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%
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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