Skip to main content

Challenges in Chronic Myeloid Leukemia Management in South America

Abstract

Purpose of Review

Chronic myeloid leukemia (CML) management in developing countries has improved in the last years, but the availability of therapeutic resources, monitoring, reimbursement, and financial issues may be a challenge and interfere with the best practices and results of CML treatment. This review points out the main challenges in CML management in South America.

Recent Findings.

In this review, we describe the access to tyrosine kinase inhibitors and monitoring in different countries of South America. We also address the ongoing discontinuation trials, the progress, and limitations of hematopoietic stem cell transplantation in the last years.

Summary

There are still many challenges for achieving the best outcomes for CML patients in South America. The continuous efforts to provide continuous education, access to tyrosine kinase inhibitors, and monitoring, providing reference centers for CML management and hematopoietic stem cell transplantation may improve patients’ outcomes.

This is a preview of subscription content, access via your institution.

References

  1. Cortes J, De Souza C, Ayala-Sanchez M, Bendit I, Best-Aguilera C, Enrico A, et al. Current patient management of chronic myeloid leukemia in Latin America: a study by the Latin American Leukemia Net (LALNET). Cancer. 2010;116(21):4991–5000.

    Article  Google Scholar 

  2. Pavlovsky C, Mela Osorio MJ. Chronic myeloid leukemia: what is the best strategy to start and monitor treatment outside academic centers? Curr Oncol Rep. 2018;20(1):4.

    Article  CAS  Google Scholar 

  3. Abello-Polo VS-M, Claudia Peña, Angela et al. ACHO (Asociación Colombiana de Hematología y Oncología), RENEHOC researchers. Impact of Insurance Differences in Outcomes in Colombian Patients with Chronic Myeloid Leukemia (CML). Clinical Lymphoma, Myeloma and Leukemia. 2020:S240

  4. Méndez Y, Giraldo-Castaño Mn, Rocha MF. Estudio sobre la identificación de necesidades emocionales, sociales y de acceso a los servicios de salud, de los pacientes diagnosticados con leucemia mieloide crónica en Colombia https://www.funleucemialinfoma.org/wp-content/uploads/2019/07/Paper-Estudio-LMC.pdf: Fundación Colombiana de Leucemia y Linfoma; 2018. Accessed 11 Apr 2021.

  5. Ylescas-Soria J, de la Torre-Lujan AH, Herrera LA, Miranda D, Grimaldo F, Rivas S, et al. Prognostic factors for overall survival in patients with chronic myeloid leukemia treated with imatinib at the National Cancer Institute - Mexico, from 2000 to 2016. Cancer Med. 2019;8(6):2942–9.

    Article  CAS  Google Scholar 

  6. Laurell AC, Giovanella L. Health Policies and Systems in Latin America. Oxford Research Encyclopedias, Global Public Health; 2018.

  7. Kanavos P, Colville Parkin G, Kamphuis B, Gill J. Latin America Healthcare System Overview. A comparative analysis of fiscal space in healthcare. https://www.lse.ac.uk/business-and-consultancy/consulting/assets/documents/latin-america-healthcare-system-overview-report-english.pdf: London School of Economics and Political Science; 2019. Accessed 12 Apr 2021.

  8. Guérin A, Chen L, Dea K, Wu EQ, Goldberg SL. Economic benefits of adequate molecular monitoring in patients with chronic myelogenous leukemia. J Med Econ. 2014;17(2):89–98.

    Article  Google Scholar 

  9. EiCM L. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood. 2013;121(22):4439–42.

    Article  CAS  Google Scholar 

  10. Campaign MA. Untangling the web of antiretroviral price reductions. https://msfaccess.org/utw; 2016. Accessed 11 Apr 2021.

  11. Margolese HC, Wolf Y, Desmarais JE, Beauclair L. Loss of response after switching from brand name to generic formulations: three cases and a discussion of key clinical considerations when switching. Int Clin Psychopharmacol. 2010;25(3):180–2.

    Article  Google Scholar 

  12. Saavedra D, Vizcarra F. Deleterious effects of non-branded versions of imatinib used for the treatment of patients with chronic myeloid leukemia in chronic phase: a case series on an escalating issue impacting patient safety. Leuk Lymphoma. 2014;55(12):2813–6.

    Article  CAS  Google Scholar 

  13. Chouffai Z. Hematologic relapse after 2 years on a non-authorized copy version of imatinib in a patient with chronic myeloid leukemia in chronic phase: a case report. Case Rep Oncol. 2010;3(2):272–6.

    Article  Google Scholar 

  14. Ćojbašić I, Mačukanović-Golubović L, Vučić M, Ćojbašić Ž. Generic imatinib in chronic myeloid leukemia treatment: long-term follow-up. Clin Lymphoma Myeloma Leuk. 2019;19(9):e526–31.

    Article  Google Scholar 

  15. Parrillo-Campiglia S, Ercoli MC, Umpierrez O, Rodríguez P, Márquez S, Guarneri C, et al. Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: a randomized, open-label, single-dose, fasting, two-period, two-sequence crossover comparison in healthy male South American volunteers. Clin Ther. 2009;31(10):2224–32.

    Article  CAS  Google Scholar 

  16. Arora R, Sharma M, Monif T, Iyer S. A Multi-centric bioequivalence trial in Ph+ chronic myeloid leukemia patients to assess bioequivalence and safety evaluation of generic imatinib mesylate 400 mg tablets. Cancer Res Treat. 2016;48(3):1120–9.

    Article  CAS  Google Scholar 

  17. Jung JA, Kim N, Yang JS, Kim TE, Kim JR, Song GS, et al. Bioequivalence study of two imatinib formulations after single-dose administration in healthy Korean male volunteers. Drug Res (Stuttg). 2014;64(12):651–5.

    Article  CAS  Google Scholar 

  18. Pagnano K, Fava C, Miranda E, Giuseppe Saglio. Efficacy and safety of generic imatinib compared to Glivec in chronic phase - chronic myeloid leukemia - a multicenter, observational study. Blood. 2018;132:46.

    Article  Google Scholar 

  19. Varela Ines A, Bendek G, Pavlovsky Carolina, Freitas MF, et al. Real world efficacy evaluation of branded and copy imatinib in chronic myeloid leukemia: a retrospective multicentric study from Argentina. Blood. 2020;136:36–7.

    Article  Google Scholar 

  20. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108(6):1809–20.

    Article  CAS  Google Scholar 

  21. Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108(1):28–37.

    Article  CAS  Google Scholar 

  22. Branford S, Fletcher L, Cross N, Müller MC, Hochhaus A, Dong-Wook Kim, et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood 2008 112 8.

  23. Ruiz MS, Sánchez MB, Vera Contreras YM, Agrielo E, Alonso M, Altuna ME, et al. Programme for Harmonization to the International Scale in Latin America for BCR-ABL1 quantification in CML patients: findings and recommendations. Clin Chem Lab Med. 2020;58(12):2025–35.

    Article  CAS  Google Scholar 

  24. Ribeiro BF, Vergílio BR, Miranda EC, Almeida MH, Delamain MT, da Silveira RA, et al. BCR-ABL1 transcript levels at 3 and 6 months are better for identifying chronic myeloid leukemia patients with poor outcome in response to second-line second-generation tyrosine kinase inhibitors after imatinib failure: a report from a single institution. Acta Haematol. 2015;134(4):248–54.

    Article  CAS  Google Scholar 

  25. Boquimpani C, Schaffel R, Biasoli I, Bendit I, Spector N. Molecular responses at 3 and 6 months after switching to a second-generation tyrosine kinase inhibitor are complementary and predictive of long-term outcomes in patients with chronic myeloid leukemia who fail imatinib. Leuk Lymphoma. 2015;56(6):1787–92.

    Article  CAS  Google Scholar 

  26. Boquimpani CM, Abdo ANR, Martins DP, Lima LBA, Torriani MS, Bendit I. Inclusion of molecular monitoring (BCR-ABL1) in the treatment of chronic myeloid leukemia in the Brazilian Public Health System (SUS): an urgent need for treatment management. Hematol Transfus Cell Ther. 2021;43(1):50–7.

    Article  Google Scholar 

  27. De Souza CA, Vigorito AC, Ruiz MA, Nucci M, Dulley FL, Funcke V, et al. Validation of the EBMT risk score in chronic myeloid leukemia in Brazil and allogeneic transplant outcome. Haematologica. 2005;90(2):232–7.

    PubMed  Google Scholar 

  28. Bittencourt H, Funke V, Fogliatto L, Magalhães S, Setubal D, Paz A, et al. Imatinib mesylate versus allogeneic BMT for patients with chronic myeloid leukemia in first chronic phase. Bone Marrow Transplant. 2008;42(9):597–600.

    Article  CAS  Google Scholar 

  29. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966–84.

    Article  CAS  Google Scholar 

  30. Pasquini MC. Hematopoietic cell transplantation for chronic myeloid leukemia in developing countries: perspectives from Latin America in the post-tyrosine kinase inhibitor era. Hematology. 2012;17(Suppl 1):S79-82.

    Article  Google Scholar 

  31. Phelan R, Arora, M., Chen, M. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR summary slides, 2020. In: CIBMTR, editor. https://www.ecosia.org/search/q=Current+use+and+outcome+of+hematopoietic+stem+cell+transplantation%3A+CIBMTR+summary+slides%2C+2020&addon=safari&addonversion=4.2.1.512020. Accessed 5 Apr 2021.

  32. Eckrich M, Pasquini M. Hematopoietic cell transplantation in Latin America. Hematology. 2012;17(Suppl 1):S189–91.

    Article  Google Scholar 

  33. Jaimovich G, Gale RP, Hanesman I, Rolón JM. The state of haematopoietic cells transplantation in Latin America. Lancet Haematol. 2021;8(1):e20–1.

    Article  Google Scholar 

  34. Jaimovich G, Martinez Rolon J, Baldomero H, Rivas M, Hanesman I, Bouzas L, et al. Latin America: the next region for haematopoietic transplant progress. Bone Marrow Transplant. 2017;52(5):671–7.

    Article  CAS  Google Scholar 

  35. Gale RP, Seber A, Bonfim C, Pasquini M. Haematopoietic cell transplants in Latin America. Bone Marrow Transplant. 2016;51(7):898–905.

    Article  CAS  Google Scholar 

  36. Padula WV, Larson RA, Dusetzina SB, Apperley JF, Hehlmann R, Baccarani M, et al. Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase After Generic Entry of Imatinib in the United States. J Natl Cancer Inst 2016 108 7.

  37. Etienne G, Guilhot J, Rea D, Rigal-Huguet F, Nicolini F, Charbonnier A, et al. Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia. J Clin Oncol. 2017;35(3):298–305.

    Article  Google Scholar 

  38. Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19(6):747–57.

    Article  CAS  Google Scholar 

  39. Hochhaus A, Saussele S, Rosti G, Mahon FX, Janssen JJWM, Hjorth-Hansen H, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018 29 (Suppl 4):iv261.

  40. Baccarani M, Abruzzese E, Accurso V, Albano F, Annunziata M, Barulli S, et al. Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP. Blood Adv. 2019;3(24):4280–90.

    Article  CAS  Google Scholar 

  41. Deninger M, Shah N, Altman J. NCCN guidelines: chronic myeloid leukemia. national Comprehensive Cancer Network (NCCN) Guidelines [Internet]. 2019.

  42. Pavlovsky C, Abello Polo V, Barbosa Pagnano KB, Varela AI, Lopez CA, Bianchini M, Boquimpani C, Torrescasana Centrone R, Conchon M, Delgado N, Araújo Moreira Funke V, Giere IA, Pinto IL, Meillon-Garcia L, Moiraghi B, Ramon Navarro J, Pilleux L, Prado AI, Soledad Undurraga M, Cortes J. Treatment free remission in patients with chronic myeloid leukemia: recommendations of LALNET expert panel. Blood Adv 2021; https://doi.org/10.1182/bloodadvances.2020003235

  43. Pagnano K. BCR-ABL1 level monitoring in chronic myeloid leukemia by real time polymerase chain reaction in Brazil – not so real. Rev Bras Hematol Hemoter. 2017:197–8.

  44. Mahon FX, Boquimpani C, Kim DW, Benyamini N, Clementino NCD, Shuvaev V, et al. Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Single-Group, Phase 2. Open-Label Study Ann Intern Med. 2018;168(7):461–70.

    PubMed  Google Scholar 

  45. Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gómez Casares MT, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31(7):1525–31.

    Article  CAS  Google Scholar 

  46. Isoppo CC, Braga AGO, Chaves HVS, Duarte GO, Delamain MT, Pagnano KBB. Descontinuaçao de Inhibidores de Tirosinquinase na práctica clínica: Relato de quatro casos. Hematology Transfusion and Cell Therapy. 2020;42(S2):120–1.

    Article  Google Scholar 

  47. Moura AC, Delamain MT, Duarte GBO, Lorand-Metze I, Souza CA, Pagnano KBB. Management of chronic myeloid leukemia during pregnancy: a retrospective analysis at a single center. Hematol Transfus Cell Ther. 2019;41(2):125–8.

    Article  Google Scholar 

  48. Pagnano K, Seguro F, Miranda E, Bendit I. Duration of Major Molecular Response and Discontinuation in Deep Molecular Response (MR4.5) Were Associated with Longer Treatment-Free Survival after Imatinib Discontinuation - Results from Two Prospective Brazilian Trials. Blood. 2019;134:1655.

    Article  Google Scholar 

  49. Pagnano KBB, Lopes ABP, Miranda EC, Delamain MT, Duarte GO, Rodrigues BRV, et al. Efficacy and safety of pioglitazone in a phase 1/2 imatinib discontinuation trial (EDI-PIO) in chronic myeloid leukemia with deep molecular response. Am J Hematol. 2020;95(12):E321–3.

    Article  CAS  Google Scholar 

  50. Lopes AM, Eliana Oliveira Póvoa , Valquíria Mariane Vergílio , Bruna Rocha Pavan Furlin , Graziele Cristina Torresan Delamain, Marcia Borba Duarte, Gislaine Souza, Carmino Antonio De Paula, Erich V Pagnano, Katia B. Pioglitazone Did Not Affect PPAR- Γ , STAT5 , HIF2 α and CITED2 Gene Expression in Chronic Myeloid Leukemia Patients with Deep Molecular Response. Blood 2019 134.

  51. Seguro FS, Maciel FVR, Santos FM, Abdo ANR, Pereira TDM, Nardinelli L, et al. MR 4log and low levels of NK cells are associated with higher molecular relapse after imatinib discontinuation: Results of a prospective trial. Leuk Res. 2021;101:106516.

    Article  CAS  Google Scholar 

  52. Pavlovsky , Carolina, Varela AI, Fernandez I, Beatriz Moiraghi B. High Level of Successful TKI Discontinuation in Chronic Myeloid Leukemia (CML) Patients: Preliminary Results of AST-Argentina Stop Trial. Blood [Internet] 2020 136 Supl 1.

  53. Abello Polo V, Sossa Melo C, Peña A, Casas C, Gomez R, Osuna M. Treatment Free Remission in Patients with Chronic Myeloid Leukemia (CML): A Real-World Cohor of Patients in Colombia. Clinical Lymphoma, Myeloma & Leukemia [Internet] 2020 S244.

Download references

Acknowledgements

We would like to acknowledge Sebastian Galeano in name of LABMT and Cynthia Correa da Silva (data manager at LABMT).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Katia B. Pagnano.

Ethics declarations

Conflicts of Interest

KBP reports Advisory Boards from Novartis, Abbvie, and lectures fees from EMS, Novartis, Pintpharma, Abbvie; AIV reports lecture fees from Novartis and Bristol Myers Squibb; VA reports participation in AB and conferences for Janssen, Abbott, Abbvie, Novartis, Bristol, Amgen. Funding for investigation from Janssen, Takeda, Abbvie, Janssen, Novartis. VF and IB report no conflict of interest.

Human and Animal Rights and Informed Consent This article is a review and contains no studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Chronic Myeloid Leukemias

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pagnano, K.B., Varela, A.I., Pavlovsky, C. et al. Challenges in Chronic Myeloid Leukemia Management in South America. Curr Hematol Malig Rep 16, 440–447 (2021). https://doi.org/10.1007/s11899-021-00654-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-021-00654-0

Keywords

  • Chronic myeloid leukemia
  • Tyrosine kinase inhibitors
  • Monitoring
  • Management
  • Hematopoietic stem cell transplantation
  • Treatment-free remission