Abstract

In the last 60 years, there have been substantial advances regarding the diagnosis and treatment of patients with acute and chronic leukemia in Mexico. Immunologic and molecular classifications of these diseases have improved both diagnosis and therapeutic capabilities. Although the pace of diagnostic and therapeutic advances has been slower compared with developed countries, Mexico is at the forefront among developing countries. Supporting research in these fields is expected to enhance the generation of new knowledge and improve the care of patients suffering from these diseases.

Keywords:
leukemia; advances; Mexico

Resumen

En los últimos 60 años ha habido avances notables en el diagnóstico y tratamiento de los pacientes con leucemia aguda y crónica en México. Las clasificaciones inmunológicas y moleculares de esta enfermedad han mejorado tanto la capacidad diagnóstica como las derivaciones terapéuticas. Si bien el ritmo de los avances diagnósticos y terapéuticos en México se ha visto retrasado cuando se compara con el de países desarrollados, se encuentra a la vanguardia entre los países en vías de desarrollo. El apoyo a las labores de investigación en estas áreas del conocimiento seguramente redundará en beneficio de la generación de nuevos conocimientos y de la atención de los pacientes que sufren estas enfermedades.

Palabras clave:
leucemia; avances; México

When Eduardo Lazcano invited me to collaborate in the preparation of the book Cancer: Advances in diagnosis, treatment, prevention and control, edited by the National Institute of Public Health, I considered the convenience of presenting a document stating some of the unique characteristics of leukemia, both acute and chronic, in Mexico. After being involved in this field for more than 30 years and having participated in the diagnosis, treatment and follow-up of more than 1 200 patients with diverse types of leukemia in our country, I have been able to perform various observations of the disease that I will attempt to summarize in a concise way.

Acute lymphoblastic leukemia (ALL)

Immunologic classification of acute leukemia has been conducted in Mexico since 1983. Prior to 1983 and beginning in 1953, the diagnosis and classification of leukemia were merely supported by morphologic criteria. This change has led to a significant improvement in the prognosis of patients with leukemia in Mexico.¹1. Ruiz-Argüelles GJ, Marín-López A, Ruiz-Argüelles A. Immunologic classification of the acute non-granular leukemias in the city of Puebla, México; Its value in the diagnosis and prognosis. Rev Invest Clin 1987;39:143-147.^,22. Ruiz-Argüelles GJ, Marín-López A, Ruiz-Argüelles A, Valls-de-Ruiz M. Estudio prospectivo de la clasificación inmunológica de 128 casos de leucemia aguda linfoblástica en la ciudad de Puebla, México. Rev Invest Clin 1987; 39:137-142. Since 1994, implementation of ALL molecular markers such as BCR/ABL, TEL/AML1, FLT3, NPM-1 chimeric genes and mutations in IKAROS, which are widely and routinely used in Mexico, has allowed a better classification, selection and treatment follow-up of these leukemias.³3. Ruiz-Argüelles GJ, Garcés-Eisele J, Ruiz-Argüelles A. Molecular follow-up of patients with promyelocytic leukaemia treated with all trans-retinoic acid. Clin Lab Haematol 1998; 20:173-176. However, nutritional aspects of patients are critical in our environment; malnourished children with ALL have a worse evolution than well-nourished children. These observations, initially performed in Mexico,⁴4. Lobato-Mendizábal E, Ruiz-Arguelles GJ, Marín-López A. Leukaemia and nutrition I: Malnutrition is an adverse prognostic factor in the outcome of treatment of patients with standard risk acute lymphoblastic leukaemia. Leuk Res 1989;13:899-906. have been corroborated in other developing countries where it has been found that nutritional status is associated with the socioeconomic condition of patients and adherence to treatment, among other variables.⁵5. Viana MB, Fernandes RA, de Oliveira BM, Murao M, de Andrade Paes C, Duarte AA. Nutritional and socio-economic status in the prognosis of childhood acute lymphoblastic leukemia. Haematologica 2001; 86(2):113-120.

Combined highly aggressive polychemotherapy treatment schemes for ALL - type HyperCVAD - are associated with higher morbimortality in treated patients. In Mexico, outcomes obtained with less aggressive and complex schemes are as efficient as other approaches but are associated with lower morbimortality.⁶6. Ruiz-Delgado GJ, Macías-Gallardo J, Lutz-Presno J, Montes-Montiel M, Ruiz-Argüelles GJ. Outcome of adults with acute lymphoblastic leukemia treated with a pediatric-inspired therapy: A single institution experience. Leukemia Lymph 2011; 52:314-316. In addition, these schemes can be administered on an outpatient basis and are associated with better quality of life for the treated patient. For high-risk or relapsing patients with ALL, bone marrow transplantation (BMT) performed with reduced-strength schemes and on an outpatient basis is associated with favorable outcomes that are better than those obtained with combined chemotherapy.⁷7. Gutiérrez-Aguirre CH, Gómez-Almaguer D, Cantú-Rodríguez OG, González-Llano O, Jaime-Pérez JC, Herena-Pérez S, et al. Non-myeloablative stem cell transplantation in patients with relapsed acute lymphoblastic leukemia: Results of a multicenter study. Bone Marrow Transplant 2007; 40:535-539. Introduction of tyrosine kinase inhibitors (TKIs) for treatment in patients with ALL and the Philadelphia chromosome has dramatically improved their prognosis.⁸8. Gutiérrez-Aguirre H, García-Rodríguez F, Cantú-Rodríguez O, González-Llano O, Jaime-Pérez J, Gómez-Almaguer D. Effectiveness of dasatinib in relapsed CNS, Ph+ ALL that is refractory to radiochemotherapy plus imatinib: a case report. Clin Adv Hematol Oncol 2011;11:875-878. New drugs for the treatment of patients with ALL, such as clofarabine and blinatumomab, have been used rarely in Mexico due to their high costs.

Acute myeloid leukemia (AML)

Acute promyelocytic (M3) and megakaryoblastic (M7) leukemias are more prevalent in Mexico than within Caucasian populations, likely owing to genetic causes.⁹9. Ruiz-Argüelles GJ, Marín-López A, Lobato-Mendizábal E, Ruiz-Argüelles A, Nichols WL, Katzmann JA. Acute megakaryoblastic leukemia: A prospective study of its identification and treatment. Br J Haematol 1986;62:55-63.^,1010. Ruiz-Argüelles GJ. Promyelocytic leukemia in Mexican mestizos. Blood 1997; 89:348-349. The poor prognosis of promyelocytic leukemia in the past has dramatically changed with the use of retinoid and arsenic trioxide. Mexico took part in a multinational study directed to improve the prognosis of patients with M3 AML using a simplified and affordable treatment and achieving very satisfactory outcomes.¹¹11. Rego EM, Kim HT, Ruiz-Argüelles GJ, Undurraga MS, Uriarte MD, Jacomo RH, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood 2013; 121: 1935-1943. The use of AML molecular markers such as AML1/ETO, inv16, PML/RARa, FLT3, NPM1 and BCR/ABL has significantly improved AML diagnosis and classification and has allowed a treatment response follow-up, which is critical for these diseases.¹²12. Ruiz-Delgado GJ, Macías-Gallardo J, Lutz-Presno J, Garcés-Eisele J, Hernández-Arizpe A, Montes-Montiel M, Ruiz-Argüelles GJ. Core binding factor acute myeloid leukemia (CBF-AML) in México: A single institution experience. Rev Invest Clin 2011;63:25-30. AML with core-binding factor (CBF) mutations is similarly prevalent in Mexico and Caucasian countries and is associated with a better prognosis than AML without these mutations.¹³13. Ruiz-Argüelles GJ, Morales-Toquero A, Manzano C, Ruiz-Delgado GJ, Jaramilo O, González-Carrillo M, Reyes-Núñez V. t (8;21) (q22;q22) acute myelogenous leukemia in México: A single institution experience. Hematology 2006;11:235-238. In Mexico, novel treatments for AML such as gemtuzumab-ozogamicin have been restricted due to their high costs. The introduction of BMT with reduced-intensity conditioning on an outpatient basis is associated with favorable AML outcomes. There has been over 20 years of BMT experience in Mexico, which has been reproduced in other developing countries, thereby improving the prognosis of patients with AML, mainly in transplants performed during first remission.¹⁴14. Ruiz-Argüelles GJ, Gómez-Almaguer D, Gómez Rangel JD, Vela-Ojeda J, Cantú-Rodríguez OG, Jaime-Pérez JC, et al. Allogeneic hematopoietic stem cell transplantation with non-myeloablative conditioning in patients with acute myelogenous leukemia eligible for conventional allografting: A prospective study. Leukemia Lymph 2004; 45:1191-1195. The acquired knowledge in Mexico regarding acute hybrid leukemia has demonstrated a poor prognosis, which has also been described in other populations worldwide.¹⁵15. Deffis-Court M, Alvarado-Ibarra M, Ruiz-Argüelles GJ, Rosas-López A, Barrera-Lumbreras G, Aguayo-González A, et al. Diagnosing and treating mixed phenotype acute leukemia: a multicenter 10-year experience in México. Ann Hematol 2014;93:595-601.

Chronic myeloid leukemia (CML)

In Mexico, these diseases usually occur in younger patients compared with those in Caucasian populations. Routine BCR/ABL tests, available since 1994 in Mexico, have allowed molecular verification of the diagnosis of CML, patient follow-up and, more recently, choice of treatment.16 Treatment with TKIs, such as imatinib, dasatinib, and nilotinib, among others, remains the treatment of choice for patients with CML. Regrettably, TKI treatments are highly expensive, restricting their use in limited economies, which are prevalent in Mexico.¹⁷17. Abboud C, Berman E, Cohen A, Cortes J, DeAngelo D, Deininger M, et al. 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; 121:4439-4442. BMT is considered the only curative therapy for the treatment of CML patients in Mexico.¹⁸18. Ruiz-Argüelles GJ, Gómez-Almaguer D, Morales-Toquero A, Gutiérrez-Aguirre CH, Vela-Ojeda J, García-Ruiz-Esparza MA, et al. The early referral for reduced-intensity stem cell transplantation in patients with Ph1 (+) chronic myelogenous leukemia in chronic phase in the imatinib era: Results of the Latin American Cooperative OncoHematology Group (LACOHG) prospective, multicenter study. Bone Marrow Transplant 2005;36:1043-1047. It is estimated that with the costs of less than one year of TKI treatment, it is possible to defray a complete BMT by means of the "Mexican method", characterized by reduced-intensity conditioning on an outpatient basis. In many cases in Mexico, decisions on whether to offer TKI or BMT treatment to CML patients depend on economic conditions, access to public or private health services, and stable employment.¹⁹19. Ruiz-Argüelles GJ, Tarín-Arzaga LC, González-Carrillo ML, Gutiérrez-Riveroll KI, Rangel-Malo R, Gutiérrez-Aguirre CH, et al. Therapeutic choices in patients with Ph1 (+) chronic myelogenous leucemia living in México in the tyrosine kinase inhibitors (TKI) era: Stem cell transplantation or TKI's? Bone Marrow Transplant 2008;42:23-28. The trend to reduce BMT in patients with CML observed in developed countries is not seen in Mexico owing to the previously described causes; a similar trend is observed in Latin American and other developing countries. The "Mexican method" for bone marrow transplant in patients with leukemia has been implemented in other countries with unfavorable economies, such as ours, and has shown similar outcomes.¹⁸18. Ruiz-Argüelles GJ, Gómez-Almaguer D, Morales-Toquero A, Gutiérrez-Aguirre CH, Vela-Ojeda J, García-Ruiz-Esparza MA, et al. The early referral for reduced-intensity stem cell transplantation in patients with Ph1 (+) chronic myelogenous leukemia in chronic phase in the imatinib era: Results of the Latin American Cooperative OncoHematology Group (LACOHG) prospective, multicenter study. Bone Marrow Transplant 2005;36:1043-1047.^,1919. Ruiz-Argüelles GJ, Tarín-Arzaga LC, González-Carrillo ML, Gutiérrez-Riveroll KI, Rangel-Malo R, Gutiérrez-Aguirre CH, et al. Therapeutic choices in patients with Ph1 (+) chronic myelogenous leucemia living in México in the tyrosine kinase inhibitors (TKI) era: Stem cell transplantation or TKI's? Bone Marrow Transplant 2008;42:23-28. The availability of molecular biology methods for the diagnosis and follow-up of patients with this neoplasm has considerably improved its prognosis.¹⁶16. Ruiz-Argüelles GJ, López-Martínez B, Ramírez-Cabrera JM, Reyes-Nuñez V, Rodríguez-Cedeño H, Garcés-Eisele J. Molecular monitoring of the treatment of patients with BCR/ABL (+) chronic myelogenous leukemia. Rev Invest Clin Mex 2001; 53:235-239. Compared with other leukemias, CML has shown the most improved prognosis during the last decade due to the availability of molecular treatment and BMT implementation. Overall survival of patients with CML has significantly increased during the last decade despite the fact that suboptimal TKI treatment responses in mixed-blood Mexicans have been documented compared with that described in Caucasian populations.²⁰20. Gutierrez-Aguirre CH, Garcia-Rodriguez F, Ortiz-Galvez VM, Cantu-Rodriguez OG, Salazar-Riojas R, Martinez-Gonzalez OL, et al. Lower than expected cytogenetic and molecular response to imatinib in Mexican patients with chronic myelogenous leukemia. Hematology 2013; 18(4):224-229. In this regard, there should be real support for the implementation of BMT in Mexican patients with CML.

Chronic lymphocytic leukemia (CLL)

CLLs are the most common leukemias in Caucasian countries but are rare in Mexico,²¹21. Ruiz-Argüelles GJ, Velázquez BM, Apreza-Molina MG, Pérez-Romano B, Ruiz-Reyes G, Ruiz-Argüelles A. Chronic lymphocytic leukemia is infrequent in Mexican Mestizos. Int J Hematol 1999;69:253-255. most likely because of the genetic composition in mixed-blood Mexicans, with a high proportion of Asian genes. Accurate identification of this neoplasm and its variants using multiparametric flow cytometry, available since 1983 in Mexico, has been highly improved and, in some cases, is determinant for treatment election.²²22. Cano-Castellanos R, Alvarado-Ibarra M, Alvarez-Pantoja E, Baltazar-Arellano S, Castellanos-Galán JE, Castillo-Rivera H, et al. Primer consenso en leucemia linfocítica crónica de la Agrupación Mexicana para el Estudio de la Hematología: epidemiología, diagnóstico y tratamiento. Medicina Universitaria 2008;10:159-167.^,2323. Ruiz-Argüelles A, Duque RE, Orfao A. Report on the first Latin American Consensus Conference for Flow Cytometric Immunophenotyping of Leukemia. Cytometry1998:15;34(1):39-42. Hairy-cell leukemia or leukemic reticuloendotheliosis, a CLL variant, is infrequent in Mexico and displays a geographic distribution that may be associated with exposure to agrochemicals.²⁴24. Ruiz-Argüelles GJ, Cantú-Rodríguez OG, Gómez-Almaguer D, Cortés-Franco J, Góngora-Biachi R, Pizzuto J, et al. Hairy cell leukemia is infrequent in Mexico and has a geographic distribution. Am J Hematol 1996;52:316-318. The use of monoclonal antibody therapies such as rituximab, which targets the CD20 antigen found in several CLL variants, has improved therapy responses, especially when combined with drugs such as fludarabine and cyclophosphamide. The low prevalence of CLL in Mexico²¹21. Ruiz-Argüelles GJ, Velázquez BM, Apreza-Molina MG, Pérez-Romano B, Ruiz-Reyes G, Ruiz-Argüelles A. Chronic lymphocytic leukemia is infrequent in Mexican Mestizos. Int J Hematol 1999;69:253-255. has resulted in little experience at the national level regarding new drug treatments such as obinutuzumab, ofatumumab, ibrutinib and idelalisib, which have drastically altered the prognosis of patients with CLL.

Donor cell leukemia (DCL)

The cumulative experience regarding allogeneic BMT²⁵25. Ruiz-Delgado GJ, Ruiz-Argüelles GJ. A Mexican way to cope with stem cell transplantation. Hematology 2012;17(Suppl 1):195-197. over the last 20 years has led to the discovery of numerous DCL characteristics, which were considered unusual in the past but are now recognized as having been under-estimated with respect to their prevalence.²⁶26. Ruiz-Argüelles GJ, Ruiz-Delgado GJ, Garcés-Eisele J, Ruiz-Argüelles A, Pérez-Romano B, Reyes-Núñez V. Donor cell leukemia after non-myeloablative allogeneic stem cell transplantation: A single institution experience. Leuk Lymphoma 2006;47:1952-1955.

27. Ruiz-Argüelles GJ, Ruiz-Argüelles A, Garcés-Eisele J. Donor cell leukemia: A critical review. Leuk Lymphoma 2007;48:25-38.^-2828. Ruiz-Delgado GJ, Hernández-Reyes J, González-Ramírez MP, Martagón-Herrera NA, Garcés-Eisele J, Ruiz-Argüelles A, et al. Leucemia en células del donador: Un estudio prospectivo de su identificación y tratamiento. Gac Med Mex 2015; 151:582-587. Understanding the mechanisms of leukemogenesis within iatrogenic conditions has allowed great advances in the knowledge of the origin of leukemias²⁷27. Ruiz-Argüelles GJ, Ruiz-Argüelles A, Garcés-Eisele J. Donor cell leukemia: A critical review. Leuk Lymphoma 2007;48:25-38. as well as the design of strategies for their optimal treatment.²⁷27. Ruiz-Argüelles GJ, Ruiz-Argüelles A, Garcés-Eisele J. Donor cell leukemia: A critical review. Leuk Lymphoma 2007;48:25-38.^,2828. Ruiz-Delgado GJ, Hernández-Reyes J, González-Ramírez MP, Martagón-Herrera NA, Garcés-Eisele J, Ruiz-Argüelles A, et al. Leucemia en células del donador: Un estudio prospectivo de su identificación y tratamiento. Gac Med Mex 2015; 151:582-587.

Conclusions

In Mexico, the distribution of leukemic types and subtypes is different compared with other countries. The implementation of novel technologies such as flow cytometry and molecular biology in the last three decades has allowed the discovery of details regarding acute and chronic leukemia in Mexico (figure 1). Leukemia treatments have been adapted to economic conditions in Mexico and have occasionally served as the basis of treatments in other developing countries. Studies conducted in Mexico on these diseases have been confirmatory but have also generated new knowledge (table I).

References

Publication Dates

History