Keywords
Relapsed/refractory acute myeloid leukemia, Salvage therapy, Hematopoietic stem-cell trasplantation, Novel agents
How to Cite
Foncuberta, M., & Cranco, S. (2019). Treatment of relapsed/refractory acute myeloid leukemia. Journal of Hematology, 21(2), 166–176. Retrieved from https://revistahematologia.com.ar/index.php/Revista/article/view/150
Abstract
Acute myeloid leukemia comprises a group of heterogeneous diseases with distinctive phenotypic and molecular characteristics. Induction chemotherapy is able to reduce tumor burden to a level sufficient to meet the complete remission criteria in the vast majority. However, a significant number of patients do not achieve remission or relapse later, and this is associated with an ominous prognosis. Challenges in the treatment of this population include accurate assessment of disease prognosis through genetic and molecular studies, performance status to assess the ability to tolerate salvage therapies options, choice of chemotherapy schedule most likely to be a success, and accurate identification of suitable patients for hematopoietic stem cell transplantation. Clinicians should consider all currently available approaches, including intensive cytotoxic chemotherapy, new-targeted agents, low intensity treatment and palliative care. Since there is no standard of care in this setting, worldwide recommendation is to enroll patients in an appropriate clinical trial; situation not available to us in most cases.
References
1. Ramos NR, Mo CC, Karp JE y col. Current Approaches in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia. J Clin Med. 2015;4:685-695.
2. Walter RB, Othus M, Burnett AK y col. Re-sistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/SAKK, SWOC and MD Anderson Cancer Center. Leu-kemia. 2014;29:312-320.
3. Bose P, Vachhani P, Cortes J. Treatment of Re-lapsed/Refractory Acute Myeloid Leukemia. Curr Treat Options in Oncol. 2017;18:17.
4. Dinardo C, Ravandi F. How Do We Treat Pa-tients with Realpsed/Refractory AML? Oncol-ogy Times. 2015; 37:14-15.
5. Ley TJ, Miller C, Ding L y col. Genomic and Epigenomic Landscapes of Adult De NovoAcute Myeloid Leukemia. N Engl J Med.2013;368:2059-2074.
6. Meggendorfer M, Alpermann T, Perglerová K y col. Genetic Patterns of Relapsed AML Dif-fer Significantly from First Manifestation and Are Dependent on Cytogenetic Risk Groups at Diagnosis: Results in 175 Patients with Paired Samples. Blood. 2014;124:1029.
7. Ferguson P, Craddock C. Allogenic Transplan-tation in Primary Refractory AML. Bone Mar-row Transplantation. 2017:1-2.
8. Döhner H, Estey E, Grimwade D y col. Di-agnosis and Management of AML in Adults: 2017 ELN recommendations from an interna-tional expert panel. Blood. 2017;129:424-447.
9. Gyurkocza B, Lazarus HM, Giralt S. Allogenic Hematopoietic Cell Transplantation in Patients with AML Not Achieving Remission: poten-tially curative therapy. Bone Marrow Trans-plantation. 2017:1-8.
10. Breems DA, Van Putten WL, Löwenberg B. Prognostic Index for Adult Patients with Acute Myeloid Leukemia in First Relapse. J Clin On-col. 2005;23:1969-78.
11. Todisco E, Ciceri F, Rambaldi A y col. Factors Predicting Outcome after Allogenic Transplant in Refractory Acute Myeloid Leukemia: a ret-rospective analysis of Gruppo Italiano Trapi-anto di Midollo Osseo (GITMO). Bone Mar-row Transplantation. 2017:1-7.
12. NCCN. Acute Myeloid Leukemia NCCN Guidelines. NCCN Clin Parct Guidelines On-col. 2017; 3.2017:1.108.
13. Fey MF, Busque C. Acute Myeloblastic Leu-kaemias in Adult Patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24:138-143
14. Forman S, Rowe J. The Myth of the Second Remission of Acute Lekemia in the Adult. Blood. 2013;121:1077-1082.
15. Itzykson R, Thépot S, Berthon C y col. Azac-itidine for the Treatment of Relapsed and Re-fractory AML in Older Patients. Leuk Res.2015;39:124-130.
16. Thol F, Schlenk R, Heuser M. How I Treat Refractory and Early Relapsed Acute Myeloid Leukemia. Blood. 2015;126:319-327.
17. Mangan J, Luger S. Salvage Therapy for Re-lapsed or Refractory Acute Myeloid Leukemia. Ther Adv Hematol. 2011;2:73-82.
18. Herzig RH, Lazarus HM, Wolff SN y col. High-dose Cytosine Arabinoside Therapy with and without Anthracycline Antibiotics for Remis-sion Reinduction of Acute Nonlymphoblastic Leukemia. J Clin Oncol. 1985;3:992-997.
19. Anders B, Veltri L, Kanate A y col. Outcomes of Six-Dose High-Dose Cytarabine as a Sal-vage Regimen for Patients with Realpsed/Re-fractory Acute Myeloid Leukemia. Advances in Hematology. 2017;27:1-4.
20. Milligan DW, Wheatley K, Littlewood T y col. Fludarabine and Cytosine are Less Effective than Standard ADE Chemotherapy in High-Risk Acute Myeloid Leukemia, and Addition of G-CSF and ATRA are not beneficial: Results of the MRC AML-HR randomized trial. Blood.2006;107:4614-4622.
21. Wierzbowska A, Robak T, Pluta A y col. Cladribine combined with High Doses of Arab-inoside Cytosine, Mitoxantrone, and G-CSF (CLAG-M) is a Highly Effective Salvage Reg-imen in Patients with Refractory and Relapsed Acute Myeloid Leukemia of Poor Risk: A final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008;80:115-126.
22. Halpern AB, Estey EH, Othus M y col. Mi-toxantrone, Etoposide, and Cytarabine (MEC) following Epigenetic Priming with Decitabine in Adults with Relapsed/Refractory Acute My-eloid Leukemia (AML) or High-Risk Myelo-dysplastic Syndrome (MDS): A phase 1/2 study. Leukemia. 2017 May 30 [Epub ahead of print].
23. Becker PS, Kantarjian HM, Appelbaum FR y col. Retrospective comparison of Clofarabine versus Fludarabine in combination with High-Dose Cytarabine with or without Granulocyte colony-stimulating Factor as Salvage Thera-pies for Acute Myeloid Leukemia. Haemato-logica.2013;98:114-118.
24. Sarkozy C, Gardin C, Gachard N y col. Out-come of Older Patients with Acute Myeloid Leukemia in First Relapse. Am J Hematol.2013;88:758-764.
25. Ivanoff S, Gruson B, Chantepie SP y col. 5-Azacytidine Treatment for Relapsed or Refractory Acute Myeloid Leukemia af-ter Intensive Chemotherapy. Am J Hematol.2013;88:601-605.
26. Ritchie EK, Feldman EJ, Roboz GJ. Decit-abine in Patients with Newly Diagnosed and Relapsed Acute Myeloid Leukemia. Leuk Lym-phoma. 2013;54:2003-2007.
27. Ravandi F, Roboz G, Kantajian H y col. Du-rable Overall Survival Benefit in Patients ≥ 60 Years with Relapsed or Refractory AML Treat-ed with Vosaroxin/Cytarabine Vs Placebo/Cy-tarabine: Updated Results from the Valor Trial. ASH 2016, San Diego, Oral abstract 903.
28. Cortes J, Goldberg S, Feldman E y col. Phase II, Multicenter, Randomized Trial of CPX-351 (cytarabine:Daunorubicin) Liposome Injection versus Intensive Salvage Therapy in Adults with First Relapse AML. Cancer. 2015;121:234-242.
29. Pilorge S, Rigaudeau S, Rabian F y col. Frac-tionated Gemtuzumab ozogamicin and Stan-dard Dose Cytarabine Produced Prolonged Second Remissions in Patients Over the Age of 55 Years with Acute Myeloid Leukemia in Late First Relapse. Am J Hematol. 2014;89:399-403.
30. Walter R, Buckley S, Pagel J y col. Significance of Minimal Residual Disease Before Myeloab-lative Allogeneic Hematopoietic Cell Trans-plantation for AML in First and Second Com-plete Remission. Blood. 2013;122:1813-1821.
31. Duval M, Klein J, He W, y col. Hematopoietic Stem-cell Transplantation for Acute Leukemia in Relapse or Primary Induction Failure. J Clin Oncol. 2010;28:3730-3738.
32. Ferguson P, Hills R, Grech A y col. An Opera-tional Definition of Primary Refractory Acute Myeloid Leukemia allowing Early identifica-tion of Patients who may benefit from Alloge-neic Stem Cell Transplantation. Haematologi-ca. 2016; 101: 1351-1358.
33. Raiola A, Dominietto A, Di Grazia C y col. Unmanipulated Haploidentical Transplants compared with Other Alternative Donors and Matched Sibling Grafts. Biol Blood Marrow Transplant. 2014;20:1573-1579.
34. Sebert M, Porcher R, Robin M y col. Equiv-alent Outcomes Using Reduced Intensity or Conventional Myeloablative Conditioning Transplantation for Patients Aged 35 Years and Over with AML. Bone Marrow Transplant.2015;50:74-81.
35. Schmid C, Schleuning M, Schwerdtfeger R y col. Long-term Survival in Refractory Acute Myeloid Leukemia after Sequential Treatment with Chemotherapy and Reduced-intensity Conditioning for Allogeneic Stem Cell Trans-plantation. Blood. 2006;108:1092-1099.
36. Mohty M, Malard F, Blaise D y col. Sequen-tial Regimen of Clofarabine, Cytosine arabino-side and Reduced Intensity Transplantation for Primary Refractory Acute Myeloid Leukemia. Haematologica. 2016;102:184-191.
37. Bejanyan N, Oran B, Shanley R y col. Clini-cal Outcomes of AML Patients Relapsing after Matched-related Donor and Umbilical Cord Blood Transplantation. Bone Marrow Trans-plant. 2014;49:1029-1035.
38. De Lima M, Giralt S, Thall P y col. Mainte-nance Therapy with Low-dose Azacitidine after Allogeneic Hematopoietic Stem Cell Transplantation for Recurrent Acute Myeloge-nous Leukemia or Myelodysplastic Syndrome: a Dose and Schedule finding Study. Cancer.2010;116: 5420-5431.
39. Craddock C, Jilani N, Siddique S y col. Toler-ability and Clinical Activity of Post-transplan-tation Azacitidine in Patients Allografted for Acute Myeloid Leukemia treated on the RI-CAZA Trial. Biol Blood Marrow Transplant.2016;22: 385-390.
2. Walter RB, Othus M, Burnett AK y col. Re-sistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/SAKK, SWOC and MD Anderson Cancer Center. Leu-kemia. 2014;29:312-320.
3. Bose P, Vachhani P, Cortes J. Treatment of Re-lapsed/Refractory Acute Myeloid Leukemia. Curr Treat Options in Oncol. 2017;18:17.
4. Dinardo C, Ravandi F. How Do We Treat Pa-tients with Realpsed/Refractory AML? Oncol-ogy Times. 2015; 37:14-15.
5. Ley TJ, Miller C, Ding L y col. Genomic and Epigenomic Landscapes of Adult De NovoAcute Myeloid Leukemia. N Engl J Med.2013;368:2059-2074.
6. Meggendorfer M, Alpermann T, Perglerová K y col. Genetic Patterns of Relapsed AML Dif-fer Significantly from First Manifestation and Are Dependent on Cytogenetic Risk Groups at Diagnosis: Results in 175 Patients with Paired Samples. Blood. 2014;124:1029.
7. Ferguson P, Craddock C. Allogenic Transplan-tation in Primary Refractory AML. Bone Mar-row Transplantation. 2017:1-2.
8. Döhner H, Estey E, Grimwade D y col. Di-agnosis and Management of AML in Adults: 2017 ELN recommendations from an interna-tional expert panel. Blood. 2017;129:424-447.
9. Gyurkocza B, Lazarus HM, Giralt S. Allogenic Hematopoietic Cell Transplantation in Patients with AML Not Achieving Remission: poten-tially curative therapy. Bone Marrow Trans-plantation. 2017:1-8.
10. Breems DA, Van Putten WL, Löwenberg B. Prognostic Index for Adult Patients with Acute Myeloid Leukemia in First Relapse. J Clin On-col. 2005;23:1969-78.
11. Todisco E, Ciceri F, Rambaldi A y col. Factors Predicting Outcome after Allogenic Transplant in Refractory Acute Myeloid Leukemia: a ret-rospective analysis of Gruppo Italiano Trapi-anto di Midollo Osseo (GITMO). Bone Mar-row Transplantation. 2017:1-7.
12. NCCN. Acute Myeloid Leukemia NCCN Guidelines. NCCN Clin Parct Guidelines On-col. 2017; 3.2017:1.108.
13. Fey MF, Busque C. Acute Myeloblastic Leu-kaemias in Adult Patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24:138-143
14. Forman S, Rowe J. The Myth of the Second Remission of Acute Lekemia in the Adult. Blood. 2013;121:1077-1082.
15. Itzykson R, Thépot S, Berthon C y col. Azac-itidine for the Treatment of Relapsed and Re-fractory AML in Older Patients. Leuk Res.2015;39:124-130.
16. Thol F, Schlenk R, Heuser M. How I Treat Refractory and Early Relapsed Acute Myeloid Leukemia. Blood. 2015;126:319-327.
17. Mangan J, Luger S. Salvage Therapy for Re-lapsed or Refractory Acute Myeloid Leukemia. Ther Adv Hematol. 2011;2:73-82.
18. Herzig RH, Lazarus HM, Wolff SN y col. High-dose Cytosine Arabinoside Therapy with and without Anthracycline Antibiotics for Remis-sion Reinduction of Acute Nonlymphoblastic Leukemia. J Clin Oncol. 1985;3:992-997.
19. Anders B, Veltri L, Kanate A y col. Outcomes of Six-Dose High-Dose Cytarabine as a Sal-vage Regimen for Patients with Realpsed/Re-fractory Acute Myeloid Leukemia. Advances in Hematology. 2017;27:1-4.
20. Milligan DW, Wheatley K, Littlewood T y col. Fludarabine and Cytosine are Less Effective than Standard ADE Chemotherapy in High-Risk Acute Myeloid Leukemia, and Addition of G-CSF and ATRA are not beneficial: Results of the MRC AML-HR randomized trial. Blood.2006;107:4614-4622.
21. Wierzbowska A, Robak T, Pluta A y col. Cladribine combined with High Doses of Arab-inoside Cytosine, Mitoxantrone, and G-CSF (CLAG-M) is a Highly Effective Salvage Reg-imen in Patients with Refractory and Relapsed Acute Myeloid Leukemia of Poor Risk: A final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008;80:115-126.
22. Halpern AB, Estey EH, Othus M y col. Mi-toxantrone, Etoposide, and Cytarabine (MEC) following Epigenetic Priming with Decitabine in Adults with Relapsed/Refractory Acute My-eloid Leukemia (AML) or High-Risk Myelo-dysplastic Syndrome (MDS): A phase 1/2 study. Leukemia. 2017 May 30 [Epub ahead of print].
23. Becker PS, Kantarjian HM, Appelbaum FR y col. Retrospective comparison of Clofarabine versus Fludarabine in combination with High-Dose Cytarabine with or without Granulocyte colony-stimulating Factor as Salvage Thera-pies for Acute Myeloid Leukemia. Haemato-logica.2013;98:114-118.
24. Sarkozy C, Gardin C, Gachard N y col. Out-come of Older Patients with Acute Myeloid Leukemia in First Relapse. Am J Hematol.2013;88:758-764.
25. Ivanoff S, Gruson B, Chantepie SP y col. 5-Azacytidine Treatment for Relapsed or Refractory Acute Myeloid Leukemia af-ter Intensive Chemotherapy. Am J Hematol.2013;88:601-605.
26. Ritchie EK, Feldman EJ, Roboz GJ. Decit-abine in Patients with Newly Diagnosed and Relapsed Acute Myeloid Leukemia. Leuk Lym-phoma. 2013;54:2003-2007.
27. Ravandi F, Roboz G, Kantajian H y col. Du-rable Overall Survival Benefit in Patients ≥ 60 Years with Relapsed or Refractory AML Treat-ed with Vosaroxin/Cytarabine Vs Placebo/Cy-tarabine: Updated Results from the Valor Trial. ASH 2016, San Diego, Oral abstract 903.
28. Cortes J, Goldberg S, Feldman E y col. Phase II, Multicenter, Randomized Trial of CPX-351 (cytarabine:Daunorubicin) Liposome Injection versus Intensive Salvage Therapy in Adults with First Relapse AML. Cancer. 2015;121:234-242.
29. Pilorge S, Rigaudeau S, Rabian F y col. Frac-tionated Gemtuzumab ozogamicin and Stan-dard Dose Cytarabine Produced Prolonged Second Remissions in Patients Over the Age of 55 Years with Acute Myeloid Leukemia in Late First Relapse. Am J Hematol. 2014;89:399-403.
30. Walter R, Buckley S, Pagel J y col. Significance of Minimal Residual Disease Before Myeloab-lative Allogeneic Hematopoietic Cell Trans-plantation for AML in First and Second Com-plete Remission. Blood. 2013;122:1813-1821.
31. Duval M, Klein J, He W, y col. Hematopoietic Stem-cell Transplantation for Acute Leukemia in Relapse or Primary Induction Failure. J Clin Oncol. 2010;28:3730-3738.
32. Ferguson P, Hills R, Grech A y col. An Opera-tional Definition of Primary Refractory Acute Myeloid Leukemia allowing Early identifica-tion of Patients who may benefit from Alloge-neic Stem Cell Transplantation. Haematologi-ca. 2016; 101: 1351-1358.
33. Raiola A, Dominietto A, Di Grazia C y col. Unmanipulated Haploidentical Transplants compared with Other Alternative Donors and Matched Sibling Grafts. Biol Blood Marrow Transplant. 2014;20:1573-1579.
34. Sebert M, Porcher R, Robin M y col. Equiv-alent Outcomes Using Reduced Intensity or Conventional Myeloablative Conditioning Transplantation for Patients Aged 35 Years and Over with AML. Bone Marrow Transplant.2015;50:74-81.
35. Schmid C, Schleuning M, Schwerdtfeger R y col. Long-term Survival in Refractory Acute Myeloid Leukemia after Sequential Treatment with Chemotherapy and Reduced-intensity Conditioning for Allogeneic Stem Cell Trans-plantation. Blood. 2006;108:1092-1099.
36. Mohty M, Malard F, Blaise D y col. Sequen-tial Regimen of Clofarabine, Cytosine arabino-side and Reduced Intensity Transplantation for Primary Refractory Acute Myeloid Leukemia. Haematologica. 2016;102:184-191.
37. Bejanyan N, Oran B, Shanley R y col. Clini-cal Outcomes of AML Patients Relapsing after Matched-related Donor and Umbilical Cord Blood Transplantation. Bone Marrow Trans-plant. 2014;49:1029-1035.
38. De Lima M, Giralt S, Thall P y col. Mainte-nance Therapy with Low-dose Azacitidine after Allogeneic Hematopoietic Stem Cell Transplantation for Recurrent Acute Myeloge-nous Leukemia or Myelodysplastic Syndrome: a Dose and Schedule finding Study. Cancer.2010;116: 5420-5431.
39. Craddock C, Jilani N, Siddique S y col. Toler-ability and Clinical Activity of Post-transplan-tation Azacitidine in Patients Allografted for Acute Myeloid Leukemia treated on the RI-CAZA Trial. Biol Blood Marrow Transplant.2016;22: 385-390.
All material published in the journal HEMATOLOGÍA (electronic and print version) is transferred to the Argentinean Society of Hematology. In accordance with the copyright Act (Act 11 723), a copyright transfer form will be sent to the authors of approved works, which has to be signed by all the authors before its publication. Authors should keep a copy of the original since the journal is not responsible for damages or losses of the material that was submitted. Authors should send an electronic version to the email: revista@sah.org.ar
Downloads
Download data is not yet available.