Acute Lymphoblastic Leukemia I2 黃 柏 瑋

 Malignancy remains the major cause of death to disease between the age of 1 and 15 years  The precise cause of childhood cancer is unknow  Leukemia, Neuroblastoma, Wilms tumor, retinoblastoma and tumor of liver

Introduction  Leukemia – the most common malignancy in childhood.  Acute leukemia– 97% Acute lymphoblastic leukemia– 75% Acute myeloblastic leukemia– 20%  Chronic leukemia– 3% Chronic myelogenous leukemia (Ph positive) Juvenile myelomonocytic leukemia ( JMML)

Introduction to pediatric neoplastic disease and tumor  Leukemia and a more pronounced rise in central nervous system tumor  Boy > girl

Leukemia  The most common childhood cancer ( 1/3 of pediatric malignancies ).  Acute lymphoblastic leukemia (ALL) represents about 75 % (peak incidence at age 4 years).  Acute myeloid leukemia (AML) accounts for about 20 % of leukemia (stable from birth through age 10)  Others : CML

Acute Lymphoblastic Leukemia  Childhood acute lymphoblastic leukemia (also called acute lymphocytic leukemia or ALL).  is a disease in which too many underdeveloped infection-fighting white blood cells, called lymphocytes, are found in a child's blood and bone marrow.

Acute Lymphoblastic Leukemia  These abnormal cells reproduce very quickly and do not function as healthy white blood cells to help fight infection.  the most common form of leukemia  the most common kind of childhood cancer.

Acute Lymphoblastic Leukemia  In the United States, about 3,000 children each year are found to have ALL  Peak incidence occurs from 3 to 5 years of age.

Acute Lymphoblastic Leukemia  the most common symptoms of leukemia:f ever, anemia, bleeding and/or bruising, persistant weakness or tiredness, achiness in the bones or joints, recurrent infections, difficulty breathing (dyspnea) or swollen lymph nodes.

Clinical manifestations  Protean  Bone marrow failure & Organ infiltration  Common symptoms Fever ( 60%) Malaise ( 50%) Pallor ( 40%)

Etiology  Unknown ( usually)  Hereditary Down’s syndrome Leukemia in siblings  Chemicals Chronic benzene exposure Alkylating agents  Ionizing radiation  Predisposing hematological disease ( MPD, AA)  Viruses ( HTLV-1)

Diagnostic criteria  ALL is often difficult to diagnose.  The early signs may be similar to the flu or other common diseases.

Diagnostic criteria  bone marrow aspiration and biopsy  complete blood count (CBC)  additional blood tests  computerized tomography scan  magnetic resonanec imaging (MRI)  x-ray  ultrasound  lymph node biopsy  spinal tap/lumbar puncture

Diagnostic criteria  Peripheral blood: anemia,thrombocytopenia, variable white cell count with or without blasts.  Bone marrow: hyper-or hypo-cellularity with excess of blasts (blasts>30% of nucleated cells).

Diagnostic criteria  Cytochemistry study and surface marker study confirm the lymphoid origin.

Diagnostic criteria  blood tests to count the number of each of the different kinds of blood cells..  If the results of the blood tests are not normal, a doctor may do a bone marrow biopsy.  The chance of recovery (prognosis) depends on how the leukemia cells look under a microscope.

V-25 Leukemic cells in acute lymphoblastic leukemia characterized by round or convoluted nuclei, high nuclear/cytoplasmic ratio and absence of cytoplasmic graulnes.

Differential diagnosis  AML.  MDS.  Non-Hodgkin‘s lymphoma with bone marrow involvement or with leukemic change.  CLL.

Differential diagnosis  Viral infection with lymphocytosis  CML with acute blastic crisis.

Acute lymphoblastic leukemia

Laboratory examinations  Full blood count  Coagulation screening – esp AML M3.  Biochemical screening  Chest radiography  Bone marrow aspiration  Immunophenotyping  Cytogenetics & molecular studies  Lumbar puncture ( CNS involvement)

Complications  Cerebral hemorrhage, pul. hemorrhage or other vital organ hemorrhage.  Infection(sepsis or septic shock ), pulmonary edema.  Tumor lysis syndrome.

Complications  Infiltration syndrome(CNS, GI tract or gonads).  Coagulopathy before or after chemotherapy.  Anemia.

Risk Grouping of TPOG (ALL)  Standard Risk  High Risk– CNS leukemia, cranial nerve palsy, testicular leukemia, pre-B ALL t(1;19) or E2A-PBX1 fusion

Very High Risk  WBC > /mm 3  T – cell  < 1y/o  Lymphoblastic lymphoma with bone marrow lymphoblasts > 25%  t(9;22) or BCR-ABL fusion  t(4;11) or MLL-AF4 fusion  Other MLL gene rearrangement  Hypodiploidy ( chr 44 or less)

Poor Prognosis (I)  Acute lymphoblastic leukemia

Relapse  Bone marrow– the most common site, blast cell increase  CNS– IICP ( vomiting, headache, papilledema, lethargy) Convulsion Behavior disturbance  Testis– painless swelling

Survival rates  75 % to 80% of children with ALL survive at least 5 years from diagnosis with current treatments that incorporate systemic therapy (e.g., combination chemotherapy) and specific central nervous system (CNS) preventive therapy (i.e., intrathecal chemotherapy with or without cranial irradiation).

Recurrent  The most important extramedullary sites of relapse are the CNS and the testes.

Treatment  Chemotherapy – reach to remission (blast<5%)  CNS prophylaxis Intrathecal C/T Cranial irradiation  Bone marrow transplantation

Management and treatment  Hydration, prevention of hyperuricemia and tumor lysis syndrome.  Antibiotics, may need the 3rd generation of cephalosporin or other strong antibiotics, even antifungal agents.

Management and treatment  Chemotherapy(include remission induction, consolidation & maintenance.  CNS prophylaxis with chemotherapeutic agents(methotrexate 10 ～ 15mg, intrathecal injection).

Management and treatment  Blood transfusion(component therapy)  Nutritional support  Bone marrow transplantation  Growth factor

Treatment  The primary treatment for ALL is chemotherapy.  Radiation therapy may be used in certain cases  Bone marrow transplantation is being studied in clinical trials.

Treatment : Chemotherapy  uses drugs to kill cancer cells  drugs may be taken by mouth, or may be put into the body by a needle in a vein or muscle.  All chemotherapy is stopped after two to three years of treatment.

Treatment : Chemotherapy Prednisone:  Used in induction and reinduction therapy and also given as intermittent pulses during continuation therapy.  toxicity : fluid retention, increased appetite, transient diabetes, acne, striae, personality changes, peptic ulcer, immunosuppression, osteoporosis, growth retardation; caution in diabetes, fungal infections, and osteonecrosis

Vincristine:  toxicity : Peripheral neuropathy manifested by constipation, ileus, ptosis, vocal cord paralysis, jaw pain, abdominal pain, loss of deep tendon reflexes; reduce dosage with severe peripheral neuropathy; bone marrow depression; local ulceration with extravasation, SIADH

Asparaginase  local rash, hives, anaphylaxis; bone marrow depression, hyperglycemia, hepatotoxicity, and bleeding may occur. Daunorubicin  Myelosuppression and thrombocytopenia; may cause cardiac arrhythmias immediately following administration and cardiomyopathy after long-term use; nausea, vomiting, stomatitis, and alopecia; extravasation may occur, resulting in severe tissue necrosis; caution with impaired hepatic, renal, or biliary function.

Methotrexate (Folex PFS)  Hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)

Radiation Therapy  uses x-rays or other high-energy rays to kill cancer cells and shrink tumors.

Treatmet for VHR Induction:(10 weeks)  Prednisolone,Vincristine,Idarubicin, Asparaginase,cyclophosphamine,cytarabine, 6-MP,TIT. Consolidation:(8 weeks)  6-MP,MTX,TIT Reinduction:(7 weeks)  Dexamethasone,,Vincristine,Idarubicin, Asparaginase,cyclophosphamine,cytarabine, 6-MP,TIT.

Bone Marrow Transplantation  Hematopoietic stem cell transplantation is an option for very high-risk cases (e.g., Philadelphia chromosome- positive ALL) or those who develop an early relapse in the bone marrow.

Bone Marrow Transplantation  a newer type of treatment.  high doses of chemotherapy with or without radiation therapy are given to destroy all of the bone marrow in the body.  Healthy marrow is then taken from another person (a donor).  autologous bone marrow transplant, is being studied in clinical trials.

Treatment Induction : 4 weeks  Hyhration.  Allopurinol  Vincristine iv qw & Prednisolone po qd  L- asparaginase  Mediastinum or spine tumor : R/T

Treatment CNS prophylaxis  Intrathecal ingestion : methotrexate  Intrathecal ingestion : methotrexate, Ara-C, hydrocortisone  High risk:Intrathecal ingestion C/T&R/T

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