Acute Leukemia 2007

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ACUTE LEUKEMIAS DR. OSAMA SULTAN 2007

DEFINITION



Acute leukemia is defined as the malignant accumulation of transformed hematopoietic progenitor cells in the bone marrow, blood and other tissues in which they retain the capability of self-renewal, but with limited or no potential for terminal differentiation.

LEUKEMIA

ACUTE

MYELOID (AML)

CHRONIC

LYMPHOBLASTIC

(ALL)

MYELOID (CML)

LYMPHOCYTIC (CLL)

EPIDEMIOLOGY



Yearly incidence of AML    

  

  

Children ~ 1.2/100000 Adults 50 yrs ~ 3.5/100000 Adults 70 yrs ~ 15/100000 Adults > 90 yrs ~ 35/100000

Yearly incidence of ALL in children ~ 9.8/100000 ALL predominates in children, whereas AML accounts for the majority of cases in adults. The median age at diagnosis of AML is about 65 years. The peak incidence of ALL occurs at ages 3 to 5 years, and childhood ALL is distinctly different from ALL in adults. Acute leukemias have a slight male predominance. Acute leukemia is more common in whites than blacks at all ages. ALL occurs in Italy, the United States, Switzerland, and Costa Rica



Saudi Arabia (2002) Leukemia is the 4th most common cancer among saudis at all age groups.  Leukemia is the 7th most common cancer among males more than 14 yrs of age.  Leukemia is the 4th most common cancer among females more than 14 yrs of age.  Leukemia is the 1st cancer among both genders less than14 yrs of age. 

ETIOLOGY



Ionizing radiation   



Benzene 



Atomic Bomb survivors - > 100 cGy of radiation. Spinal Radiotherapy – ankylosing spondylitis Radioactive phosphorus Can lead to AML,MDS and AA .

Heredity and Genetics   

Down’s syndrome - AML-M7 Fanconi’s anemia - 50 % risk AML/MDS Bloom’s syndrome - 25 % risk of AML



MPD and MDS 



May progress to acute leukemia.

Therapy-related 

Alkylating agents    



e.g. melphalan, nitrogen mustard After latency of 5 - 7yrs May be proceeded by MDS Complex cytogenetics involving chr.5 and chr.7 abnormalities

Topoisomerase II inhibitors    

e.g. etoposide, doxorubicin After 1 - 2 yrs Acute presentation with high wbc, AML-M5 Involving chr.11



Viruses ?? EBV - Burkitt’s leukemia/lymphoma  HTLV-I - adult T-cell leukemia  No conclusive data 

CLINICAL PRESENTATION



Bone marrow failure Fatigue and weakness.  Bleeding tendency  Fever - neutropenic infections 

Pneumonia, cellulites, abscesses, or sepsis  Staph., strept., enteric GNB, fungi, and viruses 



Bone pain



Leukostasis Cerebral leukostasis – headache, nausea, vomiting, visual disturbances, confusion, coma, or cranial nerve palsies ( VII, III, IV, VI ).  Pulmonary leukostasis – dyspnea at rest, tachypnea, and pulmonary infiltrates.  It is more with AML than ALL ( because of larger size of blasts and expression of adhesion proteins in AML). 



Coagulopathy DIC and 1° fibrinolysis contribute to hemorrhagic diathesis.  May result in GI H or ICH.  Common in AML-M3, AML-M5. 



Extramedullary Disease 

Leukemic blasts can infiltrate any organs e.g. RES ( liver, spleen, lymph nodes) – ALL > AML  Gum – gingival hypertrophy – AML-M5  Skin – leukemia cutis , Sweet’s syndrome ( acute neutrophilic dermatosis)  Leptomeningeal disease – meninges  2° solid tumor mass 

 

Known as chloroma, granulocytic sarcoma, or myelobastoma Develop without involvement of bone marrow or peripheral blood.

Leukemia cutis

Gingival Hypertrophy .Purpura L.L

Testicular Enlargement

CLASSIFICATION

DIAGNOSIS



CBC Leukocytosis or leukopenia  Normocytic normochromic anemia  Thrombocytopoenia 



Chemistry RFT, LFT, Ca, PO4, Mg, uric acid,  Coagulation profile ( PT, PTT, D.Dimer, fibrinogen) 

 

X- ray : chest, bony pain areas, etc. CT brain



Bone Marrow Examination Morphology  Histochemical staining  Flowcytometry  Cytogenetic studies 

AML-M0

AML-M1

AML-M2

AMLM3

AML-M3v

AML-M4

AML-M4eo

AML-M5a

AML-M5b

AML-M6

AML-M7

ALL-L1

ALL-L2

ALL-L3

Management

Supportive Care 



Insertion of indwelling catheter e.g. Hickmann’s catheter for chemotherapy, fluids and medications Blood Products Support   

Leukocyte-depleted or irradiated RBC transfusion ( PRBCs ) – keep Hgb 7 – 8 g/dL Platelets transfusion – keep above 10000  





If febrile - keep above 30000 If bleeding - keep above 50000

FFP and Cryoprecipitate - for DIC coagulopathy

Growth factors use - does not improve outcome



Leukostasis – medical emergency WBC > 100000 (AML) , > 200000 (ALL)  Avoid RBC transfusion  Leukapharesis  Cytoreduction Rx - Hydroxyurea (AML) and 

steroids (ALL)



Tumor Lysis Syndrome Adequate i.v. hydration  Electrolytes replacement  Allopurinol / rasburicase  Alkalinization of urine  Hemodialysis 



Infection Prophylactic Rx vs bacteria, viruses, fungi  Treatment 

 

Antiemetics and pain Rx Miscellaneous Nutrition support  Psychological support  Health education 

ALL

AML-nonM3

Chemotherapy 

Acute Myeloid Leukemia 

Remission Induction Chemotherapy 

Cytarabine arabinoside and anthrcycline ( 7 +3 ) 

Daunorubicin 45–60 mg/m2/day intravenously for 3 days and

Cytarabine 100 mg/m2/day for 7 days by continuous intravenous infusion. 

Complete remission is achieved in 60–90% of younger patients.

6-thioguanine, etoposide  TRM is about 10% - 25%  Mucositis, myelosuppression, infections 



Post-remission Therapy high-dose ara-C with 2–3 g/m2 twice daily on days 1, 3, 5, or twice daily for 6 days for 2 – 4 cycles.  Long-term DFS is 60% – 70% with favorable CG 



Allogeneic SCT Aim is to reconstitute normal hematopoiesis and to prevent GVL effect.  Cure rate is less than 20%  TRM is high about 20% - 30 %  DFS is 40% - 50% 



AML-M3 

ATRA ( all-trans retinoic acid )    

 

vitamin A analogue Bind PML-RARAα fusion protein and promote the differentiation of the APL cells Dose 45 mg/m2/d for 56 days ATRA ( differentiation ) syndrome :  fever, dyspnea, weight gain, pleuropericardial effusion, pulmonary infiltate, hypotension ,and renal impairment  Incidence 15% – 25 % with mortality rate 1.2 % < 5% if given with chemotherapy  Rx : hold ATRA, dexamethasone ± diuretics CR > 85 % with anthracyclines Cure rate 70% - 75%



Consolidation Therapy 



Maintenance Therapy ( 24 months )   



ATRA 15 d q 4 wks ± anthracyclines q 4 wks for 3 - 4 cycles ATRA 2 wks q 3 months 6- mercaptopurine 90 mg/m2 po daily Methotrexate 15 mg /m2 po once a wk

Arsenic Trioxide (ATO ) – 2nd line    

Induces apoptosis in the leukemic cells Dose 0.15 mg/kg iv infusion daily till remission CR 85 % Cardiotoxicity, neurotoxicity, GI, and ↑Liver enzymes



Acute Lymphoblastic Leukemia 

Induction Phase 

5 drugs regimen are given weekly 

Cyclophosphamide, daunorubicin, vincristine, L-asparaginase,

and methotrexate plus steriods and G-CSF support CR 65% - 85%  TRM 2 % - 20 % 



Consolidation- Intensification Phase 

High doses of cyclophosphamide, asparaginase, cytosine arabinoside, methotrexate and etoposide.



Maintenance ( Continuation ) Phase Usually 1 – 3 yrs  6-mercaptopurine, methotrexate, vincristine, and dexamethasone 



CNS Prophylaxis 

Intrathecal chemotherapy 



Methotrexate, cytosine arabinoside

Cranial irradiation



Allogeneic SCT For relapsed or high risk patients  Cure rate is 40%  Relapse rate 30 %  TRM rate 30% 

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