Diagnóstico y tratamiento de la leucemia linfoblástica aguda pediátrica: reseña histórica
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Keywords
Leucemia Linfoblástica, Diagnóstico, Terapéutica, Pediatría, Historia
Resumen
La leucemia linfoblástica aguda (LLA) es la neoplasia maligna más frecuente en la infancia, presentándose con mayor incidencia entre los 10 y 14 años en la población mexicana. La LLA resulta de la proliferación anormal de una clona maligna de leucocitos. La población pediátrica mexicana presenta características idiosincráticas que se asocian a una evolución menos favorable, en comparación con la población caucásica.
En 1847, Rudolph Virchow acuñó por primera vez el término leucemia. En 1976 surgió la clasificación Franco-Británico-Americana, la cual describió las características morfológicas de las células leucémicas como L1, L2 y L3, brindando mayor certeza diagnóstica y diferenciando entre leucemia mieloide y linfoide. En esa década, la sobrevida libre de enfermedad era del 20%.
En 2008, la Organización Mundial de la Salud (OMS) introdujo la clasificación inmunológica basada en el inmunofenotipo de las leucemias, marcando una nueva era en el pronóstico y la evolución de la enfermedad. Esta clasificación permitió reducir los errores de diagnóstico morfológico interobservador mediante la identificación de antígenos que clasifican la estirpe celular y el estadio de maduración.
La expresión y combinación de antígenos celulares, así como los reordenamientos moleculares, se relacionan directamente con el pronóstico de la LLA. El tratamiento ha evolucionado en paralelo con los avances diagnósticos en los últimos años, con estrategias dirigidas a limitar la toxicidad del tratamiento mediante ciclos de quimioterapia más seguros.
Referencias
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2. Fajardo-Gutiérrez A, Rendón-Macías ME, Mejia-Aranguré JM. Cancer epidemiology in Mexican children. Overall results. Rev Med Inst Mex Seguro Soc. 2011;49 (Suppl 1):S43-70.
3. Hernández-Morales AL, Zonana-Nacach A, Zaragoza-Sandoval VM. Associated risk factors in acute leukemia in children. A cases and controls study. Rev Med Inst Mex Seguro Soc. 2009;47(5):497-503.
4. Kampen KR. The discovery and early understanding of leukemia. Leuk Res. 2012;36(1):6-13. Disponible en: http://dx.doi.org/10.1016/j.leukres.2011.09.028
5. Piller G. Leukaemia - a brief historical review from ancient times to 1950. Br J Haematol. 2001;112(2):282-92. Disponible en: http://dx.doi.org/10.1046/j.1365-2141.2001.02411.x
6. Ladines-Castro W, Barragán-Ibañez G, Luna-Pérez MA, et al. Morphology of leukaemias. Rev Med Hosp Gen. 2016;79(2):107-13. Disponible en: https://www.sciencedirect.com/science/article/pii/S0185106315000724
7. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976;33(4):451-8. Disponible en: http://dx.doi.org/10.1111/j.1365-2141.1976.tb03563.x
8. Silva ASJ, Oliveira GH de M, Júnior LSDAS, et al. Clinical Utility of Flow Cytometry Immunophenotyping in Acute Lymphoblastic Leukemia. Blood. 2020;136:8. Disponible en: https://www.sciencedirect.com/science/article/pii/S0006497118729182
9. Basso G, Case C, Dell’Orto MC. Diagnosis and genetic subtypes of leukemia combining gene expression and flow cytometry. Blood Cells Mol Dis. 2007;39(2):164-8. Disponible en: http://dx.doi.org/10.1016/j.bcmd.2007.05.004
10. Ruiz-Argüelles GJ. Advances in the diagnosis and treatment of acute and chronic leukemia in Mexico. Salud Publica Mex. 2016;58(2):291-5. Disponible en: https://saludpublica.mx/index.php/spm/article/view/7799
11. Basso G, Buldini B, De Zen L, et al. New methodologic approaches for immunophenotyping acute leukemias. Haematologica. 2001;86(7):675-92. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/11454522
12. Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 2008;111(8):3941-67. Disponible en: http://dx.doi.org/10.1182/blood-2007-11-120535
13. Peters JM, Ansari MQ. Multiparameter flow cytometry in the diagnosis and management of acute leukemia. Arch Pathol Lab Med. 2011;135(1):44-54. Disponible en: http://dx.doi.org/10.5858/2010-0387-RAR.1
14. van Lochem EG, van der Velden VHJ, Wind HK, et al. Immunophenotypic differentiation patterns of normal hematopoiesis in human bone marrow: reference patterns for age-related changes and disease-induced shifts. Cytometry B Clin Cytom. 2004;60(1):1-13. Disponible en: https://onlinelibrary.wiley.com/doi/10.1002/cyto.b.20008
15. Szczepański T, van der Velden VHJ, van Dongen JJM. Flow-cytometric immunophenotyping of normal and malignant lymphocytes. Clin Chem Lab Med. 2006;44(7):775-96. Disponible en: http://dx.doi.org/10.1515/CCLM.2006.146
16. Raetz EA, Teachey DT. T-cell acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2016;2016(1):580-8. Disponible en: http://dx.doi.org/10.1182/asheducation-2016.1.580
17. van Dongen JJM, Lhermitte L, Böttcher S, et al. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012;26(9):1908-75. Disponible en: http://dx.doi.org/10.1038/leu.2012.120
18. Al-Shieban S, Byrne E, Trivedi P, et al. Immunohistochemical distinction of haematogones from B lymphoblastic leukaemia/lymphoma or B-cell acute lymphoblastic leukaemia (B-ALL) on bone marrow trephine biopsies: a study on 62 patients. Br J Haematol. 2011;154(4):466-70. Disponible en: http://dx.doi.org/10.1111/j.1365-2141.2011.08760.x
19. Owaidah TM, Rawas FI, Al Khayatt MF, et al. Expression of CD66c and CD25 in acute lymphoblastic leukemia as a predictor of the presence of BCR/ABL rearrangement. Hematol Oncol Stem Cell Ther. 2008;1(1):34-7. Disponible en: http://dx.doi.org/10.1016/s1658-3876(08)50058-6
20. Emerenciano M, Renaud G, Sant’Ana M, et al. Challenges in the use of NG2 antigen as a marker to predict MLL rearrangements in multi-center studies. Leuk Res. 2011;35(8):1001-7. Disponible en: http://dx.doi.org/10.1016/j.leukres.2011.03.006
21. Bras AE, de Haas V, van Stigt A, et al. CD123 expression levels in 846 acute leukemia patients based on standardized immunophenotyping. Cytometry B Clin Cytom. 2019;96(2):134-42. Disponible en: http://dx.doi.org/10.1002/cyto.b.21745
22. Blunck CB, Terra-Granado E, Noronha EP, et al. CD9 predicts ETV6-RUNX1 in childhood B-cell precursor acute lymphoblastic leukemia. Hematol Transfus Cell Ther. 2019;41(3):205-11. Disponible en: http://dx.doi.org/10.1016/j.htct.2018.11.007
23. Chulián S, Martínez-Rubio Á, Pérez-García VM, et al. High-Dimensional Analysis of Single-Cell Flow Cytometry Data Predicts Relapse in Childhood Acute Lymphoblastic Leukaemia. Cancers. 2020;13(1). Disponible en: http://dx.doi.org/10.3390/cancers13010017
24. Ratei R, Sperling C, Karawajew L, et al. Immunophenotype and clinical characteristics of CD45-negative and CD45-positive childhood acute lymphoblastic leukemia. Ann Hematol.1998;77(3):107-14. Disponible en: http://dx.doi.org/10.1007/s002770050424
25. Ou D-Y, Luo J-M, Ou D-L. CD20 and Outcome of Childhood Precursor B-cell Acute Lymphoblastic Leukemia: A Meta-analysis. J Pediatr Hematol Oncol. 2015;37(3):e138-42. Disponible en: http://dx.doi.org/10.1097/MPH.0000000000000256
26. Matarraz S, López A, Barrena S, et al. The immunophenotype of different immature, myeloid and B-cell lineage-committed CD34+ hematopoietic cells allows discrimination between normal/reactive and myelodysplastic syndrome precursors. Leukemia. 2008;22(6):1175-83. Disponible en: http://dx.doi.org/10.1038/leu.2008.49
27. Ten Hacken E, Gounari M, Ghia P, et al. The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia. Leukemia. 2019;33(2):287-98. Disponible en: http://dx.doi.org/10.1038/s41375-018-0303-x
28. Willier S, Rothämel P, Hastreiter M, et al. CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy. Blood. 2021;137(8):1037-49. Disponible en: http://dx.doi.org/10.1182/blood.2020006921
29. Tsagarakis NJ, Papadhimitriou SI, Pavlidis D, et al. Flow cytometric predictive scoring systems for common fusions ETV6/RUNX1, BCR/ABL1, TCF3/PBX1 and rearrangements of the KMT2A gene, proposed for the initial cytogenetic approach in cases of B-acute lymphoblastic leukemia. Int J Lab Hematol. 2019;41(3):364-72. Disponible en: http://dx.doi.org/10.1111/ijlh.12983
30. Kruse A, Abdel-Azim N, Kim HN, et al. Minimal Residual Disease Detection in Acute Lymphoblastic Leukemia. Int J Mol Sci. 2020;21(3). Disponible en: http://dx.doi.org/10.3390/ijms21031054
31. Health Quality Ontario. Minimal Residual Disease Evaluation in Childhood Acute Lymphoblastic Leukemia: A Clinical Evidence Review. Ont Health Technol Assess Ser. 2016;16(7):1-52. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/27099643
32. Berry DA, Zhou S, Higley H, et al. Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis. JAMA Oncol. 2017;3(7):e170580. Disponible en: http://dx.doi.org/10.1001/jamaoncol.2017.0580
33. Borowitz MJ, Devidas M, Hunger SP, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood. 2008;111(12):5477-85. Disponible en: https://ashpublications.org/blood/article/111/12/5477/23818/Clinical-significance-of-minimal-residual-disease
34. Heikamp EB, Pui C-H. Next-Generation Evaluation and Treatment of Pediatric Acute Lymphoblastic Leukemia. J Pediatr. 2018;203:14-24.e2. Disponible en: http://dx.doi.org/10.1016/j.jpeds.2018.07.039
35. Pinkel D. Five-Year Follow-Up of "Total Therapy" of Childhood Lymphocytic Leukemia. JAMA. 1971;216(4):648-652. DOI: 10.1001/jama.1971.03180300032007
36. Sallan SE, Hitchcock-Bryan S, Gelber R, et al. Influence of intensive asparaginase in the treatment of childhood non-T-cell acute lymphoblastic leukemia. Cancer Res. 1983;43(11):5601-7.
37. Sullivan MP, Chen T, Dyment PG, et al. Equivalence of intrathecal chemotherapy and radiotherapy as central nervous system prophylaxis in children with acute lymphatic leukemia: a pediatric oncology group study. Blood. 1982;60(4):948-58.
38. Pui C-H, Evans WE. A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol. 2013;50(3):185-96. Disponible en: http://dx.doi.org/10.1053/j.seminhematol.2013.06.007
39. Malczewska M, Kośmider K, Bednarz K, et al. Recent advances in treatment options for childhood acute lymphoblastic leukemia. Cancers (Basel). 2022;14(8):2021. Disponible en: https://pubmed.ncbi.nlm.nih.gov/35454927/
40. Kaczmarska A, Śliwa P, Lejman M, et al. The use of inhibitors of tyrosine kinase in paediatric haemato-oncology-when and why? Int J Mol Sci. 2021;22(21):12089. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584725/
41. Bӧhm JW, Sia KCS, Jones C, et al. Combination efficacy of ruxolitinib with standard-of-care drugs in CRLF2-rearranged Ph-like acute lymphoblastic leukemia. Leukemia. 2021;35(11):3101-12. Disponible en: https://www.nature.com/articles/s41375-021-01248-8
2. Fajardo-Gutiérrez A, Rendón-Macías ME, Mejia-Aranguré JM. Cancer epidemiology in Mexican children. Overall results. Rev Med Inst Mex Seguro Soc. 2011;49 (Suppl 1):S43-70.
3. Hernández-Morales AL, Zonana-Nacach A, Zaragoza-Sandoval VM. Associated risk factors in acute leukemia in children. A cases and controls study. Rev Med Inst Mex Seguro Soc. 2009;47(5):497-503.
4. Kampen KR. The discovery and early understanding of leukemia. Leuk Res. 2012;36(1):6-13. Disponible en: http://dx.doi.org/10.1016/j.leukres.2011.09.028
5. Piller G. Leukaemia - a brief historical review from ancient times to 1950. Br J Haematol. 2001;112(2):282-92. Disponible en: http://dx.doi.org/10.1046/j.1365-2141.2001.02411.x
6. Ladines-Castro W, Barragán-Ibañez G, Luna-Pérez MA, et al. Morphology of leukaemias. Rev Med Hosp Gen. 2016;79(2):107-13. Disponible en: https://www.sciencedirect.com/science/article/pii/S0185106315000724
7. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976;33(4):451-8. Disponible en: http://dx.doi.org/10.1111/j.1365-2141.1976.tb03563.x
8. Silva ASJ, Oliveira GH de M, Júnior LSDAS, et al. Clinical Utility of Flow Cytometry Immunophenotyping in Acute Lymphoblastic Leukemia. Blood. 2020;136:8. Disponible en: https://www.sciencedirect.com/science/article/pii/S0006497118729182
9. Basso G, Case C, Dell’Orto MC. Diagnosis and genetic subtypes of leukemia combining gene expression and flow cytometry. Blood Cells Mol Dis. 2007;39(2):164-8. Disponible en: http://dx.doi.org/10.1016/j.bcmd.2007.05.004
10. Ruiz-Argüelles GJ. Advances in the diagnosis and treatment of acute and chronic leukemia in Mexico. Salud Publica Mex. 2016;58(2):291-5. Disponible en: https://saludpublica.mx/index.php/spm/article/view/7799
11. Basso G, Buldini B, De Zen L, et al. New methodologic approaches for immunophenotyping acute leukemias. Haematologica. 2001;86(7):675-92. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/11454522
12. Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 2008;111(8):3941-67. Disponible en: http://dx.doi.org/10.1182/blood-2007-11-120535
13. Peters JM, Ansari MQ. Multiparameter flow cytometry in the diagnosis and management of acute leukemia. Arch Pathol Lab Med. 2011;135(1):44-54. Disponible en: http://dx.doi.org/10.5858/2010-0387-RAR.1
14. van Lochem EG, van der Velden VHJ, Wind HK, et al. Immunophenotypic differentiation patterns of normal hematopoiesis in human bone marrow: reference patterns for age-related changes and disease-induced shifts. Cytometry B Clin Cytom. 2004;60(1):1-13. Disponible en: https://onlinelibrary.wiley.com/doi/10.1002/cyto.b.20008
15. Szczepański T, van der Velden VHJ, van Dongen JJM. Flow-cytometric immunophenotyping of normal and malignant lymphocytes. Clin Chem Lab Med. 2006;44(7):775-96. Disponible en: http://dx.doi.org/10.1515/CCLM.2006.146
16. Raetz EA, Teachey DT. T-cell acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2016;2016(1):580-8. Disponible en: http://dx.doi.org/10.1182/asheducation-2016.1.580
17. van Dongen JJM, Lhermitte L, Böttcher S, et al. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012;26(9):1908-75. Disponible en: http://dx.doi.org/10.1038/leu.2012.120
18. Al-Shieban S, Byrne E, Trivedi P, et al. Immunohistochemical distinction of haematogones from B lymphoblastic leukaemia/lymphoma or B-cell acute lymphoblastic leukaemia (B-ALL) on bone marrow trephine biopsies: a study on 62 patients. Br J Haematol. 2011;154(4):466-70. Disponible en: http://dx.doi.org/10.1111/j.1365-2141.2011.08760.x
19. Owaidah TM, Rawas FI, Al Khayatt MF, et al. Expression of CD66c and CD25 in acute lymphoblastic leukemia as a predictor of the presence of BCR/ABL rearrangement. Hematol Oncol Stem Cell Ther. 2008;1(1):34-7. Disponible en: http://dx.doi.org/10.1016/s1658-3876(08)50058-6
20. Emerenciano M, Renaud G, Sant’Ana M, et al. Challenges in the use of NG2 antigen as a marker to predict MLL rearrangements in multi-center studies. Leuk Res. 2011;35(8):1001-7. Disponible en: http://dx.doi.org/10.1016/j.leukres.2011.03.006
21. Bras AE, de Haas V, van Stigt A, et al. CD123 expression levels in 846 acute leukemia patients based on standardized immunophenotyping. Cytometry B Clin Cytom. 2019;96(2):134-42. Disponible en: http://dx.doi.org/10.1002/cyto.b.21745
22. Blunck CB, Terra-Granado E, Noronha EP, et al. CD9 predicts ETV6-RUNX1 in childhood B-cell precursor acute lymphoblastic leukemia. Hematol Transfus Cell Ther. 2019;41(3):205-11. Disponible en: http://dx.doi.org/10.1016/j.htct.2018.11.007
23. Chulián S, Martínez-Rubio Á, Pérez-García VM, et al. High-Dimensional Analysis of Single-Cell Flow Cytometry Data Predicts Relapse in Childhood Acute Lymphoblastic Leukaemia. Cancers. 2020;13(1). Disponible en: http://dx.doi.org/10.3390/cancers13010017
24. Ratei R, Sperling C, Karawajew L, et al. Immunophenotype and clinical characteristics of CD45-negative and CD45-positive childhood acute lymphoblastic leukemia. Ann Hematol.1998;77(3):107-14. Disponible en: http://dx.doi.org/10.1007/s002770050424
25. Ou D-Y, Luo J-M, Ou D-L. CD20 and Outcome of Childhood Precursor B-cell Acute Lymphoblastic Leukemia: A Meta-analysis. J Pediatr Hematol Oncol. 2015;37(3):e138-42. Disponible en: http://dx.doi.org/10.1097/MPH.0000000000000256
26. Matarraz S, López A, Barrena S, et al. The immunophenotype of different immature, myeloid and B-cell lineage-committed CD34+ hematopoietic cells allows discrimination between normal/reactive and myelodysplastic syndrome precursors. Leukemia. 2008;22(6):1175-83. Disponible en: http://dx.doi.org/10.1038/leu.2008.49
27. Ten Hacken E, Gounari M, Ghia P, et al. The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia. Leukemia. 2019;33(2):287-98. Disponible en: http://dx.doi.org/10.1038/s41375-018-0303-x
28. Willier S, Rothämel P, Hastreiter M, et al. CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy. Blood. 2021;137(8):1037-49. Disponible en: http://dx.doi.org/10.1182/blood.2020006921
29. Tsagarakis NJ, Papadhimitriou SI, Pavlidis D, et al. Flow cytometric predictive scoring systems for common fusions ETV6/RUNX1, BCR/ABL1, TCF3/PBX1 and rearrangements of the KMT2A gene, proposed for the initial cytogenetic approach in cases of B-acute lymphoblastic leukemia. Int J Lab Hematol. 2019;41(3):364-72. Disponible en: http://dx.doi.org/10.1111/ijlh.12983
30. Kruse A, Abdel-Azim N, Kim HN, et al. Minimal Residual Disease Detection in Acute Lymphoblastic Leukemia. Int J Mol Sci. 2020;21(3). Disponible en: http://dx.doi.org/10.3390/ijms21031054
31. Health Quality Ontario. Minimal Residual Disease Evaluation in Childhood Acute Lymphoblastic Leukemia: A Clinical Evidence Review. Ont Health Technol Assess Ser. 2016;16(7):1-52. Disponible en: https://www.ncbi.nlm.nih.gov/pubmed/27099643
32. Berry DA, Zhou S, Higley H, et al. Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis. JAMA Oncol. 2017;3(7):e170580. Disponible en: http://dx.doi.org/10.1001/jamaoncol.2017.0580
33. Borowitz MJ, Devidas M, Hunger SP, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood. 2008;111(12):5477-85. Disponible en: https://ashpublications.org/blood/article/111/12/5477/23818/Clinical-significance-of-minimal-residual-disease
34. Heikamp EB, Pui C-H. Next-Generation Evaluation and Treatment of Pediatric Acute Lymphoblastic Leukemia. J Pediatr. 2018;203:14-24.e2. Disponible en: http://dx.doi.org/10.1016/j.jpeds.2018.07.039
35. Pinkel D. Five-Year Follow-Up of "Total Therapy" of Childhood Lymphocytic Leukemia. JAMA. 1971;216(4):648-652. DOI: 10.1001/jama.1971.03180300032007
36. Sallan SE, Hitchcock-Bryan S, Gelber R, et al. Influence of intensive asparaginase in the treatment of childhood non-T-cell acute lymphoblastic leukemia. Cancer Res. 1983;43(11):5601-7.
37. Sullivan MP, Chen T, Dyment PG, et al. Equivalence of intrathecal chemotherapy and radiotherapy as central nervous system prophylaxis in children with acute lymphatic leukemia: a pediatric oncology group study. Blood. 1982;60(4):948-58.
38. Pui C-H, Evans WE. A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol. 2013;50(3):185-96. Disponible en: http://dx.doi.org/10.1053/j.seminhematol.2013.06.007
39. Malczewska M, Kośmider K, Bednarz K, et al. Recent advances in treatment options for childhood acute lymphoblastic leukemia. Cancers (Basel). 2022;14(8):2021. Disponible en: https://pubmed.ncbi.nlm.nih.gov/35454927/
40. Kaczmarska A, Śliwa P, Lejman M, et al. The use of inhibitors of tyrosine kinase in paediatric haemato-oncology-when and why? Int J Mol Sci. 2021;22(21):12089. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584725/
41. Bӧhm JW, Sia KCS, Jones C, et al. Combination efficacy of ruxolitinib with standard-of-care drugs in CRLF2-rearranged Ph-like acute lymphoblastic leukemia. Leukemia. 2021;35(11):3101-12. Disponible en: https://www.nature.com/articles/s41375-021-01248-8
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Valdez-Garibay B, Sosa-Bustamante GP, González AP, Linares-Segovia B, Martínez-Villegas O, Reyes-Sosa AM, et al. Diagnóstico y tratamiento de la leucemia linfoblástica aguda pediátrica: reseña histórica. Rev Med Inst Mex Seguro Soc [Internet]. 2025 Jul. 1 [cited 2025 Jul. 12];63(4):e6552. Available from: https://revistamedica.imss.gob.mx/index.php/revista_medica/article/view/6552