I- DEFINITION :
Acute leukemias are acute clonal proliferations , developed from hematopoietic precursors (blastes) myeloblastic and lymphoblastic cell lines.
these blooms develop in the bone marrow with a passage in the blood and other blood-forming organs (rate, ganglia, foie …) or non-hematopoietic (skin, gums, central nervous system )
II- EPIDEMIOLOGY :
the LAM, with an overall incidence of & rsquo; order 3 for 100.000 inhabitants per year in France, are for the majority of adult diseases .Their incidence increases steadily with & rsquo; occurrence of median age is 65 years
LAL : child ++++
- However, there is a second peak frequency after LAL 60 years.
- LAL of & rsquo; child = 30-35% of cancers of the & rsquo; child
- 85% LA s & rsquo; children are LAL.
- Must be distinguished LAL B lineage and T lineage those of.
III- ETIOLOGY :
- leukaemogenic risk factors have been identified.
1- Constitutional Genetic Diseases :
- trisomy 21
- Bloom syndrome Fanconi -Anémiede
- Ataxia telangiectasia
- Syndrome de Klinefelter
- Osteogenesis imperfecta
- Syndrome de Wiskott-Aldrich
2- environmental toxic exposures :
- ionizing radiation
- organic solvents
3- chemotherapeutics :
- Alkylating and nitrosoureas
- Inhibitors of topoisomerase II
4- Personal history of blood disease :
- myelodysplastic syndromes
- myeloproliferative (in particular chronic myeloid leukemia)
- PNH marrow -Aplasie
5- acute leukemia history in a monozygotic twin
6- Virus (Human T-cell lymphoma virus-l and leukemia / lymphoma T cells)
IV- PATHOPHYSIOLOGY :
- AML develop from d & rsquo; a myeloid progenitor that can be either pluripotent, is already engaged in the grainy line.
- The mechanism of leukemogenesis: is of type ” multi-stage ” with successive mutations of oncogenic genes or tumor suppressor genes resulting in a leukemic phenotype.
Causes d’accumulation des blastes :
l & rsquo; accumulation of leukemia cells:
- increased proliferation capacity
- total loss of differentiation capacity up & rsquo; to the mature cell, conferring to tumor cells a survival benefit linked to an exhaust to programmed cell death rules (apoptosis).
Pathophysiology signs :
- marrow involvement: d & rsquo signs marrow failure.
- Flooding d & rsquo; organs: Sd tumoral
- Blasts = young cells rich nucleic acids => Tumor lysis - "° metabolic cmplc: renal insf ,K +, etc….
V- CLINIQUE :
Circumstances of discovery :
- an alteration of the & rsquo; condition
- d & rsquo syndrome, myelosuppression
- bone pain
- a tumor disease associated with a tumor tissue infiltration
- a d & rsquo syndrome hyperviscosity in large hyperleucocytosis blast ;
- tumor lysis syndrome with its metabolic and renal procession in the forms of rapid proliferation in acute leukemia.
- Signs of bone marrow failure
- Tumor events
Tumor events :
- hypertrophy forming organs : superficial lymphadenopathy, hepatomegaly, splenomegaly ;
- skin lesions : or nodules embedded in the dermis farms cupboards, indolores.
- neuro-meningeal location : to seek and to prevent systematically by PL. There are signs of & rsquo; cranial hypertension (cephalalgia, vomiting), cranial nerves…They are more frequent during relapse.
- achievement of gonads (testicles, ovary) : especially during relapses (Rare initial testicular damage : 1-2% boys).
- gingival hypertrophy : highly suggestive of acute monoblastic leukemia .
- bone disease : infrequent
- localized tumor : rare but can be a diagnostic trap, (chlorome) nature of variable seat myelogenous
- syndrome leukostasis matching shapes of LA very hyperleucocytaires and rapid doubling time. The infants develop neurological signs (confusion…) and pulmonary signs (dyspnea, cyanose…).
Signs of bone marrow failure :
- an anemic syndrome : pallor, dyspnea, tachycardia
- an infectious syndrome : isolated fever or associated with a clinical point of call (pneumonitis, angina, mucocutaneous lesions secondary infection…)
- hemorrhagic syndrome : spontaneous
- skin (petechiae, hematomas)
- mucous (gingivorragies, épistaxis)
- social : existence of large bruises or prolonged bleeding with stitches should suggest (intra vascular coagulation disseminated).
WE- BIOLOGY :
- GB : normal / ↗ / ↙ neutropenia ++++
- HB : normocytic anemia or normocytic macro AREGENERATIVE
- Plaq : thrombocytopenia
Blood smear :
GR : NN
GB: neutropenia / inversion of the formula / relative lymphocytosis
BLASTES ++++: young cells
cut 15 – 20 micron
N / P ratio : ↗
core: fine chromatin nucleolée
cytoplasm: basophile …granulations +/-
Bâtonnets the clock = LAM +++ / Certainty
- Puncture: superior iliac spine postero, usually under general anesthesia in children.
- performing multiple medullary samples allowing the realization :
1-cytological study: juice medullary / spreading / MGG staining
3- Cytogenetic and molecular biology.
- The confirms the diagnosis showing bone marrow infiltration by blastes > 20%
Colorations cytochimiques :
- Myeloperroxydase or Sudan Black :
LAM si blastes + >3%
LAL si blastes + <3%
AML4 or LAM5
Histological study of the bone marrow biopsy bone marrow (GOOD) has no indication in the diagnosis outside certain forms in which the bone is too hard and inaspirable marrow testifying in general a myelofibrosis associated (LAM7).
immunological study :
- diagnostic interest :
1- identify the relevant line
CD79a for the B,
CD3 for T lineage,
myeloperoxidase for myeloid lineage
2- identifying the stage of maturation
3- d & rsquo; identify a Biphenotypic acute leukemia
- prognostic value :
THE Biphenotypic / LAMO /
CYTOGENETIC STUDY :
- diagnostic : Typical anomalies of certain types of LAM Lalet
- Prognosis: important for treatment decisions surtoutde l & rsquo; child (ex : Philadelphia chromosome in ALL : very poor prognosis) requiring use of a spinal allograft
MORPHOLOGICAL CLASSIFICATION OF LAIVl:
|Type FAB||Definition||per oxydase / Sudan black||esterase|
|LAM 1||without maturation||+||–|
|LA M2||with maturation||++||–|
|Lamo||éryth roi eucém ie||+|
MORPHOLOGICAL CLASSIFICATION OF ALL:
|Cut||small homogeneous||great heterogeneous||great homogeneous|
|N / P ratio||Student||Lower||way|
|Core||regular, normal||irregular, slotted||regular, round or oval|
|Nucleolus||0 or 1, small||1 or +, bulky||1 or +, bulky|
|variable, sometimes intense||very intense|
|vacuoles||variable presence||variable presence||present and bulky|
other exams :
routine chest radiography in & rsquo; entry to search
- an infectious outbreak,
- cardiomegaly can testify d & rsquo; heart failure,
- a lung leukostasis.
d & rsquo balance sheet hemostasis : social :LAM3 +++
VII- Complications :
– lonogramme blood
– renal function tests : creatinine and blood urea
– Serum calcium
These metabolic abnormalities should be corrected before starting treatment.
– Blood cultures,
– throat swab and possible infection in case of fever, stool if diarrhea.
VIII- prognostic factors :
immediate prognosis and therapeutic emergencies
The immediate prognosis is engaged :
1/ in hyper leukocyte forms (more than 50.000 leukocytes per mm3 in the peripheral blood) ;
2/ severe hemorrhagic syndrome: thrombocytopenia less than 20 000/Retinal mm3 / cerebrospinal meningitis ; Disseminated intravascular coagulation DIC =).
3/ severe infectious syndrome : infection Gram negative bacilli,Gram-positive cocci, d & rsquo; origin ENT, digestive or skin (Echerichia Coli, Proteus, streptococcus, staph …) ; hospitalization & rsquo; emergency in a specialized service
4/ anemia below 6 g / l & rsquo; Hb or angina
5/ rapid haematological changes appreciated by the progression of & rsquo; leukocytosis on successive hemograms
6/ Neurological signs may involve risk of specific localization observed mainly in the forms and hyperleucocytaires monoblastic (LAM 4 and 5) or neuro-meningeal bleeding
7/ leukostasis associated with visceral forms hyperleucocytaires, related to the & rsquo; s blood viscosity & rsquo; speaking generally as pulmonary leukostasis (respiratory distress) or brain (neurological signs), and potentially triggered or aggravated by the realization of RBC transfusions.
FACTEURS PC LAM :
- L & rsquo; age : most patient is elderly (>60 years) the greater the risk of & rsquo; failure are important ;
- The secondary character of AML.
- initial leukocytosis > 30 x 109/1 ;
- Type cytologique : better prognosis shapes M3 and M4 eosinophils, worse prognosis forms MO and M7 ;
- immunological phenotype : l & rsquo; expression of the CD34 marker and / or gpl70 protein encoding the MDR1 gene (multiple drug resistance) is correlated with a poor prognosis
- biphénotypiques forms
Anomalies cytogénétiques clonales :
good pc :
- la translocation t(15 ;17) characteristic of LAM 3 ♦
- la translocation t(8 ;21) found in about 25 % LAM 2 ♦
- l’inversion du chromosome 16 characteristic of LAM 4 ♦
bad pc :
- deletion 5 and or 7, trisomies 8, chromosome abnormalities 11 [(bandaged (llq23)], or complex chromosomal rearrangements, associated acute d & rsquo transformations RAEB and secondary AML ; intermediate prognosis.
- normal karyotypes
BAD ALL FACTORS PC :
1/ Age :
- < 12 months and above 6 month ;
- > 10 years and above 15 years.
The prognosis is particularly bleak after 60 years mainly due to the frequency of chromosome Phi search d & rsquo; age.
2/ The forms hyperleucocytaires > 50 Giga I / O.
3/ tumor syndrome and mediastinal widening.
4/ neurological immediately : l & rsquo; CNS involvement at diagnosis is rare (1.5%) and is a poor prognostic factor.
5/ immunological criteria :
- CD 10 or negative CALLA
- THE biphenotypic (myéloïdesetlymphoïdes markers)
- The T-ALL considered historically unfavorable
6/ cytogenetic criteria :
- Hypoploïdie ;
- t(9 ;22) or Philadelphia chromosome ;
- t(4 ; 11) ;
- t(l ;19) in the & rsquo; adult.
7/ response criteria in the therapeutic :
- Initial corticorésistance and chemoresistance ;
- significant residual disease in & rsquo; after the & rsquo; induction
IN CHILDREN, the 3 prognosis of the major criteria in the LAL
- l & rsquo; age : < 1 an > 10 years ;
- the leukocytosis diagnosis : < or > 50 Giga I / O ;
ADULTS, the presence of a Philadelphia chromosome and / or expression of a bcr-abl transcript constitute LAL severity factors in adults.
IX- préthérapeutique :
- Blood with comprehensive phenotyping
- search & rsquo; irregular antibodies in anticipation and platelet transfusions globular
- viral serology: HIV,HBV,HCV
- Blood Sugar
- Electrocardiogram and echocardiogram indispensable looking & rsquo; myocardial suffering against-indicating & rsquo; use of anthracyclines.
X- TREATMENT :
1/Preserving the immediate pc :TRT Complications
2/Obtaining complete remission:
- Disappearance of the tumor syndrome (normal clinical examination) ;
- Normal Hémogramme ;
- Less of 5% marrow blasts
3/Getting a cure: greffe MO
1/ Symptomatic TRT :
- l & rsquo; anemia : red blood cell transfusion phenotyped
- hemorrhagic sd : corticosteroids hemostatic dose:0,25mg / kg / day, tranfusion :CUP,CSP
- infectious sd : .hygiène body isolation, bathroom bouche.si t °>38 => search of infection =>ATB broad spectrum subsequently adapt antibiogram
- Metabolic CPL : hyperhydratation: 3 L/m2 SB1/3 ,SSl/3 ,SGl/3
2/ Specific TRT :
- treatment of & rsquo; induction which aims to reduce the tumor burden to a level of minimal residual disease and restore normal hematopoiesis ;
- The meningeal prophylaxis
- consolidation therapy that aims to reduce residual disease ;
- and the implementation according to the & rsquo; age and the & rsquo; whether or not there & rsquo; an HLA-identical family donor:
– or d & rsquo; intensive treatment with hematopoietic stem cell transplant autologous or allogeneic,
– is a consolidation 2nd treatment
– or treatment of & rsquo; maintenance in most elderly
Induction LAL :
The drugs used are :
Anthracycline Cardiotoxicité, alopecia, mucite. Nausea asparaginase Thrombosis, diabetes, pancreatitis
other treatment modalities are in evaluation :
- monoclonal antibody : Ac anti CD 20, CD 22…
- Imatinib (Glivec )in Philadelphia chromosome
TRT LAM :
Treatment d & rsquo; induction of AML :
l & rsquo; & rsquo association; an anthracycline and cytosine arabinoside (VEHICLE) (possibly associated with a third drug) allowing d & rsquo; achieve complete remission rate (RC) from 75 at 80 %.
Consolidation : ARA-C in high doses
Relapse Prevention Three methods are then possible for :
- L & rsquo; allogeneic hematopoietic stem cells
- L & rsquo; autogreffe // //
- Intensive chemotherapy.
The results :
LAL of & rsquo; child :
globally more are obtained 90% complete remission, and more 70% healing.
LAL of & rsquo; adult :
The complete remission rate in the & rsquo; young adults is 80%, but relapses are frequent with only 20 at 30% persistent remissions (50% if we can allograft).
average obtained 70% complete remissions (80% before 60 years, 50% beyond) and 30 at 40% prolonged remissions (50% si allogreffe, less of 25% after 60 years).
They occur most often in the first two years of remission.
The new remission rate is lower and shorter than the first outbreak, except in cases of & rsquo; use of different treatment modalities (eg transplant if not used initially).
Dr Chehili's course – Faculty of Constantine