Charles Mxxx – DCEM2

Toulouse Purpan Medical School

01/26/2012

ECN Item 162

� Definition � Pathophysiology

� Clinical signs and symptoms

� Biology and Diagnosis

� Different types of AL

� Prognosis and Treatment

� Malignant Hemopathy: cancer

- Accumulation of blasts in the bone marrow

- Affects the production of normal blood cell (↘)

- Rapid evolution without TTT

� ≠ Chronic leukemia: - ↗ production

- slow evolution

� Rare disease: 4-5/100,000/year

� 2 main types

- Acute Myelogenous Leukemia (age++)

- Acute Lymphoblastic Leukemia: 1/3 of children K

+ several subtypes

http://www.articlesbeach.com/wp-content/uploads/2011/08/Sub-Type-of-Leukemia.jpg

� Mutagenic event � Successive mutations (many genes involved) � Leukemic phenotype

� Maturational arrest of bone marrow cells

� Early stages of development

= Clonal proliferation of immature cells

1. Accumulation of immature cells

in the bone marrow (+/-other organs)

2. Decreased production of normal blood cells

� Etiological Factors: - Mostly unknown

- Hematological disorder: myelodisplastic syndrome ++

- Chemotherapeutic agents: alkylating agents, topoisomerase II inhibitors

- Genetic factors: Trisomy 21, Fanconi disease, Li-Fraumeni syndrom, …

- Environmental exposures: ionizing radiations, benzene

http://www.articlesbeach.com/disease-illness/leukemia/acute-leukemias-etiology-clinical-features-laboratory-features-treatment/

� Tumoral syndrome: infiltration by leukemic cells

- Adenopathies

- Hepato-Splenomegaly- Visceral localisations: gums, bones, skin, testicles, ... - If WBC>100,000 cells/uL

= leukostasis = clump of leukocytes in pulmonary or brain capillaries

(ARD, coma, convulsions � emergency)

� Signs of medullar insufficiency- Anemic syndrome (asthenia, paleness, dizziness, …)

- Haemorrhagic syndrome (bleeding gums, ecchymoses)- +/- Infectious signs (fever++): located infection �

septicemia

•VARIABLE• UNSPECIFIC: ORIENTATION ++

http://www.leucemie-espoir.org/spip.php?article72

http://www.lookfordiagnosis.com/mesh_info.php

� Diagnosis: Based on biological results

� Complete Blood Count: - Aregenerative Anemia ++ - Thrombocytopenia- Neutropenia- Leukocytopenia vs. Hyperleukocytosis- +/- Blasts (myeloid or lymphoid)

� Bone marrow Aspiration: - Rich marrow- >20% Blasts- ↘ normal cells

� Complementary studies: - morphological studies - immunophenotyping ESSENTIAL TO - cytochemistry investigations (MPO reaction) CLASSIFY- cytogenetic studies: karyotype (prognosis++) THE - molecular evaluation of BW DISEASE

http://www.picturesdepot.com/medical/12057/acute+lymphoblastic+leukemia.html

FURTHER INVESTIGATIONS

o Clotting studies: Disseminated Intravascular Coagulation (AML3++)

- ↗ Prothrombin time

- ↗fibrinogen level

- fibrin split product

o Blood electrolytes profile: ↗ LDH, ↗Uric acid,

↗K+, ↘ Ca++ (tumor lysis syndrome)

o Lumbar Puncture: systematic (brain localization ?)

o Chest X-ray: pneumopathy, leukostasis

o +/- Fever: Blood culture, urine culture

o +/- Pre-transfusion procedures = blood group, serologies (HIV, HBV, HCV, CMV)

http://www.santetropicale.com/club/pdf/1206/5312_10.pdf

Acute Myeloid Leukemia

(AML)

Acute Lymphoblastic Leukemia

(ALL)

Classification FAB: morphology, degree of

differenciation of blasts (LAM 0 to LAM 7 )

OMS: Clinical, morphological &

cytogenetic characteristics

preB-cell ALL (>85%)

preT-cell ALL (10-15%)

Cytology Myeloblasts: - big size

- granulations

- Auer rods

Lymphoblasts: - small size

- shape: rounded cells

- reduced cytoplasm

Cytochemistry MPO positive MPO negative

Immunophenotyping Myeloid markers (CD13, CD33,…) Lymphoid markers

http://med2.univ-angers.fr/discipline/lab_hema/Archives_ABP/html/2009%2013.htmhttp://www.leucemie-espoir.org/spip.php?article149

Gravity Signs Symptomatic Treatment

Thrombocytopenia / Bleedings � Platelets Transfusions

Septic shock / Fever � ATB +/- Intensive care

Agranulocytosis + Fever � IV ATB with broad spectrum

Leukostasis (Oncologic ER) �Chemotherapy/ Leukopheresis

Tumor lysis syndrome �Hydratation, Alcalinisation, …

Anemia (Hb<8g/dL) � Red blood cells Transfusions

� Objectives of Treatment: - Complete Remission (<5% blasts in BW, normalization of CBC)

- Maintain the complete Remission

- Avoid relapses

1) Induction therapy: INTENSIVE CHEMOTHERAPY = ↘ of leukemic cells

- ≈ 1 month

- AML: anthracyclins + arabinosylcytosine

- ALL: anthracyclins, vincristin, prednisone, cyclophosphamide.

� Induced aplasia

2) Consolidation therapy: Maintain complete remission

- chemotherapy (several months)

+/- allogeneic HSCT: efficient to avoid relapses � ALL: children, only if bad prognosis

� AML: age <60 (sepsis, toxicity++)

+/- autologous HSCT

*HSCT = ↘ of relapse rate, ↗ of 6-year survival rate in patients younger than 50

Some cases: supportive chemotherapy (2 years): children ALL if no HSCT, APL

3) Supportive care: Heavy treatment

- « Hematologic resuscitation »: � transfusions support

� anti-infectious care (isolation, ATB)

- nutritional supplements

- staff: experience ++ in treatment of leukemias

4) New treatments:

Advanced knowledges on the pathophysiology of AL = New treatment perspectives

- Azacitidine (VIDAZA): DNA hypomethylation

* no AMM in this indication: trial in process

- Monoclonal Antibodies: new targets

- Histone Deacetylase Inhibitors: « Ras » inactivation = cell growth

arrest

http://fr.dreamstime.com/image-stock-transfusion-sanguine-image

http://www.medic-abc.com.mx/hoja_vidaza.html

Accumulation of blasts in the bone marrow

http://defi-anthony.org/default.aspx

↗ production of normal blood cells

CLINIC: ONLY ORIENTATION

Tumoral syndrom Medullar Insuffisiency

Bone Marrow Aspiration: > 20% blasts CBC results: always abnormal

Heavy Treatment: Etiological, treatment of gravity signs, supportive care

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� http://emedicine.medscape.com

� http://www.fascicules.fr/data/consulter/hematologie-polycopie-leucemie-

aigue.pdf

� http://www-sante.ujf-grenoble.fr

� http://www.medecine.ups-tlse.fr/dcem3/

� http://theoncologist.alphamedpress.org/content/10/8/565.abstract

� Livre du Collège National des Enseignants d’Hématologie

� Livre du Collège National des Enseignants en Médecine Interne (éd.Ellipses)

� Dictionnaire Médical, 5ème édition (éd. MASSON)

� http://www.leucemie-espoir.org

� http://sfh.hematologie.net