Results of chemotherapy in the treatment of chronic lymphoid leukemia in Black Africa: Experience of Côte d’Ivoire

Chronic lymphoid leukemia (CLL) is the most common leukemia in western countries [1]. The median of patients during the diagnosis is 64 years-old and 10% of patients are diagnosed before 50 years old [1,2]. The prognosis of this disease is heterogeneous, since some patients die two years after diagnosis while others survive for more than 20 years and die of non-disease related causes [3]. Regarding treatment, according to the recommendations of the national cancer institute (NCI), polychemotherapy remains broadened to a group of patients in stages B or C of BINET and refractory forms of initial forms A of BINET [4]. In addition, the therapeutic progress observed during the CLL has been marked by the discovery of news therapeutics such as ludarabine, monoclonal antibodies and purine derivatives. However, since the opening of department of hematology in Côte d’Ivoire, the choice of the use of monochemotherapy and polychemotherapy remain diversi ied with sometimes controversial results [5]. The objective of this study was to evaluate the place of polychemotherapy in the treatment of CLL of black African subjects and to identify their therapeutic and evolutionary characteristics. Abstract


Introduction
Chronic lymphoid leukemia (CLL) is the most common leukemia in western countries [1]. The median of patients during the diagnosis is 64 years-old and 10% of patients are diagnosed before 50 years old [1,2]. The prognosis of this disease is heterogeneous, since some patients die two years after diagnosis while others survive for more than 20 years and die of non-disease related causes [3]. Regarding treatment, according to the recommendations of the national cancer institute (NCI), polychemotherapy remains broadened to a group of patients in stages B or C of BINET and refractory forms of initial forms A of BINET [4]. In addition, the therapeutic progress observed during the CLL has been marked by the discovery of news therapeutics such as ludarabine, monoclonal antibodies and purine derivatives. However, since the opening of department of hematology in Côte d'Ivoire, the choice of the use of monochemotherapy and polychemotherapy remain diversi ied with sometimes controversial results [5]. The objective of this study was to evaluate the place of polychemotherapy in the treatment of CLL of black African subjects and to identify their therapeutic and evolutionary characteristics.

Abstract
Background: The treatment of chronic lymphoid leukemia currently uses news drugs which are more expensive in our countries. Its why, the results of chemotherapy remains a challenge in our sector.

Aims:
To evaluate the place of polychemotherapy in the treatment of chronic lymphoid leukemia in black Africa.

Methods:
It was a prospective, descriptive, analytic and non-comparative study, concerning the records of patients with chronic lymphoid leukemia treated and followed at the department of clinical hematology in Abidjan.

Results:
We included 56 patients. The average age was 62 years with extremes of 38 and 84 years. The sex ratio was 0.8 in favor of female. The clinical signs noted a tumor syndrome among which splenomegaly, classifi ed stage III (46, 43%) and adenopathy (64, 29%). Biologically, we observed a blood lymphocytosis (50%), an anemia (39.29%) and a thrombocytopenia (62.50%). The majority of patients were classifi ed stage A of BINET (51.79%). The COP protocol (44.64%) and the monochemotherapy with chlorambucil (39.29%) were the most used. The therapeutic response of polychemotherapy was low (12.5%) compared to 35, 71% for monochemotherapy (p = 0.0001) with overall survival signifi cantly better in monochemotherapy. The outcome of patients used polychemotherapy were more adverse that of patients used chlorambucil alone (p = 0,003). The overall probability of survival at 12 months was 90, 9% for patients who used monochemotherapy and 63, 4% for polychemotherapy.

Conclusion:
Polychemotherapy in chronic lymphoid leukemia of black African has an adverse therapeutic response hence the interest of using new therapeutic possibilities.

Materials and Method
It was a retrospective, descriptive, analytic and noncomparative study with duration of two years (From August 2017 to September 2019), conducted at the department of clinical hematology in Abidjan. This study concerned the iles of black African patients with CCL, treated and followed during this period. 56 patients were included in our study. The recruitment was systematic random. The data were collected using a survey sheet prepared and standardized. The parameters studied were epidemiological, clinical, biological and therapeutic. The therapeutical's parameters had concerned the patients who were treated using CHOP, COP or Chlorambucil protocols according to the posology and the following modes of administration: The total number of cycles of treatment was 6 or 8 cycles for COP or CHOP protocol and 12 cycles for chlorambucil protocol. As for the therapeutic responses, we de ined the Complete Response as the disappearance of clinical signs and a number greater than 4G/L of blood lymphocytes. Partial Response was de ined as a decrease of 50% of tumor and of lymphocytosis. The progressing disease involved increased tumor syndrome and lymphocytosis by more than 50%. This study was conducted in compliance with all the applicable institutional ethical guidelines for the care, welfare and use of animals.

Data entry and statistical analyses
Data analysis was performed using EPI-INFO 6.04b software at the signi icance level of 5%. The independence and percentage comparison tests were performed using the chi-square test (X²). The calculation of survival was done according to the Kaplan-Meir method, taking into account the different prognostic factors. The comparison of the survival curves was made using "log-rank" test.

Results
Our sample was constituted of 56 patients. The tables 1 and 2 summarize respectively the descriptive characteristic and Therapeutical protocol, Therapeutical responses and Outcome of patients. As for the table 3, it shows the analytical characteristic of therapeutical responses of patients. The igure 1 gives the overall survival curve of patient.

Discussion
Our study was prospective, descriptive, analytic and noncomparative. It concerned the black Africans patients with CCL during the period from August 2017 to September 2019. It consisted to evaluate the place of polychemotherapy in the treatment of CCL. This present study showed that CLL is   [6,7]. These differences with our study could be explained by the size of the sample. Clinically, blood lymphocytosis (23, 21%) and splenomegaly (39, 29%) were the most frequent and our data were similar to those of Merle, et al. [8]. The African literature showed that, CCL of African black is very tumoral and this seems to be related to a consultation delay [9,10]. The disease has a slow and chronic course; patients can live for ten years or can have a relatively normal life. Indeed in our study, the majority of our patients had a good general condition (85, 7%). Our results were identical of Kof i, et al. [9]. Lymphadenopathy were present clinically in 35.71% of cases, and de ined the features of CCL of African black which splenomegaly is more predominate than lymphadenopathy. These data were found by all the previous studies [8][9][10]. Biologically, blood lymphocytosis was variable from one patient to another with a lymphocyte count of up to 200 G/L according to Merle, et al. [8]. Anemia is usually related to bone marrow failure. But it can be due to autoimmune hemolytic or an erythroblastopenia The majority of our patients were stage A of BINET (51.79%), similar to the study of Kof i, et al. and Ayemou, et al. [5,9]. Stage A of BINET is attributed to the independent factor of mortality and associated with a good factor. Indeed, the prognosis of the disease is a factor impacting the clinical, biological characteristics, the treatment, the therapeutic responses and the survival of the patients in our environment in Africa. Polychemotherapy was performed in 34 patients and 22 patients were treated by mono chemotherapy including chlorambucil. The choice of our treatment related to the stage of BINET, the presence of comorbidity and the inancial means of patients. Apart from these conventional therapeutic protocols, the treatment of CLL has been disrupted since the discovery of new molecules such as monoclonal antibodies and ludarabine. These news drugs are used in particular during the advanced stages B and C and the emergence of refractory forms. Indeed, these news therapeutic molecules are available in Africa in our hospitals but inaccessible for the majority of our patients because of high cost. Thus conventional chemotherapy remains the only therapeutic alternative for the management of our patients. Therapeutically, 51.79% of our patients were CR while 48.21% had PR. We noted 33.92% of deaths, 39.29% of cases alive and 26.79% of Lost to follow-up. The CCL remains primarily an incurable disease, which can be cured at the cost of an allogeneic hematopoetic sterm cell graft. But, the age restricts this indication. Nowadays, the evaluation of the therapeutic response uses classical criteria of Complete Response (CR), Partial Response and Progressive Disease, but also phenotypic and medullar remission. The quality of the CR is evaluated by PCR on the Ig heavy chain genes and seems to be an essential factor of the prognosis after therapeutic intensi ication. Such explorations are inaccessible in our exercise condition, so that CR remains purely clinical and long-term, anecdotal RC. The analytical characteristic showed in our study that therapeutic response rates with polychemotherapy was worse comparated to the results of monochemotherapy. Our results were similar to the study of Lepetre, et al. [10].
Another meta-analysis study involving 2,000 patients from 10 trials con irms the ef icacy of chlorambucil compared to combinations with ± doxorubicin alkylating agents [11,12]. However, the study of Leblond, et al. had showed that monochemotherapy by chlorambucil give worse results with less 10% of CR [13]. These differences could be explained by the indication of use of chemotherapy during CCL. Endeed, the polychemotherapy protocol in CLL applies to advanced stage of BINET B and C where complications are already established, unlike the monochemotherapy which is used at an early stage of the disease with a patient in good general state. In the CCL-80 and CCL-85 protocols, using polychemotherapy protocols, 60% response rates in advanced stages B were higher than that in our study [14]. However, in no study, this difference in ef icacy has resulted in an increase in survival. The ef icacy in terms of survival of the monochemotherapy on multidrug therapy observed during our study was con irmed by Jaksi, et al. using high doses of chlorambucil (10 mg/m²/day) until the RC [15].

Conclusion
Polychemotherapy in chronic lymphoid leukemia of African black has an adverse therapeutic response hence the interest of using new therapeutic possibilities.

Funding
This study was not funded and had no personal or inancial relationship that may have improperly in luenced the writing. It was done as part of the professional activities of the authors.