Uso de medicamentos e terapias biotecnológicas no tratamento de leucemia linfoblástica aguda
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May 8, 2025
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Resumo
Objetivo: Realizar uma análise sobre a eficácia terapêutica e segurança dos medicamentos e terapias oriundos da biotecnologia moderna para o tratamento da Leucemia Linfoblástica Aguda (LLA). Métodos: Foi realizada uma revisão integrativa conduzindo uma busca nas bases de dados do PubMed/MEDLINE, SCOPUS, Web of Science e LiLACS, e os estudos foram selecionados conforme critérios de inclusão e exclusão. Resultados: Após a busca e seleção, 30 artigos foram selecionados para leitura completa, sendo agrupados em 3 diferentes grupos. Os estudos conduzidos com L-asparaginase (L-ASNase) indicaram que este medicamento é utilizado em esquema de poliquimioterapia, e em alguns indivíduos, a administração de L-ASNase nativa de E. coli resulta no desenvolvimento de alergia, sendo necessária sua substituição. Os anticorpos monoclonais vêm sendo utilizados especialmente em casos de LLA R/R, com destaque para o Inotuzumabe Ozogamicina. Por fim, a terapia com células CAR-T, também utilizada em indivíduos com LLA R/R, Esta terapia apresenta uma série de eventos adversos que necessitam ser melhor compreendidos e cautelosamente monitorados. Considerações finais: Estes produtos terapêuticos, oriundos destas tecnologias são seguros e eficazes no tratamento de LLA, desde que seus efeitos sejam devidamente monitorados e os eventuais eventos adversos, sejam prontamente administrados.
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Como Citar
AbreuJ. A. C. de, & AlbuquerqueE. P. A. (2025). Uso de medicamentos e terapias biotecnológicas no tratamento de leucemia linfoblástica aguda. Revista Eletrônica Acervo Saúde, 25(5), e19561. https://doi.org/10.25248/reas.e19561.2025
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Revisão Bibliográfica
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Referências
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2. ANVISA. AGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA. Gerência-geral de medicamentos e produtos biológicos. Parecer Público de Avaliação do Medicamento. Brasília, 2019; 18. Disponível em: https ://consult as.anvisa.gov.br/#/pareceres/q/?nomeProduto=Besponsa. Acessado em 17 de junho de 2024.
3. ALBERTSEN BK, et al. Intermittent versus continuous PEG-asparaginase to reduce asparaginase-associated toxicities: A NOPHO ALL2008 randomized study. Journal of Clinical Oncology, 2019; 37(19): 1638–1646.
4. AL-SALAMA ZT. Inotuzumab Ozogamicin: A Review in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia. Targeted Oncology, 2018; 13(4): 525–532.
5. ACS. AMERICAN CANCER SOCIETY. Key Statistics for Acute Lymphocytic Leukemia (ALL) - American Cancer Society. 2024. Disponível em: https ://www.cancer.org/cancer/types/acute-lymphocytic-leukemia/about/key-statistics.html. Acessado em 14 junho de 2024.
6. AN F, et al. Influence of patient characteristics on chimeric antigen receptor T cell therapy in B-cell acute lymphoblastic leukemia. Nature Communications, 2020; 11(1): 5928.
7. BATTISTEL AP, et al. Allergic reactions to asparaginase: Retrospective cohort study in pediatric patients with acute lymphoid leukemia. Hematology, Transfusion and Cell Therapy, 2020; 3(1): 9–14.
8. BROWNEEK, et al. Clinical Characteristics of Intravenous PEG-Asparaginase Hypersensitivity Reactions in Patients Undergoing Treatment for Acute Lymphoblastic Leukemia. Journal of Pediatric Oncology Nursing, 2018; 35(2): 103-109.
9. CHEN S, et al. Estimates and Projections of the Global Economic Cost of 29 Cancers in 204 Countries and Territories from 2020 to 2050. JAMA Oncology, 2023; 9(4): 465–472.
10. DINNDORF PA, et al. FDA Drug Approval Summary: Pegaspargase (Oncaspar®) for the First-Line Treatment of Children with Acute Lymphoblastic Leukemia (ALL). The Oncologist, 2007; 12(8): 991–998.
11. ETTINGER LJ, et al. An open‐label, multicenter study of polyethylene glycol‐L‐asparaginase for the treatment of acute lymphoblastic leukemia. Cancer, 1995; 75(5): 1176–1181.
12. FREY N e PORTERD. Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy. Biology of Blood and Marrow Transplantation, 2019; 25(4): 123–127.
13. FURZERJ, et al. Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada. JAMA Oncology, 2020; 6(3): 393–401.
14. HAY KA, et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood, 2019; 133(15): 1652–1663.
15. HERNANDEZN e BESSONEF. Hepatotoxicity Induced by Biological Agents: Clinical Features and Current Controversies. Journal of Clinical and Translational Hepatology, 2022; 10(3): 486–495.
16. INABA H, et al. Acute lymphoblastic leukaemia. The Lancet, 2013, 381(9881): 1943–1955.
17. JABBOUR E, et al. Chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD, with or without blinatumomab, is highly effective in patients with Philadelphia chromosome–negative acute lymphoblastic leukemia in first salvage. Cancer, 2018; 124(20): 4044–4055.
18. JABBOUR E, et al. Prognostic factors for outcome in patients with refractory and relapsed acute lymphocytic leukemia treated with inotuzumab ozogamicin, a CD22 monoclonal antibody. American Journal of Hematology, 2015; 90 (3): 193–196.
19. JABBOUR EJ, et al. Efficacy and safety analysis by age cohort of inotuzumab ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia enrolled in INO-VATE. Cancer, 2018; 124(8): 1722–1732.
20. JIANG H, et al. Anti-CD19 chimeric antigen receptor-modified T-cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia: An open-label pragmatic clinical trial. American Journal of Hematology, 2019a; 94(10): 1113–1122.
21. JIANG H, et al. Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy. Annals of Hematology, 2019b; 98(7): 1721–1732.
22. KANTARJIAN H, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. The Lancet Oncology, 2018; 19(2): 240–248.
23. KANTARJIAN H, et al. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: A phase 2 study. The Lancet Oncology, 2012; 13(4): 403–411.
24. KANTARJIAN HM, et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. The Lancet Haematology, 2017; 4(8): 387–398.
25. KANTARJIAN HM, et al. Inotuzumab Ozogamicin Versus Standard Care for Acute Lymphoblastic Leukemia. New England Journal of Medicine, 2016; 375(8): 740–753.
26. KANTARJIANH, et al. Blinatumomab versus Chemotherapy for Advenced Acute Lymphoblastic Leukemia. New England Journal of Medicine, 2017; 376(9): 836–847.
27. KAUL S, et al. A retrospective analysis of treatment-related hospitalization costs of pediatric, adolescent, and young adult acute lymphoblastic leukemia. Cancer Medicine, 2016; 5(2): 221–229.
28. MA Y, et al. A phase I study of CAR-T bridging HSCT in patients with acute CD19+ relapse/refractory B-cell leukemia. Oncology Letters, 2020; 20(4): 20.
29. MALARD F e MOHTY M. Acute lymphoblastic leukaemia. The Lancet, 2020; 395(10230): 1146–1162.
30. MARKS DI, et al. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. The Lancet Haematology, 2022; 9(4): 262–275.
31. MAUDESL, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. New England Journal of Medicine, 2018; 378(5): 439–448.
32. MEANY HJ, et al. Feasibility study of a novel Experimental induction protocol combining B43-PAP (anti-CD19) immunotoxin with standard induction chemotherapy in children and adolescents with relapsed B-lineage ALL: A report from the children’s oncology group. Journal of Immunotherapy, 2015; 38(7): 299–305.
33. MICHOT JM, et al.Immune-related adverse events with immune checkpoint blockade: A comprehensive review. European Journal of Cancer, 2016; 54: 139–148.
34. MS. MINISTÉRIO DA SAÚDE - AGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA. Resolução - RE No560, de 18 de fevereiro de 2022. Brasília, 2022. Disponível em: https ://www.in.gov.br/en/web/dou/-/resolucao-re-n-560-de-18-de-fevereiro-de-2022-382329255. Acessado em 14 de junho de 2024.
35. MS. MINISTÉRIO DA SAÚDE - INSTITUTO NACIONAL DE CÂNCER. Atlas On-line de Mortalidade. 2024. Disponível em: https ://mortalidade.inca.gov.br/MortalidadeWeb/pages/Modelo01/consultar.xhtml. Acessado em 14 junho de 2024.
36. NAGURA E, et al. Nation-wide randomized comparative study of doxorubicin, vincristine and prednisolone combination therapy with and without L-asparaginase for adult acute lymphoblastic leukemia. Cancer Chemotherapy and Pharmacology, 1994; 33(5): 359–365.
37. OUZZANI M, et al. Rayyan—a web and mobile app for systematic reviews. Systematic Review, 2016; 5: 210.
38. PAGE MJ, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. The British Medical Journal, 2021; 372: 71.
39. PANOSYAN EH, et al. Asparaginase Antibody and Asparaginase Activity in Children with Higher-Risk Acute Lymphoblastic Leukemia: Children’s Cancer Group Study CCG-1961. Journal of Pediatric Hematology/Oncology, 2004; 26(4): 217–226.
40. PATEL B, et al. Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: Toxicity data from the UKALL14 trial. Leukemia, 2017; 31(1): 58–64.
41. PEDROSAF e LINS M. Leucemia linfóide aguda: uma doença curável Revista Brasileira de Saúde Materno Infantil, 2002; 2(1): 63–68.
42. PIETERS R, et al. Pharmacokinetics, pharmacodynamics, efficacy, and safety of a new recombinant asparaginase preparation in children with previously untreated acute lymphoblastic leukemia: A randomized phase 2 clinical trial. Blood, 2008; 112(13): 4832–4838.
43. PLACE AE, et al. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): A randomised, open-label phase 3 trial. The Lancet Oncology, 2015; 16(16): 1677–1690.
44. RAETZEA, et al. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: A children’s oncology group pilot study. Journal of Clinical Oncology, 2008; 26(22): 3756–3762.
45. RAETZEA, et al. Re-Induction Chemoimmunotherapy with Epratuzumab in Relapsed Acute Lymphoblastic Leukemia (ALL): Phase II Results from Children’s Oncology Group (COG) Study ADVL04P2. Pediatric Blood & Cancer, 2015; 62: 1171–1175.
46. RAPONI S, et al. A. Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: Analysis of 552 cases. Leukemia and Lymphoma, 2011; 52(6): 1098–1107.
47. SMITH OP e HANN IM. Clinical Features and Therapy of Lymphoblastic Leukemia. In: ARCECIRJ, HANN IM, SMITHOP. (orgs). Pediatric Hematology. Third Edit.: Blackwell Publishing, 2006; 450–481.
48. SUZMAN DL, et al. Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents. Liver International, 2018; 38(6): 976–987.
49. TERWILLIGERT e ABDUL-HAYM. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer Journal, 2017; 7(6): 577.
50. THOMASDA, et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome - Negative precursor B-lineage acute lymphoblastic leukemia. Journal of Clinical Oncology, 2010; 28(24): 3880–3889.
51. TURCOTTE LM, et al. Cost of Pediatric Acute Lymphoblastic Leukemia Care in the Current Treatment Era. Bood, 2021; 138(1): 663.
52. TURTLE CJ, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. Journal of Clinical Investigation, 2016; 126(6): 2123–2138.
53. VOLLMAR BS, et al. Calicheamicin antibody-drug conjugates with improved properties. Molecular Cancer Therapeutics, 2021; 20(6): 1112–1120.
54. WIDJAJANTO PH, et al. L-asparaginase: Long-term results of a randomized trial of the effect of additional 3 doses during consolidation treatment in the indonesian WK-ALL-2000 protocol. Journal of Pediatric Hematology/Oncology, 2013; 35(8): 597–602.
55. ZENY e YEHMM. Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy. Seminars in Diagnostic Pathology, 2019; 36(6): 434–440.
56. ZHANG N, et al. Humanized CD19-directed CAR-T Cell Therapy in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia With CNSL or Neurological Comorbidity. Journal of Immunotherapy, 2022; 45(9): 396–406.
2. ANVISA. AGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA. Gerência-geral de medicamentos e produtos biológicos. Parecer Público de Avaliação do Medicamento. Brasília, 2019; 18. Disponível em: https ://consult as.anvisa.gov.br/#/pareceres/q/?nomeProduto=Besponsa. Acessado em 17 de junho de 2024.
3. ALBERTSEN BK, et al. Intermittent versus continuous PEG-asparaginase to reduce asparaginase-associated toxicities: A NOPHO ALL2008 randomized study. Journal of Clinical Oncology, 2019; 37(19): 1638–1646.
4. AL-SALAMA ZT. Inotuzumab Ozogamicin: A Review in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia. Targeted Oncology, 2018; 13(4): 525–532.
5. ACS. AMERICAN CANCER SOCIETY. Key Statistics for Acute Lymphocytic Leukemia (ALL) - American Cancer Society. 2024. Disponível em: https ://www.cancer.org/cancer/types/acute-lymphocytic-leukemia/about/key-statistics.html. Acessado em 14 junho de 2024.
6. AN F, et al. Influence of patient characteristics on chimeric antigen receptor T cell therapy in B-cell acute lymphoblastic leukemia. Nature Communications, 2020; 11(1): 5928.
7. BATTISTEL AP, et al. Allergic reactions to asparaginase: Retrospective cohort study in pediatric patients with acute lymphoid leukemia. Hematology, Transfusion and Cell Therapy, 2020; 3(1): 9–14.
8. BROWNEEK, et al. Clinical Characteristics of Intravenous PEG-Asparaginase Hypersensitivity Reactions in Patients Undergoing Treatment for Acute Lymphoblastic Leukemia. Journal of Pediatric Oncology Nursing, 2018; 35(2): 103-109.
9. CHEN S, et al. Estimates and Projections of the Global Economic Cost of 29 Cancers in 204 Countries and Territories from 2020 to 2050. JAMA Oncology, 2023; 9(4): 465–472.
10. DINNDORF PA, et al. FDA Drug Approval Summary: Pegaspargase (Oncaspar®) for the First-Line Treatment of Children with Acute Lymphoblastic Leukemia (ALL). The Oncologist, 2007; 12(8): 991–998.
11. ETTINGER LJ, et al. An open‐label, multicenter study of polyethylene glycol‐L‐asparaginase for the treatment of acute lymphoblastic leukemia. Cancer, 1995; 75(5): 1176–1181.
12. FREY N e PORTERD. Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy. Biology of Blood and Marrow Transplantation, 2019; 25(4): 123–127.
13. FURZERJ, et al. Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada. JAMA Oncology, 2020; 6(3): 393–401.
14. HAY KA, et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood, 2019; 133(15): 1652–1663.
15. HERNANDEZN e BESSONEF. Hepatotoxicity Induced by Biological Agents: Clinical Features and Current Controversies. Journal of Clinical and Translational Hepatology, 2022; 10(3): 486–495.
16. INABA H, et al. Acute lymphoblastic leukaemia. The Lancet, 2013, 381(9881): 1943–1955.
17. JABBOUR E, et al. Chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD, with or without blinatumomab, is highly effective in patients with Philadelphia chromosome–negative acute lymphoblastic leukemia in first salvage. Cancer, 2018; 124(20): 4044–4055.
18. JABBOUR E, et al. Prognostic factors for outcome in patients with refractory and relapsed acute lymphocytic leukemia treated with inotuzumab ozogamicin, a CD22 monoclonal antibody. American Journal of Hematology, 2015; 90 (3): 193–196.
19. JABBOUR EJ, et al. Efficacy and safety analysis by age cohort of inotuzumab ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia enrolled in INO-VATE. Cancer, 2018; 124(8): 1722–1732.
20. JIANG H, et al. Anti-CD19 chimeric antigen receptor-modified T-cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia: An open-label pragmatic clinical trial. American Journal of Hematology, 2019a; 94(10): 1113–1122.
21. JIANG H, et al. Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy. Annals of Hematology, 2019b; 98(7): 1721–1732.
22. KANTARJIAN H, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. The Lancet Oncology, 2018; 19(2): 240–248.
23. KANTARJIAN H, et al. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: A phase 2 study. The Lancet Oncology, 2012; 13(4): 403–411.
24. KANTARJIAN HM, et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. The Lancet Haematology, 2017; 4(8): 387–398.
25. KANTARJIAN HM, et al. Inotuzumab Ozogamicin Versus Standard Care for Acute Lymphoblastic Leukemia. New England Journal of Medicine, 2016; 375(8): 740–753.
26. KANTARJIANH, et al. Blinatumomab versus Chemotherapy for Advenced Acute Lymphoblastic Leukemia. New England Journal of Medicine, 2017; 376(9): 836–847.
27. KAUL S, et al. A retrospective analysis of treatment-related hospitalization costs of pediatric, adolescent, and young adult acute lymphoblastic leukemia. Cancer Medicine, 2016; 5(2): 221–229.
28. MA Y, et al. A phase I study of CAR-T bridging HSCT in patients with acute CD19+ relapse/refractory B-cell leukemia. Oncology Letters, 2020; 20(4): 20.
29. MALARD F e MOHTY M. Acute lymphoblastic leukaemia. The Lancet, 2020; 395(10230): 1146–1162.
30. MARKS DI, et al. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. The Lancet Haematology, 2022; 9(4): 262–275.
31. MAUDESL, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. New England Journal of Medicine, 2018; 378(5): 439–448.
32. MEANY HJ, et al. Feasibility study of a novel Experimental induction protocol combining B43-PAP (anti-CD19) immunotoxin with standard induction chemotherapy in children and adolescents with relapsed B-lineage ALL: A report from the children’s oncology group. Journal of Immunotherapy, 2015; 38(7): 299–305.
33. MICHOT JM, et al.Immune-related adverse events with immune checkpoint blockade: A comprehensive review. European Journal of Cancer, 2016; 54: 139–148.
34. MS. MINISTÉRIO DA SAÚDE - AGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA. Resolução - RE No560, de 18 de fevereiro de 2022. Brasília, 2022. Disponível em: https ://www.in.gov.br/en/web/dou/-/resolucao-re-n-560-de-18-de-fevereiro-de-2022-382329255. Acessado em 14 de junho de 2024.
35. MS. MINISTÉRIO DA SAÚDE - INSTITUTO NACIONAL DE CÂNCER. Atlas On-line de Mortalidade. 2024. Disponível em: https ://mortalidade.inca.gov.br/MortalidadeWeb/pages/Modelo01/consultar.xhtml. Acessado em 14 junho de 2024.
36. NAGURA E, et al. Nation-wide randomized comparative study of doxorubicin, vincristine and prednisolone combination therapy with and without L-asparaginase for adult acute lymphoblastic leukemia. Cancer Chemotherapy and Pharmacology, 1994; 33(5): 359–365.
37. OUZZANI M, et al. Rayyan—a web and mobile app for systematic reviews. Systematic Review, 2016; 5: 210.
38. PAGE MJ, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. The British Medical Journal, 2021; 372: 71.
39. PANOSYAN EH, et al. Asparaginase Antibody and Asparaginase Activity in Children with Higher-Risk Acute Lymphoblastic Leukemia: Children’s Cancer Group Study CCG-1961. Journal of Pediatric Hematology/Oncology, 2004; 26(4): 217–226.
40. PATEL B, et al. Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: Toxicity data from the UKALL14 trial. Leukemia, 2017; 31(1): 58–64.
41. PEDROSAF e LINS M. Leucemia linfóide aguda: uma doença curável Revista Brasileira de Saúde Materno Infantil, 2002; 2(1): 63–68.
42. PIETERS R, et al. Pharmacokinetics, pharmacodynamics, efficacy, and safety of a new recombinant asparaginase preparation in children with previously untreated acute lymphoblastic leukemia: A randomized phase 2 clinical trial. Blood, 2008; 112(13): 4832–4838.
43. PLACE AE, et al. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): A randomised, open-label phase 3 trial. The Lancet Oncology, 2015; 16(16): 1677–1690.
44. RAETZEA, et al. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: A children’s oncology group pilot study. Journal of Clinical Oncology, 2008; 26(22): 3756–3762.
45. RAETZEA, et al. Re-Induction Chemoimmunotherapy with Epratuzumab in Relapsed Acute Lymphoblastic Leukemia (ALL): Phase II Results from Children’s Oncology Group (COG) Study ADVL04P2. Pediatric Blood & Cancer, 2015; 62: 1171–1175.
46. RAPONI S, et al. A. Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: Analysis of 552 cases. Leukemia and Lymphoma, 2011; 52(6): 1098–1107.
47. SMITH OP e HANN IM. Clinical Features and Therapy of Lymphoblastic Leukemia. In: ARCECIRJ, HANN IM, SMITHOP. (orgs). Pediatric Hematology. Third Edit.: Blackwell Publishing, 2006; 450–481.
48. SUZMAN DL, et al. Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents. Liver International, 2018; 38(6): 976–987.
49. TERWILLIGERT e ABDUL-HAYM. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer Journal, 2017; 7(6): 577.
50. THOMASDA, et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome - Negative precursor B-lineage acute lymphoblastic leukemia. Journal of Clinical Oncology, 2010; 28(24): 3880–3889.
51. TURCOTTE LM, et al. Cost of Pediatric Acute Lymphoblastic Leukemia Care in the Current Treatment Era. Bood, 2021; 138(1): 663.
52. TURTLE CJ, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. Journal of Clinical Investigation, 2016; 126(6): 2123–2138.
53. VOLLMAR BS, et al. Calicheamicin antibody-drug conjugates with improved properties. Molecular Cancer Therapeutics, 2021; 20(6): 1112–1120.
54. WIDJAJANTO PH, et al. L-asparaginase: Long-term results of a randomized trial of the effect of additional 3 doses during consolidation treatment in the indonesian WK-ALL-2000 protocol. Journal of Pediatric Hematology/Oncology, 2013; 35(8): 597–602.
55. ZENY e YEHMM. Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy. Seminars in Diagnostic Pathology, 2019; 36(6): 434–440.
56. ZHANG N, et al. Humanized CD19-directed CAR-T Cell Therapy in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia With CNSL or Neurological Comorbidity. Journal of Immunotherapy, 2022; 45(9): 396–406.