Acute Leukemias

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CONTENTS Introduction Epidemiology and Aetiology Pathophysiology of Acute Leukemias Investigation and Diagnosis Clinical Feature of Acute Leukemias Treatment of Acute Leukemias


The acute leukemias (ALs) are diseases of bone marrow resulting from aberrant proliferation of hematopoietic precursors. The hallmark of these malignancies is the leukemic blast cell , a visibly immature and abnormal cell in the peripheral blood that often replaces the bone marrow and interferes with normal hematopoiesis . INTRODUCTION


EPIDEMIOLOGY AND ETIOLOGY Type of Leukemia Incidence per 100,000* Overall 6–10 (including CL) AML 2–3 ALL 1–2 Incidence of Hematologic Malignancies

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Epidemiology Leukemias are traditionally classified into four main groups: (western figure) Acute lymphoblastic leukemia/ALL(11% ) Acute myeloid leukemia/AML(46%) Chronic lymphocytic leukemia/CLL(29%) Chronic myeloid leukemia/CML(14%) ** Ethiopia =more than 50% of leukemia is CML

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The incidence of leukemias of all types in the population is approximately 10/100 000 per annum. Males are affected more frequently than females , the ratio being about 3:2 in acute leukemia, 2:1 in CLL and 1.3:1 in CML

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ALL is the most common cancer in children younger than 15 years of age , with the maximum incidence between 2 -10 years ages , and un common in middle adult but increase as age goes. In contrast, the incidence of AML gradually increases with age , without an early peak.

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ETIOLOGY In most cases of acute leukemia the cause(s) is(are) not known A) Hereditary disorders or syndromes with chromosomal abnormalities (defective DNA repair) & a high risk of acute leukemia Examples Down’s syndrome {AML &ALL} Neurofibromatosis(AML) Leukemia in siblings: siblings of patients with AL have a five fold increased risk

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B) Acquired disorders 1. Radiation exposure – AML and child hood exposure -T-ALL 2. Chemicals : chronic Exposure to benzene is associated with an increased incidence of AML . Smoking and exposure to petroleum products , paint , ethylene oxide , herbicides , and pesticides , have also been associated with an increased risk of AML & ALL in adult Drugs …

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4.Disease transformation Myelodysplastic syndromes , myeloproliferative disorders , and aplastic anemia are known to transform to acute leukemia 4. Viruses viruses have not yet been associated with AML in humans but infection by EBV during infancy in developing countries is associated with -L-3 ALL


CLASSIFICATION Criteria : - Morphology :apperance of cell under microscope. -Cytochemistry:chemical activity of the cell.(myeloperoxidase , Sudan Black B) -immunophenotyping: antigen pressent in the cell membrane - Cytogenetics: chromosome of the cell - Molecular biology: Classification: 3 groups of acute leukemias: - acute myeloid leukemias AML(M1 –M6). - acute lymphoblastic leukemias ALL (L1-L3). - Biphenotypic leukemias or Acute undifferentiated leukemia

Acute Lymphoblastic Leukemia(ALL) :

Acute Lymphoblastic Leukemia(ALL) It is monoclonal expansion of lymphoblasts Commonly affect children More common in white boys Two types: 1- B-cell ALL (more common) 2- T-cell ALL

Precursor B-cell ALL:

Precursor B-cell ALL It is 80-85% of ALL Patients suffer from pancytopenia Extramedullary involvement: o CNS (very common) -> Don't miss to give patient intrathecal chemotherapy. o Gonads (tests) o Skin o Lymph node o Liver & spleen

Precursor T-cell ALL :

Precursor T-cell ALL It is 15% of ALL More common in adolescent than children . Affect males more than females. Clinical presentation: Mediastinal mass (present in up to 70%) Mediastinal lymph n ode is a primary target for T-cell ALL. Extramediastinal involvement: CNS (very common) Other Lymph nodes Skin Liver & spleen gonads

Morphologic subtypes of acute lymphoblastic leukemias (FAB classification):

Morphologic subtypes of acute lymphoblastic leukemias ( FAB classification ) Subtype Morphology Occurrence (%) L1 Small round blasts 75 clumped chromatin L2 Pleomor p hic larger blasts 20 clefted nuclei , fine chromatin L3 Large blasts , nucleoli, 5 vacuolated cytoplasm

Acute lymphoblastic leukemias - reactivity with special stains:

Acute lymphoblastic leukemias - reactivity with special stains Subtype Peroxidase or Non-specific Periodic Sudan black esterase acid-Schiff L1 - - +++ L2 - - +++ L3 - - +++

AML (acute myeloid leukemia) :

AML (acute myeloid leukemia) It is monoclonal expansion of myeloblast cells. Myeloblast in AML, will have Auer rod. According to FAB classification, there is 8 types of AML; M0 to M7. The treatment of AML differs to each type. In order to know the type cytogenetic analysis and flow cytometry should be done .


In acute leukemia the involved cell give rise to progeny that fail to differentiate but continue to proliferate in an uncontrolled fashion . As a result, immature myeloid cells ( AML) or lymphoid cell (ALL) blasts—rapidly accumulate and progressively replace the bone marrow, diminishing the production of normal red cells, white cells, and platelets. PATHOPHYSIOLOGY OF ACUTE LEUKEMIAS

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This loss of normal marrow function in turn gives rise to the common clinical complications of leukemia: anemia, infection, and bleeding . With time, the leukemic blasts pour out into the blood stream and eventually occupy the lymph nodes, spleen, and other vital organs.

Risk Factors:

Risk Factors Age Older adults are more likely to develop AML Smoking 20% of AML cases are linked to smoking Doubles the risk of disease in people older than 60 Genetic disorders Down syndrome, Fanconi’s anemia High doses of radiation Long-term survivors of atomic bombs Previous chemotherapy treatment Breast cancer, ovarian cancer, lymphoma Exposure to industrial chemicals Benzene


GENERAL Typically a 1- to 3-month history of vague symptoms such as tiredness, lack of exercise tolerance, chest pain, and “feeling unwell,” but in no obvious distress. CLINICAL FEATURES OF ACUTE LEUKEMIAS

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Pt Will present with sign or symptoms related to : Pancytopenia: WBCinfection. Hb anemia. platelets bleeding. Organ infiltration: Lymphadenopathy. Splenomegally. Hepatomegally. CNS:5-10% of patient with ALL More common with ALL than AML .

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Symptoms Fatigue and dyspnea Cutaneous or mucosal bleeding, petechiae High grade fever ( due to low neutrophil count) chills sweating and weight loss Symptoms of CNS involvement Signs of anemia and its complication of thrombocytopenia complication Fever and other signs of infection Tissue/organ leukemic infiltration Gingival hyperplasia (AML M4 and AML M5 subtypes) hepatosplenomegaly (ALL) Bone tenderness Soft tissue tumors Meningismus and cranial nerve palsies (ALL)


LABORATORY TESTS Anemia is normochromic and normocytic (without a compensatory increase in reticulocytes). Thrombocytopenia (severe, less than 50,000/mm3 platelets) is present in approximately 50% of cases. Leukopenia/leukocytosis : approximately 20% of patients will present with an elevated white blood cell (WBC) count, 20%with a low WBC count Uric acid is elevated in 50% of patients due to rapid cellular turnover


LABORATORY TESTS Electrolytes : potassium and phosphate are usually ele-vated. Coagulation : elevated prothrombin time, partial thromboplastin time, D-dimers; hypofibrinogenemia. (AML) LP- for sign of CNS involvement (CNS involvement is common with AML M4 and M5 subtypes, and ALL patients, and is a common cause of relapse.)

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Investigations: CBC : 60% of pts have an elevated WBC. Most are anemic Most are thrombocytopenic 90%have blast in the periphral blood film. electrolytes: Hypo/hyper kalemia Hypomagnesimia hyperphosphatemia Hypermetabolism :  LDH. uric acid. DIC: Most common with promyelocytic leukemia, small% monocytic leukemia &ALL Bone marrow biopsy and aspirate : 30%or more of all nucleated cells are blast. Radiology: CXR: mediastinal mass (T-cell ALL) Osteopenia or lytic lesion 50% of patients with ALL.(intractable pain).


DIAGNOSIS The presence of 20% or more blast cells in the peripheral blood or bone marrow makes the diagnosis of Acute leukemia as per WHO. ALL terminal deoxynucleotideyl transferase ( TdT )+, periodic acid-Schiff positive (PAS+) AML  Myeloblasts are myeloperoxidase + , Auer rod+, Sudan black +

Cytogenetic analysis :

Cytogenetic analysis Presence of Philadelphia chromosome: t(9;22) Post-CML (acute leukemia on top of chronic myeloid leukemia) Poor prognosis Presence of t(15;17) Occur in M3 (acute promyelocytic leukemia) Good prognosis

Differential diagnosis of Acute leukemias::

Differential diagnosis of Acute leukemias: Lymphoma ( Burkitt lymphoma ~ similar wz ALL-L3) Myelodysplastic syndrome. Multiple myeloma. Aplastic anemia Sever megaloblastic anemia due to B12 defeciency. Severe lymphocytosis due to infections.




TREATMENT GOALS The short-term goa l of treatment for acute leukemia is to rapidly achieve a complete clinical and hematologic remission. After a CR is achieved, the goal is to maintain the patient in continuous CR.

Pretreatment Evaluation:

Pretreatment Evaluation Once the diagnosis of AL is suspected, a rapid evaluation and initiation of appropriate therapy should follow Clarifying the subtype of leukemia Evaluate the overall functional integrity of the major organ systems and pretreatment prognostic factor assessment All patients should be evaluated for infection

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As a result of the treatment of acute leukemias , especially ALL, the number of survivors has increased dramatically in the last 30 or more years. If left untreated, most patients with acute leukemia will die of their disease within 2 to 3 months..


Management: A-Supportive measure : -isolation in positive laminer flux room -insertion of central line -family and patient support by permanent social worker -AlKaline diuresis to prevent tumor lysis syndrome -oropharynx/GIT decontamination to prevent fungal infection -IV antibiotics for infection -Blood transfusion if anemia and thrombocytopenia.

Therapeutic option:

Therapeutic option B-Curative intent : only allogenic bone marrow transplant . C~Classical approch (curative/palliative) -induction chemotherapy -consolidation of remission -intensification -maintenance chemotherapy -CNS prophylaxis

Therapeutic option…:

Therapeutic option… Special consideration : CNS : - neuroprophylaxis: - meningeal infiltration : Testis : - orchidectomy/radiotherapy if testis involvement. by intrathecal chemotherapy,high dose systemic MTX or Aracytine. OR cerebrospinal irradiation

There are three stages of treatment: :

There are three stages of treatment: 1- Induction -The Goal: to kill all detectable disease & reach CR "complete remission" Complete remission ≠ complete cure 2- Consolidation -The Goal: to eliminate tumor cells with short-term intensive therapy. 3- Maintenance - The Goal: to continue eradicating any remaining undetectable cells through low doses of Tx over a longer period of time.

Outcome of ALL :

Outcome of ALL 95-99% of children reach complete remission. LFS ) is 70-80% 80-85% of Adult reach complete remission. Leukemia-free survival (LFS ) is 30-40%

Outcome of AML :

Outcome of AML 60% achieve complete remission Only 20% of those patients will have a durable remission The other 80% will relapse in 1-2 years. At relapse, it is harder to achieve responses

Prognosis in ALL :

Prognosis in ALL parameters Good poor WBC low High(>50x10 9 /l) Gender Girls Boys Age Child Adult or infant. Cytogenetic Normal,hyperdiploid , Ph+,11q23rearrangements. Time to clear blast from blood < 1week >1week Time to remission <4weeks >4weeks Cns disease at presentation Absent Present Minimal residual disease . Negative at 1-3 months Still positive at 3-6 months.

Prognosis in AML :

Prognosis in AML parameters Favorable unfavorable Response to remission induction <5% blasts after first course >20% blasts after first course. age <60yrs >60yrs


Summary Leukemias proliferation of immature blast cells (Acute Leukemias) proliferation of mature, differentiated cells (chronic leukemia) Associated with benzene (AML) Most common in children (ALL)~ in adult (AML) Bimodal distribution (Acute Leukemias) Philadelphia ch. t(9,22) is 90% in CML where as in ALL it’s occurrence is 30%


References Joseph T. DiPiro P, FCCP; Executive Dean and Professor, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina and Medical University of South Carolina, Charleston, South Carolina. Pharmacotherapy A Pathophysiologic Approach. Seventh Edition ed.: McGraw-Hill; 2008. Curtis L. Triplitt CAR, and William L. Isley. PHARMACOTHERAPY A Pathophysiologic Approach. Sixth Edition ed. Joseph T. DiPiro P, FCCPProfessor and Executive Dean, South Carolina College of Pharmacy,University of South Carolina, Columbia, and Medical University of South Carolina, Charleston, editor.: The McGraw-Hill Companies, Inc.; 2005. Lindsey MRGaCC. PHARMACOTHERAPY PRINCIPLES & PRACTICE. MARIE A. CHISHOLM-BURNS P, FCCP, FASHP,BARBARA G.WELLS,PHARMD, FASHP, FCCP, BCPP,TERRY L. SCHWINGHAMMER,PHARMD, FCCP, FASHP,, BCPS PMM, PHARMD, FASHP,JILL M. KOLESAR,PHARMD, BCPS, FCCP,JOHN C. ROTSCHAFER,PHARMD, FCCP,JOSEPH T. DIPIRO,PHARMD, FCCP, editors.: McGraw-Hill 2008 …


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