Chronic Lymphocytic Leukemia Treatment in México: Up to Half Patients May Not Requiere Treatment
Authors: Sánchez-Valledor Luisa Fernanda , Córdova-Ramírez Carmina Alejandra , Elias-de-la-Cruz Gilberto David , Rivera-Álvarez Montserrat , Cruz-Mora Antonio , Cantero-Fortiz Yahveth , Khalaf Dina , Olivares-Gazca Juan Carlos , León-Peña Andrés A. , Murrieta-Álvarez Iván , Ruiz-Delgado Guillermo J. , Ruiz-Argüelles Guillermo J. 
Published: November 2020

Introduction
Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasm which represents the most frequent hematologic malignancy in Caucasians. Every year, there are15,000 new diagnoses and 5000 CLL deaths in the United States. Its prevalence in México and other non-Caucasian populations is substantially lower and the clinical course of CLL patients has been described to be less aggressive
Methods
All consecutive patients seeking medical care after 1983 in our institution as a result of CLL and followed for at least 3 months were entered in the study. The study was approved by the institutional review board. The treatment of patients was withheld in: (a) Persons with CLL Rai stage 0 or 1, until progression; (b) Persons with CLL Rai stage 2-4, with a negative expression of ZAP-70 until progression. Progression was defined by: Anemia, thrombocytopenia, massive symptomatic or progressive splenomegaly and or adenopathy, progressive lymphocytosis (&gt;50% increase in two months or lymphocyte doubling timeless than 6 months), autoimmune hemolytic anemia not responding to standard therapies, or constitutional symptoms: Weight loss greater than 10% in 6 months, unexplained night sweats or unexplained fever for 2 or more weeks. Refractoriness of the disease was defined as progression despite treatment for a minimum of 3 months.
Results
Among 98 patients with CLL who were accrued in the study between 1983 and 2019, 49 (50%) were followed for three or more months and accordingly, entered in the study. Median follow up time of the patients is 61 months (95% CI 46.1-75.8). There were 15 females and 34 males, the median age was 65 years (range 23-86). According to the Rai staging system, there were 24 stage 0, 7 stage I, 8 stageII, 0 stage III and 10 stage IV; 80% of patients were identified in stages 0-II. In 28 patients a complete immune phenotype of the malignant cells was analyzed: 89% of patients were ZAP-70 negative (ZAP expression in less than 20% of malignant cells), 79% expressed CD5, 100% CD19 and 86% CD23. Three patients were born in European countries, whereas 6 had an immediate European ancestor, indicating that a Caucasian background was identified in 9/49patients (18%). There were no instances of T-cell CLL. Median OS for all the patients has not been reached, being above 247 months (20 years). The OS of patients given or not any treatment was not statistically different (p= 0.09). It is clear that patients who needed treatment did worse than those not needing treatment but the differences were not significant. Patients with advanced stages (III and IV) had a worse outcome than those in early stages. Median OS for patients given no treatment at all has not been reached and is above 247 months; median OS for patients given CP was 115 months, median OS for those given FC has not been reached and is above 132 months, whereas median OS for persons given FCR has not been reached, being above 136 months; all these differences are not statistically significant. Eight of 49 patients were found to be refractory to treatment; they were receiving CP (5 cases); FC (2 cases) and FCR (one case); these refractory patients were given, FCR (7 cases) and rituximab/ifosfamide/carboplatin/etoposide (one case). No patient had to be given cladribine, pentostatin, alemtuzumab (anti-CD52), bendamustine, ofatumumab (anti-CD20), obinutuzumab (anti-CD20), lenalidomide, ibrutinib nor idelalisib.
Conclusion
In the era of novel anti-CLL drugs, we have found that the clinical course of these patients in México seems to be less aggressive than in Caucasian populations and that, in consequence, circa 50% of them do not need any treatment at all. In those needing treatment, the use of a simplified approach and taking advantage of improved supportive care measures, acceptable results are obtained even if all of the new CLL drugs are not employed. These observations may be critical in developing countries, where the cost of the drugs will continue to be a major factor in choosing therapies.

Disclosures
No relevant conflicts of interest to declare.