ACUTE LYMPHOBLASTIC LEUKEMIA

2. ACUTE LYMPHOBLASTIC LEUKEMIA Majid .vafaie

3. The leukemias are the most common malignant neoplasms in childhood • about 31 % of all malignancies that occur in children <15 yr of age • Each year leukemia is diagnosed in approximately 3,250 children <15 yr of age in the USA • an annual incidence of 4.5 cases per 100,000

4. ALL accounts for about 77% of cases of childhood leukemia • AML for about 11 % • CML for 2-3% • JMML for 1-2% • Remaining cases consist of a variety of acute and chronic leukemias that do not fit classic definitions for ALL, AML, CML, or JMML

5. Acute Lymphoblastic Leukemia • Childhood ALL was the first disseminated cancer shown to be curable • consequently has represented the model malignancy for the principles of cancer diagnosis, prognosis, and treatment • It actually is a heterogeneous group of malignancies with a number of distinctivegenetic abnormalities that result in varying clinical behaviors and responses to therapy

6. EPIDEMIOLOGY • ALL is diagnosed in approximately 2,400 children <15 yr of age in the USA each year • peak incidence at 2-3 yr of age and occurs more in boys than in girls at all ages

7. chromosomal abnormalities • The disease is more common in children with certain chromosomal abnormalities • Down syndrome • Bloom syndrome • ataxia-telangiectasia • Fanconi anemia

8. identical twins • The risk is >70% if ALL is diagnosed in the first twin during the first year of life and the twins shared the same (monochorionic) placenta • If the first twin develops ALL by 5-7 yr of age, the risk to the second twin is at least twice that in the general population, regardless of zygosity

9. ETIOLOGY • The etiology of ALL is unknown • although several genetic and environmental factors are associated with childhood leukemia • Exposure to medical diagnostic radiation both in utero and in childhood has been associated with an increased incidence of ALL

10. no such factors other than radiation have been identified in the USA • In certain developing countries,there has been an association between B-cell ALL and Epstein-Barr viral infections

11. CELLULAR CLASSIFICATION • The classification of ALL depends on characterizing the malignant cells in the bone marrow to determine the morphology,phenotypic characteristics as measured by cell membrane markers,and cytogenetic and molecular genetic features

12. Morphology alone usually is adequate to establish a diagnosis • the other studies are essential for disease classification, which can have a major influence on the prognosis and the choice of appropriate therapy

13. FAB Classification • The most important distinguishing morphologic feature is the French-American-British (FAB) L3 subtype, which is evidence of a mature B-cell leukemia • The L3 type, also known as Burkitt leukemia, is one of the most rapidly growing cancers in humans and requires a different therapeutic approach than other subtypes of ALL

19. Phenotypically, surface markers show that about 85% of cases of ALL are derived from progenitors of B cells, about 15% are derived from T cells, and about 1% are derived from B cells • A small percentage of children with leukemia have a disease characterized by surface markers of both lymphoid and myeloid derivation

21. The Polymerase Chain Reaction and Fluorescence In Situ Hybridization techniques offer the ability to pinpoint molecular genetic abnormalities and to detect small numbers of malignant cells during follow-up and are of proven clinical utility

22. CLINICAL MANIFESTATIONS • The initial presentation of ALL usually is nonspecific and relatively brief • Anorexia, fatigue, malaise, and irritability often are present, as is an intermittent, low-grade fever • Bone or, less often, joint pain, particularly in the lower extremities, may be present • Patients often have a history of an upper respiratory tract infection in the preceding 1-2 mo

24. Less commonly, symptoms may be of several months' duration • may be localized predominantly to the bones or joints, and can include joint swelling • Bone pain is severe and can wake the patient at night

25. As the disease progresses,signs and symptoms of bone marrow failure become more obvious with the occurrence of pallor, fatigue, exercise intolerance, bruising,or epistaxis, as well as fever, which may be caused by infection or the disease

26. an infiltration can cause lymphadenopathy, hepatosplenomegaly, testicular enlargement, or (CNS) involvement (cranial neuropathies headache, seizures) • Respiratory distress may be due to severe anemia or mediastinal node comparison of the airways

27. On physical examination, findings of pallor, listlessness, purpuric and petechial skin lesions, or mucous membrane hemorrhage can reflect bone marrow failure • The proliferative nature of the disease may be manifested a lymphadenopathy,splenomegaly, or, less commonly, hepatomegaly

28. In patients with bone or joint pain, there may be exquisite tenderness over the bone or objective evidence of joint swelling and effusion • with marrow involvement, deep bone pain may be present but tenderness will not be elicited

29. Rarely, patients show signs of Increased intraCranial Pressure that indicate leukemic involvement of the CNS • These include papilledema ,retinal hemorrhages, and cranial nerve palsies

30. mediastinal mass • Respiratory distress usually is related to anemia but can occur in patients with an obstructive airway problem (wheezing) due to a large anterior mediastinal mass (e.g., in the thymus or nodes) • This problem is most typically seen in adolescent boys with T-cell ALL • T-cell ALL also has a higher leukocyte count

31. Precursor B-cell ALL (CD10+ or common acute lymphoblastic leukemia antigen [CALLA] positive) is the most common immunophenotype with onset at 1-10 yr of age

32. The medianleukocyte count at presentation is 33,000, although 75% of patients have counts <20,000 • thrombocytopenia is seen in75% of patients • hepatosplenomegaly is seen in 30-40% of patients

33. In all types of leukemia, CNS symptoms are seen at presentation in 5% of patients (5-10% have blasts in the CSF) • Testicular involvement is rarely evident at diagnosis, but prior studies have indicated occult involvement in 25% of boys • There is no indication for testicular biopsy

34. DIAGNOSIS • The diagnosis of ALL is strongly suggested by peripheral blood findings that indicate bone marrow failure • Anemia and thrombocytopenia are seen in most patients • Leukemic cells might not be reported in the peripheral blood in routine laboratory examinations

36. Many patients with ALL present with total leukocyte counts of <10,000/1lL • In such cases, the leukemic cells often are reported initially to be atypical lymphocytes, and it is only on further evaluation that the cells are found to be part of a malignant clone

37. When the results of an analysis of peripheral blood suggest the possibility of leukemia, the bone marrow should be examined promptly to establish the diagnosis • It is important that all studies necessary to confirm a diagnosis and adequately classify the type of leukemia be performed, including bone marrow aspiration and biopsy, flow cytometry, cytogenetics, and molecular studies

38. ALL is diagnosed by a bone marrow evaluation that demonstrates>25% of the bone marrow cells as a homogeneous population of Iymphoblasts

39. Staging of ALL is based partly on a cerebrospinal fluid (CSF) examination • If Iymphoblasts are found and the CSF leukocyte count is elevated, overt CNS or meningeal leukemia is present • This finding reflects a worse stage and indicates the need for additional CNS and systemic therapies

41. The staging lumbar puncture may be performed in conjunction with the first dose of intrathecal chemotherapy, if the diagnosis of leukemia has been previously established from bone marrow evaluation • The initial lumbar puncture should be performed by an experienced proceduralist, because a traumatic lumbar puncture is associated with an increased risk of CNS relapse

42. DIFFERENTIAL DIAGNOSIS • The diagnosis of leukemia is readily made in the patient with typical signs and symptoms, anemia, thrombocytopenia, and elevated white blood count with blasts present on smear • Elevation of the lactate dehydrogenase (LDH) is often a clue to the diagnosis of ALL

43. When only pancytopenia is present, aplastic • anemia (congenital or acquired) and myelofibrosis should be considered • Failure of a single cell line, as seen in transient erythroblastopenia of childhood, immune thrombocytopenia, and congenital or acquired neutropenia, sometimes produces a clinical picture that is difficult to distinguish from ALL and that can require bone marrow examination

44. A high index of suspicion is required to differentiate ALL from infectiousmononucleosis in patients with acute onset of fever and lymphadenopathy and from rheumatoid arthritis in patients with fever, bone pain but often no tenderness, and joint swelling • These presentations also can require bone marrow examination

45. ALL must be differentiated from acute myelogenous leukemia (AML) and other malignant diseases that invade the bone marrow and can have clinical and laboratory findings similar to ALL,including neuroblastoma, rhabdomyosarcoma, Ewing sarcoma,and retinoblastoma.

47. TREATMENT • The single most important prognostic factor in ALL is the treatment • Without effective therapy, the disease is fatal • The survival rates of children with ALL since the 1970s have improved as the results of clinical trials have improved the therapies and outcomes Survival is also related to age and subtype

48. The choice of treatment of ALL is based on the estimated clinical risk of relapse in the patient, which varies widely among the subtypes of ALL • Three of the most important predictive factors are the age of the patient at the time of diagnosis, the initial leukocyte count, and the speed of response to treatment

50. Different study groups use various factors to define risk, but age between 1 and 10 yr and a leukocyte count of <50,000/IlL are widely used to define average risk • Children who are >10 yr of age or who have an initial leukocyte count of >50,000/IlL are considered to be at higher risk