) 2021; 12 (6): 792. DOI: 10.3390/genes12060792
20. Sharma N., Liesveld J.L. NPM1 Mutations in AML-The Landscape in 2023. Cancers (Basel) 2023; 15 (4): 1177. DOI: 10.3390/cancers15041177
21. Matsukawa T., Yin M., Nigam N., et al. NUP98::Nsd1 and FLT3-ITD collaborate to generate acute myeloid leukemia. Leukemia 2023; 37: 1545–8. DOI: 10.1038/s41375-023-01913-0
22. Potluri S., Kellaway S.G., Coleman D.J.L., Keane P., Imperato M.R., Assi S.A., et al. Gene regulation in t(6;9) DEK::NUP214 Acute Myeloid Leukemia resembles that of FLT3ITD/NPM1 Acute Myeloid Leukemia but with an altered HOX/MEIS axis. Leukemia 2024; 38 (2): 403–7. DOI: 10.1038/s41375-023-02118-1
23. Liu J., Han W., Cai X., Wang Z., Cao L., Hua H., et al. Molecular genetic and clinical characterization of acute myeloid leukemia with trisomy 8 as the sole chromosome abnormality. Hematology 2022; 27 (1): 565–74. DOI: 10.1080/16078454.2022.2071799
24. Bhatnagar B., Kohlschmidt J.,Orwick S.J., Buelow D.R., Fobare S., Oakes C.C., et al. Framework of clonal mutations concurrent with WT1 mutations in adults with acute myeloid leukemia: Alliance for Clinical Trials in Oncology study. Blood Adv 2023; 7 (16): 4671–5. DOI: 10.1182/bloodadvances.2023010482
25. Stone R.M., Mandrekar S.J., Sanford B.L., Laumann K., Geyer S., Bloomfield C.D., et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017; 377: 454–64. DOI: 10.1056/NEJMoa1614359
26. Maziarz R.T.T., Patnaik M.M., Scott B.L., Mohan R.S., Deol A., Rowley S.D., et al. Radius: A phase 2 randomized trial investigating standard of care ± midostaurin after allogeneic stem cell transplant in FLT3ITD-Mutated AML. Blood 2018; 132 (S1): 662. DOI: 10.1182/blood-201899-113582 29954750
27. Alotaibi A.S., Yilmaz M., Kanagal-Shamanna R., Loghavi S., Kadia T.M., DiNardo C.D., et al. Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 inhibitors. Blood Cancer Discov 2021; 2 (2): 125–34. DOI: 10.1158/2643-3230.BCD-20-0143
