Evolution of the Outcomes of Children with Acute Leukemia in Congo

Background: To lower the mori-mortality related to the aggressiveness of acute leukemia’s chemotherapy regimens, we have implemented in 2017 two low toxicity chemotherapy regimens and new supportive care strategies. The aim of the study is to evaluate our new treatments. Materials and Method: A retrospective study was carried out from January 2014 to May 2021 in the hematology department of the teaching hospital in Brazzaville. The study concerned 47 children diagnosed with acute leukemia. Participants were divided into two groups: acute leukemia diagnosed before 2017 (group 1: 23 children) and after 2017 (group 2: 14 children). They were compared using the chi-square. Results: The median age was 10.0 ± 5.01 years. Features and outcomes of group 2 were better. The median duration of symptoms was shorter: 2.45 ± 2.87 months (p = 0.036). The Karnosky score was higher (p = 0.002) and white blood cell count lower (p = 0.331). Both groups started the treatment with a delay of 6 days. The induction treatment was completed in 69.6% before 2017 versus 93.3% after. The rate of relapse was more important for group 1: 85.7% versus 14.3% (p = 0.01). Conclusion: Trainings of professionals have improved the characteristics outcomes of our patients and should be pursued. Considering the high relapse rate, our protocol will need to be intensified.

The survival of children is poor, related to the lack of capacity diagnosis, trained providers, and access to care. The distribution of malignant tumors throughout the continent differs depending on the country. In the Republic of Congo, for instance, acute leukemia stands as the most common malignant tumor in the child population [2] [3]. Its morbid-mortality rate is the highest among malignant hematological diseases and its outcome, the poorest [4]. The mobi-mortality is mainly associated with the agressiveness of western countries' chemotherapy regimens responsible for profound immunodeficiency [5]. The rate of complications in Congo is exacerbated by the poor hygiene standard of the hospital's environment, nonsustainability of blood products, and antibiotherapy.
In regard to that, we have taken multiple actions to improve the prognosis and quality of life of children with acute leukemia. We have implemented in 2017 new chemotherapy regimens trained our nurses on oncology care and increased our hygiene standards. These have led to a better management of both leukemia (lymphoblastic and myeloid) and have changed some features of childhood malignant.
The aim of our study is to review the clinical, biological and outcome features of patients with acute leukemia treated with low toxicity regimen chemotherapy.

Materials and Method
The study was conducted in compliance with the ethical standards of the responsible institution for human subjects as well as with the Helsinki Declaration.
We conducted a cross-sectional study during 7 years and 4 months in the hematology department in the University hospital in Brazzaville which is a tertiary and biggest healthcare facility in Congo.
We reviewed during the study period all records of children aged less than 21, diagnosed with acute leukemia and admitted in the hematology department. The diagnosis was made based on cytology studies of the bone marrow aspiration.
The period of study was divided into two subperiods: January 2014 to December 2016 (group 1) and from January 1, 2017 to May, 2021 (group 2).
The period from January 2014 to December 2016 was labelled before 2017 January, the one from January 2017 to May, 2021 was labelled after 2017.
All patients with acute leukemia (lymphoblastic and myeloid) admitted in the Hematology Department during the study period were included in the study.
For each patient we collected: Patient loss of follow for a period of more than 6 months was recorded as dead.
Loss of follow refers to a patient that did not show up for a scheduled therapy up to 6 months.
The length of the medical history is defined as the period spanning from the onset of symptoms related to the acute malignancy to the admission to the hematology department.
Criteria for remission were less than 5% of blasts in the peripheral blood, no tumoral syndrome, absolute neutrophile ≥ 1 G/L, platelets ≥ 100 G/L. Relapse was defined as the recurrence of the disease after remission. The criteria were: recurrence of tumoral syndrome, leukocytosis and ≥5% of blast in the peripheral blood.
Outcome is defined as the status of the patient at the end of the study period: December 31, 2016 for the participants in group 1 and May 30, 2021 for the participants in group 2.

Statistical Analysis
The data were analyzed by the software R version 4.0.0. The count data are presented as frequency (percentage) and the differences between groups were assessed using the chi square test. Quantitative were presented as the mean ± standard deviation.

Results
A total of 47 patients (32 in group1 and 15 in group 2) were included in the study.
The global median age was 10.0 ± 5.01 years.

Discussion
Two -year survival rate of children with acute leukemia in Sub-Saharan Africa is very low [6]. It is due to the lack of diagnosis capacities, supportive therapies, low accessibility to cancer drugs, shortage of physicians, and nurses trained in oncology. Intensive therapy in conjunction with supportive therapy has increased survival rates more than 70% and 80% for ALL and AML in high resource countries [7] [8]. In low resource countries, like the Congo, myelosuppressive therapies are associated with a high rate of toxic death [5]. Taking into account our limitations and challenges to treat children with acute leukemia, we have offered training to professionals and implemented low toxicity protocols to increase the survival rate of our patients. We did not find any difference in the average age at the onset of acute leukemia. It is a malignant hematology disease that affects most frequently children in their first decade [3] [9] [10]. Awareness sessions on the disease have significantly reduced the diagnostic time by nearly 2 and a half months after 2017 (p = 0.038). This resulted in a better clinical feature at the time of diagnosis. All patients scored 70% after 2017, while 34% had a score below 60% (p = 0.002) before that period. The prognosis was also more favorable as the peripheral white blood cell count was lower (p = 0.331). However, in both groups the number of leukocytes was over 50 giga/L. It is associated with the low survival rate [11] [12]

The Congo is located in Central
[13].
We have implemented interprofessional consultations with government-owned peripheral hospitals that are geographically and financially more accessible to the population. The goal was to build hematology expertise in the secondary professional health facilities and decentralize the diagnostic point. As a result, after 2017, they became the first referral health facilities. Peripheral hospitals referred 87.5% suspected cases of acute leukemia to the university hospital versus 46% before 2017.
In average, the initiation time for acute leukemia treatment regimens is 6 days.
The Congolese government does not subsidize treatment of cancer, nor does it offer a medical insurance program. Therefore, the cost of chemotherapy is the major obstacle to begin it. Most patients 'families cannot afford it or go into debt to purchase drugs for the first phase of treatment. They usually turned away for the second phase of it. The time to begin chemotherapy is also linked to the unavailability of certain cancer drugs such as L-Asparaginase, idarubicine, and etoposide. Therefore, considering these limited factors and the high morbi mortality related to chemotherapy, in 2016, we have implemented two low toxicity protocols to treat acute leukemia. All patients diagnosed with ALL were treated with the modified Hunger protocol without L-asparaginase [14].  [16].
The poor outcome observed in both groups after completion of the consolidation was related to factors that vary depending on the intensity of the regimen administered. As expected, the low toxicity protocol was associated with a high relapse rate: 85.5%, the highest reported. The lack of L-Asparaginase in our ALL's protocol may have worsened the prognosis since the drug is known to significantly increase the complete remission and survival rate [6]. Death related toxicity in group 1 accounted for 11.1%, which is lower when we compare with Kersen et al., in Tanzania (26%) [6].
In the standard protocol group (group 2), death-related toxicities were without surprise, the major source of death: 88.9%. They occurred precociously during the treatment induction. In our unit, hospital-acquired infections are the main related toxicity treatment observed [5]. They increase substantially medical expenses and delay the initiation of the second phase of treatment which is source of relapse. toxicity regimen did not substantially improve the outcomes of our patients since the protocols were not complete. However, the progress was significant in other aspects such as treatment abandonment, delay of survival, and related toxicity deaths. Thus far, with limited resources at our disposal, we have been able to improve the care of children with acute leukemia. We are confident that with the help of our government and non-governmental organizations, significant results will be achieved.

Conclusion
The low chemotherapy regimens have improved the quality of life of children with acute leukemia but increased the rate of relapse, which advocates to gradually increase our treatment. Open Journal of Blood Diseases

Consent
Written informed consent was obtained from the parents of the patients for publication of this study.

Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.

Authors Contribution
Ngolet Lydie coordinated the field study and conducted the study and analyzed the data. Simo Josué Luokdom, Alexis Fortuné Bolenga Liboko, Firmine Olivia Galiba Atipo Tsiba, Alexis Elira Dokekias reviewed the draft. All authors read and approved the final manuscript.