Acute lymphoblastic leukemia (ALL) is defined as the abnormal proliferation in the bone marrow, abnormal cell clone, derived from the lymphocyte line and stuck at a specific stage of Differencia tion. In Europe and the United States, they represent 80% of leukemia and about 35% of childhood cancers. In adults, they are instead 4 times rarer than acute myeloid leukemia.
Combines the typical form of bone marrow failure syndrome, tumor syndrome, and metabolic signs. Their respective intensity can be varied, and sometimes require extreme emergency care.
1- marrow failure syndrome:
• Anemia is responsible pallor, tachycardia, dyspnoea exertional, systolic murmur.
• Thrombocytopenia with hemorrhagic signs from simple ecchymotic purpura intracerebral hemorrhage in which the risk is increased in the presence of retinal hemorrhages in the fundus.
• The granulocytopenia source of serious infectious complications. However, the fever is at least as often qu’infectieuse tumor origin.
2- tumor syndrome:
After the marrow and blood, all organs can be invaded. The involvement of lymphoid organs, invasion of the testicles or the central nervous system lymphoblastic evoke the character of acute leukemia.
• Device or deep lymphadenopathy, hepatomegaly and (or) splenomegaly variable size present 3 out of 4 are not distinctive except anterior mediastinal masses sometimes compressive suggesting acute lymphoblastic leukemia phenotype T.
• The invasion of the central nervous system may be manifested by cranial nerve (oculomotor paralysis), meningeal syndrome, intracranial hypertension signs, hypo-estésie the chin tuft … In any case, the puncture Lumbar is necessary to affirm the meningeal or detect subclinical involvement.
• The initial testicular damage, rare, resulting in large farms and painless testicles. Diagnosis is by aspiration and (or) biopsy. Testicular infiltration and bone pain epiphyseal metaphyseal with clear tape on radiographs (20 to 40% of cases) are more the preserve of the forms of the child. A limp, a refusal of walking can result. Skin cancer sites as gingival infiltration or hyperleucocytaire respiratory distress only found in practice that in acute myeloid leukemia.
3- tumor lysis syndrome:
Rare but characteristic anuria by hyperuraturie, dehydration hypercalcemia, rhythm disorders hyperkalemia by a formidable spontaneous short-term prognosis. The intensity of each of these disorders and their association is variable. In the most acute forms, symptomatology is noisy, likely to take an urgent nature (acute anemia, hemorrhagic syndrome, signs of leukostasis in the forms very hyperleucocytaires).
They claim the diagnosis of acute leukemia and features of the blast population (essential for the establishment of a regimen adapted), specify different locations of the disease and allow to stand in the safest conditions.
1- Complete blood count:
It can show the circulating blast cells but this is neither necessary nor sufficient for diagnosis. It also allows to assess:
• the degree of anemia (normochromic normocytic hypoplastic). A normal hemoglobin figure often reflects a rapidly progressive form, poor prognosis;
• the degree of thrombocytopenia and bleeding risk;
• the number of leukocytosis, major prognostic factor distinguishes forms cytopenic forms hyperleucocytaires. These can (8 to 15% of cases) exceed 100,000 / mm3. The degree of absolute neutropenia predicted immediate infection risk.
Essential for the diagnosis, even in circulating blasts. It is generally practiced in the adult sternum in children under analgesic sedation anterior or posterior iliac spine. It allows three types of examinations.
• The cytology: morphological appearance (coloration May-Grünwald-Giemsa) on said blade the diagnosis of acute leukemia (more than 30% of blast cells) and often proposes the cell type. FAB (French-American-British), the most used, describes 3 groups:
– LI: very common in children, rare in adults; the cells are small, monomorphic;
– L2, characterized by the heterogeneity of blasts in their size and in their appearance;
– L3, Burkitt type: malignant cells of medium size, very special by their intensely basophilic cytoplasm containing vacuoles. Myeloid cytochemical reactions are negative (myeloperoxidase and Sudan black B, esterase fluorosensibles) or non-specific [cytoplasmic clumps in Periodic Acid Schiff positivity]). Ultrastructural cytochemistry, when practiced, confirms the absence of peroxidase. The bone marrow biopsy is practiced in case of failure of the bone marrow aspirate. Thus, the cytological definition of acute lymphoblastic leukemia is essentially negative: blasts proliferation without negative peroxidase grains. The limitations of this FAB classification resident of one hand unable to classify the morphology about 25% of acute leukemia, the other in the absence of any correlation between the cytological appearance and belonging to a line B or T, with the notable exception of acute lymphoblastic leukemia that is still 3 B. intake has been designed to be the determination of the immunophenotype of leukemic cells through the availability of monoclonal antibodies.
• Immunological study helps to establish the nature of acute leukemia and to specify the stage of differentiation. It is most often used flow cytometry. The immunophenotype is defined as the set of membrane antigens (CD) expressed by leukemic cells. There is no neoantigen leukemia, as the malignant nature of the blasts is it deducted either the number or the abnormal coexistence of antigens into mutually exclusive theory or the unusual nature of their presence within a body or tissue. It is thus possible to locate, with a variable accuracy of a case to the other, the stage of the normal maturation that the leukemic blasts failed to clear. The clinical use has distinguished four forms of varying age distribution and in children down as follows:
– Acute lymphoblastic leukemia t (15 to 20% of cases);
– Acute lymphoblastic leukemia pre-pre B (70 to 75% of cases) characterized by the antigen CD10 or CALLA;
– Pre-B acute lymphoblastic leukemia (about 10% of cases);
– Acute lymphoblastic leukemia B (<5% of cases). In a few cases, the leukemia cells express both lymphoid and myeloid markers; it is called bi-phenotypic leukemia (6-15% of acute lymphoblastic leukemia), exact meaning and unknown prognostic value.
• The genetic study: the deficiency affects the genome. They are acquired, clonal and not random. Frequently, but not mandatory, it can significantly contribute to the definition of prognostic factors in acute lymphoblastic leukemia. There are 2 types of anomalies:
– Number of anomalies (assessed by cytogenetic study and measurement of the DNA index). the forms hyperdiploid (> 50 chromosomes or DNA index> 1.16) rather associated with pre-pre B phenotype and better prognosis; . the hypodiploid shapes (o 45 chromosomes) rare (less than 8% of cases) to significantly poor prognosis; ploidy of between 47 and 50 intermediate prognosis of chromosomes (as forms very hyperploid);
– Structural abnormalities detected either by cytogenetic or molecular biology [PCR and (or) fluorescent in situ hybridization]. Have a poor prognosis: t (9; 22) (q34; q11) or “Philadelphia chromosome” (Ph1), disastrous prognosis. Cytogenetic appearance is the same, but the molecular abnormalities (Bcr-Abl fusion) are sometimes different from those observed in chronic myeloid leukemia including acute transformation. Frequency, low child (5%) amounts in adults, to nearly 1 in 2 after 50 years; t (4; 11) (q21; q23) found in about 2-5% of cases associated with younger age, leukocytosis. Other anomalies involving the 11q23 region are very common in children: the gene of interest (MLL gene) seems heavily involved in cell differentiation; t (1; 19) (q23; p13) gives rise to a fusion gene E2A-PBX1 and to a hybrid protein, a transcription factor with transforming properties. His poor initial prognosis was deleted in children by using intensive protocols. Appear to have a better prognosis with current treatments: 8q24 abnormalities “Burkitt ‘. They include the t (8; 14) (q24; q32), t (2; 8) (p12; q24) and t (8; 22) (q24; q11) that all interested the c-myc oncogene which deregulation appears critical in the malignant transformation process then juxtaposed to genes encoding the heavy or light chains of immunoglobulins. All three are associated with an immunophenotype B. Their prognosis once terrible, was transformed by the current chemotherapies; t (12; 21) (p13; q11): it seems very common (20-30% of acute lymphoblastic leukemia in children), the gene of interest such. The apparent good prognosis remains to be confirmed over the long term.
3- Lumbar puncture:
The meningeal involvement is defined by the existence of more than 5 cells / mm3 in the CSF with the presence of blasts. It influences the prognosis and especially therapeutic modalities.
4- Other tests:
• chest radiograph: in search of a big mediastinum, a alveolar-interstitial syndrome (leukostasis), infectious pneumonitis.
• The study of hemostasis with research disseminated intravascular coagulation (DIC): essential, particularly in hyperleucocytaires acute lymphoblastic leukemia.
• The electrolytes and calcium and phosphate levels: to assess renal function, search hyperuricemia or metabolic impact of the blast lysis.
• The LDH assay reflects the tumor mass and its renewal.
• A study of liver function before a potentially toxic chemotherapy.
• A complete erythrocyte phenotype, with research irregular antibodies before transfusion, to reduce the risk of immunization in patients for multiple transfusions.
• An HLA typing to predict platelet transfusion immunization even in the event of a subsequent bone marrow transplant.
• A bacteriological and viral investigation to determine the cause of an initial fever as well as the HIV status vis-à-vis the hepatitis B and C and human immunodeficiency virus (HIV) which has immediate practical interest ( predictable transfusions) but subsequent forensic.
• Abdominal ultrasound when clinical prompted, for detecting a mesenteric or renal tumor infiltration.
• An echocardiogram before use of anthracyclines.
There is no differential diagnosis of acute leukemia practice. Yet it is important to:
• do not ignore the diagnosis before a misleading or incomplete clinical picture suggestive of juvenile chronic arthritis or infectious mononucleosis. Analysis of hematologic data must be rigorous, medullary control performed in doubt;
• Do not make the diagnosis too hastily on single blood data: myelogram is still essential to the diagnosis of acute lymphoblastic leukemia. The real difficulty may come from the affirmation of the character of acute lymphocytic leukemia, because of the negativity or inconsistent examinations implemented. The distinction between acute lymphoblastic leukemia and acute transformation Ph1 chronic myeloid leukemia is currently purely intellectual: their prognosis is equally appalling; on the border between the differential diagnosis and clinical forms are the leucémisés lymphomas, in which it is the node that is the original site of the malignant proliferation, but where marrow and blood can be invaded at diagnosis.
The conventional threshold
– 30% marrow blasts
– Defines acute leukemia. For artificial it may seem, it is very useful clinically.
Two forms deserve to be individualized by their particular semiotics:
• acute lymphoblastic leukemia T, characterized by high mediastinal tumor mass developed at the expense of the thymus and cerebro-meningeal marked tropism;
• acute lymphoblastic leukemia mature B of Burkitt [not related to Epstein-Barr virus (EBV) unlike African Burkitt lymphoma]: L3 morphology blasts carry at their surface membrane of monotypic immunoglobulin. The immediate prognosis depends on the quality of haematological resuscitation as the metabolic syndrome is in the foreground.The tumor mass is considerable, often with abdominal location and (or) neuromeningitis.
1- Factors related to the patient:
• Age is the most important factor; in adults, the risk of relapse or primary failure increases above 35; in children age less than 1 year of poor prognosis: the disease is often hyperleucocytaire with initial meningeal involvement, and most toxic treatment at this age; in children more, prognosis deteriorates from 10-11 years old to join the adult from 15 years.
• The initial infection, obesity are all derogatory items.
2- Factors related to the disease:
• The tumor syndrome: the existence of a large tumor syndrome, initial central nervous system are poor prognosis.
• The number of white blood cells: the prognosis is most favorable when the leukocytosis is less than 10 000 GB / mm3. It is very unfavorable over 100,000 GB in children, from 30,000 / mm3 in adults.
• The immunophenotype:
– Very useful to precisely define the acute lymphoblastic leukemia, immunological phenotype is a prognostic factor probably minor, and in any case not independent;
– Acute lymphoblastic leukemia T may, depending on the protocols used, the “best” or “worst”. Typically poor prognosis in children, they justify therapeutic intensification. Instead, they are rather better in the adult;
3. Factors related to treatment:
• Response to treatment: the speed and quality of response to initial chemotherapy are of major importance.Remission speed of installation appears as an essential predictor for the occurrence of late relapses. It can be appreciated in 3 ways:
– Medullary appearance between J7 and J14 of the treatment;
– Number of circulating blasts on day 8;
– Obtaining a complete remission after the first cycle of chemotherapy.
• Above all, the quality of forgiveness is best appreciated by molecular detection of residual disease. 1012 estimated the number of cells present in the diagnosis of acute leukemia and 109 those that persist in the body in the state called complete remission, undetectable by conventional morphological methods. Better detect the residual disease through its molecular features could help define a rational basis for individualized therapeutic intensification.
Highlights to understand:
• The diagnosis of acute leukemia is increased whenever there is more than 30% blasts in bone marrow. The term “acute”, oddly, does not relate to a chronological element nor an apparent gravity.
• The leukemia process leads to a proliferation of young cells, abnormal, having lost the power of differentiation and maturation. The associated myelosuppression is from inhibition of normal hematopoiesis.
• Morphological and cytochemical definition of acute lymphoblastic leukemia blasts appears almost negative: cells without grain negative peroxidase. Immunological characterization is much more efficient: leukemia B or T more or less mature or Biphenotypic.
• The initial lesion is genetic, acquired, clonal (interest only or all of the leukemic cells), not random (defined tables stereotyped clinical and biological).
• The terms of diagnosis in adults and in children are similar. The differences come from the tolerance of the treatment and a different distribution of poor prognostic factors (especially the Philadelphia chromosome and resistance to chemotherapy).
• The principle of treatment is to reduce the tumor mass by successive assaults a non-selective chemotherapy, accompanied by cerebrospinal meningitis prophylaxis and maintenance therapy. The hematopoietic stem cells, allogeneic or autologous are reserved for the most severe forms.
Strong Points to remember:
• The clinico-biological characteristic triad combines marrow failure syndrome, tumor syndrome and metabolic syndrome.
• Achievement of lymphoid organs, meningeal system and testes evokes the lymphoid nature of acute leukemia.
• The blood count quantifies leukocytosis (prognostic factor) and to evaluate the residual hematopoiesis (numbers of platelets, granulocytes and reticulocytes), but not enough to make the diagnosis.
• Bone marrow is essential for diagnosis with at least 30% blasts. Complete characterization combines morphology, immunophenotype, karyotype or molecular biology.
• The urgency of the treatment can be extreme, especially in the forms T and Burkitt.
• The definition of complete remission requires standardization for a month of clinical examination, blood counts and bone marrow aspirate (less than 5% blasts). Yet there is at this stage a detectable residual disease in particular by molecular biology.
• The prognosis of acute lymphoblastic leukemia in children is two times better than that of the adult.
• The Philadelphia chromosome leukemia prognosis is catastrophic.
• In children, it is important to know the long-term complications of treatment (brain, endocrine, cardiac and secondary cancers).
FOR PROBE: TREATMENT
• General Principles of Management Current protocols are stratified according to prognostic factors to adapt their aggressiveness foreseeable risks. There is no agent forcing differentiation in acute lymphoblastic leukemia. So the result chemotherapy comprehensive and sustainable cytopenias. The treatment (an average of 2 to 3 years following the protocols) is generally divided into 4 phases. – Induction is designed to obtain complete remission, defined by clinical examination and a normal count involving more than 1000 granulocytes and over 100,000 platelets per mm3, bone marrow aspiration for wealth and normal composition containing less than 5% blasts , the whole being maintained for at least one month. Lymphoid and acute myeloid leukemia are not sensitive to the same drugs. Most protocols combine several drugs: vincristine, corticosteroids, anthracycline asparaginase. This initial phase burdened with severe morbidity, including infectious, is conceived in specialized areas. Prevention by alkaline lysis syndrome and hyperdiuresis hypouricaemic, antibiotics and transfusion procedures involved in the quality of care. Complete remission was achieved in 90% of children, nearly 80% of adults.
– Consolidation uses different drugs with similar toxicity to avoid the selection of resistant clones: etoposide, aracytine, cyclophosphamide, methotrexate and anti-metabolites (6-mercaptopurine and thioguanine).
– Intensification usually takes drugs originally used at the time of induction.
– The maintenance treatment is usually based on a combination 6-mercaptopurine and methotrexate for 18 months.Its goal is to eradicate residual disease. Monthly or quarterly réinductions can add it on.
– The prevention of harm neuromeningeal, systematic, mainly based on intrathecal chemotherapy and systemic administration of high-dose methotrexate. Radiation therapy to the brain C2, formerly reference treatment, is now often reserved for special cases at high risk.
• Place of hematopoietic stem cells
– Allograft geno-identical: in first remission, it is discussed with the child and forms of poor prognosis. In adults this discussion is the first full remission if there is at least one poor prognostic criteria. It becomes essential in very severe forms such as acute lymphoblastic leukemia Ph1 why the dual effect of cytoreductive conditioning and active immunotherapy [antileukemic effect of the graft or GVL (graft versus leukemia)] represents the only chance of cure. In this indication there is a consensus to use if necessary to unrelated pheno-identical donors.
– Autologous hematopoietic stem cells collected in complete remission, pure or purged in vitro residual malignant cells by chemical, physical or immunological is an alternative proposed by the number of teams when allograft intrafamily is not possible, with results variables. Less toxic due to the absence of disease graft against the host, this method does not benefit from the GVL effect. This shows the importance of the quality of the graft, and thus the detection of subclinical residual disease.
• Relapses Relapses may occur during treatment or much later. Sometimes spinal cord and massive, they can be even more insidious remain temporarily confined to a meningeal or testicular sanctuary. If the cell type is mostly unchanged drug resistance is much more common. The second remission was obtained in only 20-50% of cases and only lasts a few months. A geno-identical allograft is then proposed if it is possible. If not, can be discussed transplants from HLA identical donors or volunteers spinal autograft (bone marrow taken from remission).
• Results Currently in children, the relapse-free survival at 7 years varies from 50% in the forms at very high risk to about 80% for the more favorable. In adults, the results are much less satisfactory: one third of patients at best have a chance of recovery. The reasons for this chemoresistance are not precisely known: the high frequency of Ph1, the worst adult tolerance to chemotherapy
– Which often leads to non-compliance of doses and dates “ideal”
– Are undoubtedly one hand.
• Late Effects
– Neurological complications with frequent reduction in performance evaluated on standardized tests of general intelligence, but sometimes even leukoencephalopathy glioblastomas assigned to the chemoradiotherapy combination Hence the current trend of reducing meningitis prophylaxis.
– Long-Term Cardiac complications that led to reduce cumulative anthracycline doses in modern protocols.
– Risk of second cancers estimated at 2% at 15 years. Leukemia involving the 11q23 chromosomal region (secondary to the cumulative toxicity of etoposide), and brain tumors are the most common.
– Endocrine Complications with an impact on growth (over net before 4 years), but also
– Poorly predictable
– On gonadal function, even if puberty is possible to rule.