Evaluation of Therapeutic Results of A Series of Moroccan Patients Aged 20 To 60 Years Treated According To The Acute Myeloid Leukaemia 03 Protocol At The Paediatric Haematology Oncology Centre In Casablanca

Acute Myeloblastic Leukaemia (AML) is a malignant haemopathy characterized by inltration and accumulation in the bone marrow by myeloblastic-type blast cells causing medullary insuciency. At the global level, the search for improved AML treatment is a long-standing concern. Purpose To evaluate a new protocol AML MA 2003 its therapeutic results and tolerance in de novo AML patients. Methods It was a prospective and descriptive unicentre study carried out from 2003 to 2010. It included adults of 20 to 60 years with a diagnosis of de AML except a promyelocytic and without treatment by hydroxyurea.


Introduction
Acute Myeloblastic leukaemia (AML) is a malignant blood disease characterised by the in ltration and accumulation in bone marrow of blast cells, type myeloblast, causing bone marrow failure. (1) Their management is not easy. A global search for improved AML treatment is a long-standing concern.
The experience of the Haematology and Paediatric Oncology Service of Casablanca, in the treatment of AML, started in the 1980s and can be surmised in four major therapeutic periods. Before 1985, the attitude varied between abstention and treatment with 6 Mercaptopurine (6MP) (4). In 1989, the treatment used was the French protocol "CHA". The evaluation found a high death rate before and during induction treatment. The AML 6.96 protocol was implemented in 1996. The overall CR rate was 60%, death rate had increased to 14% and 16% of patients were in failure. (5)

Aim of this study
To evaluate a new protocol AML MA 2003 its therapeutic results and tolerance in de novo AML patients on the Paediatric Haematology/Oncology Unit at the Ibn Rochd University Hospital of Casablanca.

Patients And Methods
From January 2003 to December 2010 on the Paediatric Haematology/Oncology Unit at the University Hospital Casablanca, patients of 20 to 60 years with a diagnosis of de novo AML (outside of acute promyelocytic leukaemia) untreated (except for the administration of hydroxyurea (HU) to stem a threatening leukocytosis) without cardiac problems, major liver or kidney failure and positive HIV serology were included. The study responded to the recommendations of the national ethics committee on the use of human data. All patients or their representent signed a consent form after being informed of the development of the protocol.
The diagnosis of AML was selected according to the D of classi cation of the cooperative group, French-American-British (FAB). Imuno-phenotyping and cytogenetic analysis, were performed at diagnosis in medullary sampling. According to the World Health Organization (WHO) classi cation patients were on favourable prognosis (t (8; 21) or inversion of chromosome 16), unfavourable prognosis (deletions of chromosome 5, 7, 3q inversion, 11q abnormality of l9q, t (6; 9), t (9; 22) and the complex karyotype). The group with an intermediate prognosis, corresponded to all other types of karyotypes.
For hyper-leucocytaire forms (WBC> 50,109 / l), as a pre-induction, a cyto-reductive treatment by HU at 50 mg / kg / day per day was administered for 4 days. The chemotherapy protocol included an induction for all patients, a bone marrow aspirate evaluation was performed on D15. For patients whose marrow had more than 20% blasts, intensi cation was started at D16. For those who had a bone marrow aspirate of less than 20% blasts, a second aspirate was conducted between D28-D30 after exit from aplasia. The second induction, identical to the rst, was started at D30 after aplasia, for patients who had not needed the intensi cation cure. The two consolidation treatments included patients in complete remission at the end of the 2 courses of induction and catching up. Prophylactic treatment of the Central Nervous System was administered by intra-thecal injections (IT) on day one of each course. The maintenance treatment lasted 18 months. (Figure 1) For supportive care, patients received antifungal prophylaxis and digestive decontamination. Mucositis was prevented by administrating mouthwashes containing oral fungizone, and blood transfusion. Febrile neutropenia was brought under control by antibiotics.
Treatment responses were based on the revised criteria Cheson et al: de ning the complete response, partial and failure. (6) On the periphery, haematological recovery included a neutrophil count > 1.1 09 / L and a platelet count > 100. 1 09 / l. Early and toxic mortality is de ned as any death occurring during preinduction, or during the induction phase related to a complication of the disease or toxicity secondary to treatment. Deaths occurring during the consolidation period will be analysed separately.
Statistical Analyses was conducted using the SPSS software. The overall survival (OS) and event-free survival (SES) were determined according to the Kaplan-Meir method.

Discussion
Improving the treatment of AML patients is a longstanding preoccupation. It has led to the creation of a support service for all AML patients throughout the country. The high cost of care in private facilities, limiting access, brought the major number of patients to the public sector. This study while not multicenter can be regarded as a re ection of the treatment of AML across the country.
The average age of patients, 39.8 years, was different from what is found in developed countries due to the inversion of the age pyramid between these 2 types of population. This result was close to that of developing countries because of the younger age of the population. (7,8) In recent years many molecular discoveries and therapeutic strategies have been put in place for the treatment of AML and have imposed that cytogenetic tests and molecular biology be carried out before starting chemotherapy. The results are available within 72 hours, at most 5 days after. (9) This has the effect of delaying by a few days the beginning of treatment, an average of 5 to 8 days with an impact on the complete remission and progression-free survival according to studies. (10,11) Alongside the role of laboratory tests, a higher number of leukocytes and the advanced age of patients will be responsible for prolonging the time of care for patients. (10) In our study the processing delay causes are different. The time between diagnosis and treatment in hospital, on average 20.5 days, from the results published to date was extended for other reasons. These, though they were not listed, would be dominated by a reduced bed capacity while demand was high. This capacity problem is not only found in developing countries because many of the major Western centers encounter it also. (10) During the study 64 (15.3%) patients were lost sight for various reasons: the distance from the treatment center because patients came from all across the country without possibility of residence in Casablanca in inter-treatment, lack of a local health centre capable of managing infections, transfusions or emergencies, limited access to telephone coverage making it di cult for any regular contact with the patient or family, the long time between hospitalisation due to the large number of patients and limited bed capacity. The cost of treatment for patients often from rural areas without health insurance was also an important parameter for discontinuation of treatment especially after the rst induction, during which more than half of patients were lost of view. While it is recognised that the cost of treatment of AML is by far the highest compared to other cancers, in many countries the cost is reduced for the patient by the existence of social coverage or entry into research protocols. (12,13) Prephase-induction One of the rst attitudes at diagnosis of AML is aimed at correcting the immediate complications of which one is hyper-leukocytosis. It is known to be responsible for a poor prognosis and clinical and biologic complications that can be fatal for the patient. Hyper-leukocytosis in AML is characterized by a mortality ranging from 4 to 29% at diagnosis, a low rate of complete remission and progression free survival. (14) Cyto-reductive strategies are the subject of much debate between leukopheresis and hydroxyurea use. In our protocol hydroxyurea treatment was used in 158 (36.1%) patients. It has resulted in a fall of more than 50% of white blood cells in 65.2% (103) cases. However 12 (7.6%) died. This phase of treatment was useful for patients who were subsequently able to receive chemotherapy.

Inductions
During our 8-year study we evaluated the response to a new chemotherapy regimen that used doses of ara-c and daunorubicin as recommended in international standards for patients 20 to 60 years with a diagnosis of LAM novo. The rst induction treatment administered to patients allowed 171 (40.5%) CR, which is an improvement on the previous protocol where there were only 36%. The addition of a second induction increased the rate to 76.3% or 203 patients of 266 who received it, as described in the literature (60-80%) (3,15,16). But again, the poor results in the rst induction could partly be explained by the early realisation of the bone marrow aspiration at D15 while spinal cord recovery was not effective on that date. This attitude is questionable because conventionally, evaluation is performed between day 21 and day 28 of induction except for some studies that test new agents or use induction treatment intensi cation like ours. (16) Intensi cation The intensi cation was used for all patients whith more than 20% blasts at the evaluation. It favoured remission of 28 (47.5%) among the 59 patients who received it. They subsequently accessed to the next phase of the protocol. For our patients, failing to provide a transplant for those whose prognostic factors indicated it, we administered two consolidation treatments which helped to maintain a good response in 82.9% of patients after the rst consolidation and 91.6% for those who received the second. The international study groups recommend AML patients in clinical and haematological remission be administered several consolidation cycles while knowing that there is no consensus on a post-induction treatment strategy. The mortality observed in the treatment of AML has led many teams to focus their activities on preventive measures by giving supportive care to reduce deaths from infections and bleeding. Antimicrobial prophylaxis and administration of growth factor have allowed this goal to be widely achieved. (21,22) Survival at 5 years for 32.4% among all the patients in our study was well below the standards of 40-50%  Figure 1