UNDERSTANDING THE ACUTE LYMPHOBLASTIC LEUKEMIA Malignant Proliferation of Lymphoid Cells

Mikael Stevan Jodjana 030.08.161

FAKULTAS KEDOKTERAN UNIVERSITAS TRISAKTI 27 Mei 201

ABSTRACT

Acute lymphoblastic leukemia (ALL) is a malignant proliferation of lymphoid cells blocked at an early stage of differentiation and accounts for of all cases of childhood leukemia. About 3,000 children in the United States and 5,000 children in Europe are diagnosed with ALL each year. The peak incidence of ALL occurs between age 2 and 5 years. ALL is a biologically heterogeneous disorder, so that morphologic, immunologic, cytogenetic,

biochemical, and molecular genetic characterizations of leukemia lymphoblasts are needed to establish the diagnosis or to exclude other possible causes of bone marrow failure and, finally, to classify ALL subtypes. ALL may be either asymptomatic or acute with life threatening hemorrhage, infection, or episode of respiratory distress. Although ALL is a disease primarily of the bone marrow and peripheral blood, any organ or tissue may be infiltrated by the abnormal cells. The most frequent signs are

lymphadenopathies, hepatosplenomegaly, fever, signs of hemorrhage, and bone pain. Biological findings include hyperleukocytosis due to circulating lymphoblasts, anemia and

thrombocytopenia. Diagnosis is established by bone marrow biopsy, which evidences the leukemic cells infiltration. Most of the cases of ALL show chromosomal and genetic

abnormalities, which occur spontaneously in important regulatory genes in a lymphoid cell population. The most common ALL translocation, the t(12;21), appears to have good prognostic implications. Four main treatment elements can be generally recognized in chemotherapy

protocols adopted by international cooperative groups: induction with the aim of complete remission, CNS preventive therapy, consolidation/reinduction, and maintenance therapy.

The survival rate for children younger than 15 years of age reaches about 75%,but, despite the significant improvement of outcome during the last decades, still roughly 25% of patients suffer from a relapse of the disease. Even if the management of relapse remains largely controversial, an increasing use of high dose chemotherapy blocks and stem cell transplantation is adopted in most cases. With the need to stratify patients in risk groups and to provide riskadapted therapy, treatment requires high levels of organization, expertise and knowledge.

Key-words Acute lymphoblastic leukemia (ALL), childhood leukaemia, t(12,21), Philadelphia chromosome

CHAPTER I INTRODUCTION

Acute Lymphoblastic Leukemia is primarily disease of childhood, the majority of cases occur between ages of 2 and 10 years. Although it is rare in adults, a second peak in incidence does occur among elderly patients. Treatment of childhood ALL is a triumph of modern hematology. A uniform fatal disease before 1970, good prognosis ALL has a 90% rate of complete remission, and 60% of the patients are cured. Unfortunately, adults with the disorder have a bleaker outlook: a 68-91% rate of complete remission and 25-41% cure rate. Only half of patients with ALL have leukocytosis and may not have circulating lymphoblast. Neutropenia, thrombocytopenia, and anemia are usually present. Because of this pancytopenia, the patients have symptom of fatique (caused by anemia), fever (caused by neutropenia and infection), and bleeding (a result of thrombocytopenia). There often

accompanying lymph node enlargement (lymphadenopathy), and mediastinal mass is present in 5-10% of patients. Enlargement of the spleen (Spleenomegaly) and of the Liver (Hepatomegaly) may be seen. Bone pain often result from infiltration of leukemic cells into the bone covering (periosteum). Eventual infiltration of malignant cells into the meninges occurs in 50% of patients, and lymphoblast are found in the cerebrospinal fluid (CSF). In addition, lymphoblast infiltration into the testes and ovaries is common, especially in relapse.

CHAPTER II ACUTE LYMPHOBLASTIC LEUKEMIA

Definition Acute lymphoblastic leukemia (ALL) is a malignant proliferation of lymphoid cells blocked at an early stage of differentiation. ALL is a biologically heterogeneous disorder, so that morphologic, immunologic, cytogenetic, biochemical, and molecular genetic

characterizations of leukemia lymphoblasts are needed to establish the diagnosis or to exclude other possible causes of bone marrow failure and, finally, to classify ALL subtypes. This heterogeneity reflects the fact that leukemia may develop at any point during the multiple stages of normal lymphoid differentiation. ALL Morphology Classification Three morphologic subtypes of blast have been identified in ALL according to the French-American-British classification system. 1. The FAB-L1 blast is a small lymphoblast (1-2,5 times size of a normal lymphocytes). It has scant, blue cytoplasm, and indistinct nucleoli and is the most common type of blast encountered in ALL; 71% of cases have the L1 morphology. 2. The FAB-L2 blast is larger (2-3 times the size of a lymphocyte) and has prominent nucleoli and nuclear membrane irregularities. Bone marrow specimen with L2 type of ALL display variation in cell size ( a heterogenous population), as opposed to the specimens of patiens with FAB-L1, whose blast appear monotonous. L2 morphology is

seen second most commonly in ALL and accounts for approximately 27% of ALL cases. The FAB-L2 blast may be confused with the blast of Acute Myeloid Leukemia. Unfortunately, from morphology alone, the immunophenotype of L1 and L2 blast cannot be determined. 3. The FAB-L3 lymphoblast are very large, have three to five prominent nucleoli and midnight blue cytoplasm, and often contain cytoplasmic vacuoles. Immunophenotyping In General, four types of ALL are identified immunologically: CALLa (CD10) expressing immature B-Cell ALL; pre-B-Cell ALL without CALLa (CD10); T-Cell ALL; and BCell ALL. Further subtyping is possible, but the only distinction with therapeutic importance are those between B-cell precursor immunotype and T-cell or mature B-cell immunotype. In the most common type of immature B-Cell ALL, the marker CALLa (Common ALL antigen) or CD 10 is expressed on the cell surface. Other immature B-cell markers are expressed, but not cytoplasmic immunoglobulin (Cig) or surface Immunoglobulin (Sig). This type constitutes 80% of pre-B-cell ALLs. Pre-B-Cell ALL, in which immature B-Cell markers but not CD10 are expressed is the second most common ALL, and Cig but not Sig is expressed. Immature B-cell ALL is associated with the best prognosis. B-cell ALL is the most uncommon ALL, and Sig as well as kappa or lambda light chain restriction is expressed. Morphologically, a large number of B cell ALLs correspond to FABL3. This condition historically carried a very poor prognosis; however recent advances in therapy have improved survival. Mature B-cell ALL is rare and accounts for only 1 to 2% of all cases.

This type of ALL is defined by the presence of surface immunoglobulin, most often IgM, which is monoclonal for or light chains. In T-cell ALL, a variety of T-cell surface antigens are expressed. T-cell ALL has been subclassified into three stages of differentiation: early (stage I), intermediate (stage II), and late (stage III). Conventional Cytogenetics and Molecular Genetics Conventional cytogenetic analysis detects only in mitotically active (metaphase) neoplastic cells. Nowadays, the recent development of molecular cytogenetic techniques, including newer methods of chromosomal banding and standard fluorescent in situ hybridization (FISH) with the molecular genetic techniques of spectral karyotyping (SKY) and comparative genomic hybridization (CGH), allows to recognize chromosomal abnormalities in the leukemia cells of most of the cases of pediatric ALL. The cytogenetic abnormalities reported in ALL involve both chromosomal number (ploidy) and structural rearrangement. ALL can be classified into 4 subtypes based on the

modal number of chromosomes: hyperdiploid with more than 47 chromosome (35-45% of cases), pseudodiploid (46 chromosome with structural or numeric abnormalities: about 40% of cases), diploid (46 chromosome: 10-15% of cases) and hypodiploid (fewer than 46 chromosome: about 8% of cases). Children with higher ploidy (greater than 50 chromosomes) have the best prognosis; prognosis. on the contrary, those in the pseudodiploid category have a relatively poor

An exception to the general rule that hyperdiploid ALL cases have good prognoses is the relatively rare group of hyperdiploid ALL cases with the near-tetraploid subtype (82 to 84 chromosomes), which appears to have a poorer prognosis. Translocations are the most common structural chromosomal changes in ALL , particularly frequent in the pseudodiploid and hypodiploid groups. They are assumed to play a fundamental role in the leukemogenic process and in most cases i.e. translocations t(9;22), t(4;11), and t(1;19)] are associated with elevate risk of early treatment failure; the most common ALL translocation, the t(12;21), however appears to have good prognostic implications. The first fusion gene described in ALL was BCR-ABL, created by the del(22) of the t(9;22)(q34;q11), also referred to as the Philadelphia (Ph) chromosome, and has been identified as the

translocation with the worst prognosis in pediatric ALL.

The q23 region of chromosome 11 is a relatively frequent site of structural rearrangements in children with ALL; these abnormalities (including translocation, deletion and partial duplication) are detected in 4.5% to 5.7% of blasts cells, 80% of infant leukemia (i.e.,

ALL and AML in patients younger than 1 year. The patients with 11q23 abnormalities are usually young, lack hyperdiploidy, and have high leukocyte counts, organomegaly, central nervous system (CNS) involvement, an early pre-B cell immunophenotype, myeloid-related antigen expression, and a poor prognosis. Pathogenesis In most cases of ALL, as in other lymphoid malignancies, a single damaged progenitor cell,capable of expansion by (theoretically) indefinite self-renewal, gives rise to malignant, poorly differentiated precursors. In pediatric ALL there is evidence that these events occur in committed lymphoid precursors, whereas in acute myeloid leukemia (AML) and Philadelphia chromosomepositive ALL, it appears that they may occur at an earlier stage of blood cell development because there is evidence of mutation in multiple cell lineages . Several congenital disorders are associated with an increased risk of leukemia. Children with trisomy 21 (i.e., Down syndrome) are up to 15 times more likely to develop leukemia than normal children. Other less common pre-existing chromosomal abnormalities have been linked to leukemia. Included among these are Klinefelter's syndrome, Bloom syndrome, and Fanconi's anemia. Lymphoid malignancies, with a predominance of T-ALL, have been reported in patients with ataxia-telangiectasia (AT), an autosomal recessive disorder characterized increased chromosomal fragility. Predisposing Factors 1. Radiation Exposure by

Ionizing radiation can play a role in the development of acute leukemia; in fact a high incidence of leukemia was seen after the atomic bomb explosions in Hiroshima and Nagasaki with ALL being more frequent in children and AML more common in adults. 2. Chemical exposure The role of toxic chemical exposure (e.g., to benzene) in the development of childhood ALL is questionable. Other factors that could be involved in the development of ALL include parental cigarette smoking, paternal herbicide and pesticide exposure; maternal use of alcohol, contraceptives, and diethylstilbestrol,household radon exposure, and chemical contamination of ground water.

3. Other possible predisposing factors The role played by viral infection in the pathogenesis of human leukemia has been investigated intensively. Some authors have suggested an increased risk of ALL in children born to mothers infected recently with influenza, varicella, or other viruses, but no definitive link between prenatal viral exposure and leukaemia risk has been confirmed. The only link found is the association between the Epstein-Barr virus (EBV) and cases of endemic Burkitt's ymphoma-leukemia, the L3 morphologic subtype of ALL. Sign and Symptom

Acute Leukemia are charactherized by abrubt onset of clinical sign (e.g., fatique, weakness, bone and joint pain), and death occurs within months if treatment is nor instituted. Overall, peripheral white blood cell counts can be incrased, decreased, or normal, although they are typically increased. Normocytic anemia and neutropenia are also hallmarks of the acute leukemia. Thrombocytopenia is usually found in patients with acute leukemia

Clinical and laboratory features at diagnosis in children with ALL

Treatment

Four main treatment elements can be generally recognized in chemotherapy protocols adopted by international cooperative groups: induction, CNS preventive therapy, consolidation /reinduction, and maintenance therapy. 1. Induction The treatment planned in this phase is aimed ateradicating signs and symptoms of the disease and to re-establish a normal hematopoiesis. This goal is generally indicated with the term of complete remission (CR). Children in CR must have no physical evidence of leukemia, normal complete blood cell count and normally regenerating bone marrow (with < 5% leukemic blasts). Induction treatment intensity has increased over the years, consisting of a combination of two (vincristine + steroids), three (+ anthracycline) or four (+ asparaginase) drugs, which remission rate comprised from 85% to approximately 95%. can induce a complete

2. Central Nervous System Preventive Therapy Leukemia cells, undetected in the CSF at the time of diagnosis, may proliferate because systemically administered antileukemic agents do not penetrate the bloodbrain intrathecal chemotherapy, barrier. given Intrathecal methotrexate alone or triple periodically throughout maintenance

chemotherapy, provide adequate CNS preventive therapy for these patients.

3. Consolidation/Reinduction

Conclusion/Reinduction is defined by one /more periods of intensified treatment administered after remission induction and is considered a relevant component of many chemotherapy protocols, particularly for higher-risk patients.

4. Maintainance therapy In particular the use of low dose methotrexat and 6-MP, administered continuously, is widely accepted and constitutes the principal element in most maintenance therapy regimens. In general weekly methotrexate and daily 6-MP appears the optimal schedule.

Stem Cell Transplantation Although successful BMT in patients with endstage leukemia have been performed for 30 years, there is still no clear agreement about the indications for BMT in second remission. Furthermore, relapses rates after BMT remain high. . Comparative data from Germany and Italy show similar results with a statistically significant benefit for BMT over chemotherapy in early marrow relapses. A reasonable conclusion is that BMT is associated with a modest increase in leukemia free survival and that this may be most evident in children with a short early remission. Transplantation of bone marrow is the last line of treatment for unresponsive or relapse ALL.

Prognosis Prognosis in ALL is dependent primarily on age at the time of diagnosis, on lymphoblast load, and on immunophenotype. Chromosamal tranlocation are proving to be the strongest predictor of adverse treatment outcome for both children and adults. The presence of Philadhelpia chromosome, t(9,22), is an indicator of significant adverse effect. The t(12;21) marker is found in a significant number of childhood ALL patients. Patients 2-10 years of age have the best prognosis. Children less than 1 year of age do poorly. Children between 1 and 2 have an intermediate prognosis, as do teenagers and young adults. Elevated peripheral blood lymphoblast counts greater than 20-30 x 10 9/L, hepatosplenomegaly, and lymphadenopathy all adversely affect outcome and are considered high risk factors.

CHAPTER III CONCLUSION

Acute Lymphoblastic Leukemia ia a disease of unregulatede proliferation of malignant blood cells. This disease can be studied by light microscopy, cytochemical stain, electron microscopy, immunologic testing, such as nuclear and surface markers, and cytogenetic techniques such as karyotyping, fluorescence in situ hybridization, and polymerase chain reaction. Using FAB system, there are three main subtypes of lymphoblast, L1(homogenous lymphoblast population); L2(mixed large and small lymphoblasts); and L3, often called immunoblastic or burkitt like. Only half of patients with ALL have leukocytosis and may not have circulating lymphoblast, but neutropenia, thrombocytopenia, and anemia are usually present. Childhood ALL is a disease in which the good-prognosis ALL has a 90%rate of complete remission. Infiltration of malignant cells into meninges can occur with lymphoblasts

found in the cerebrospinal fluid, testes, and ovaries. The presence of Philadelphia chromosome, t(9;22), is an indicator of significant adverse effects. Prognosis in ALL is dependent primarily on age at the time of diagnosis, on lymphoblast load, and on immubophenotype. Chromosomal translocation appear to be the strongest predictor of adverse treatment outcomes for both children and adults. Four main treatment elements can be generally recognized in chemotherapy protocols adopted by international cooperative groups: induction, CNS preventive therapy, consolidation /reinduction, and maintenance therapy. BMT (Bone Marrow Transplantation) is associated with a modest increase in leukemia free survival and that this may be most evident in children with a short early remission. Transplantation of bone marrow is the last line of treatment for unresponsive or relapse ALL.

CHAPTER III REFERENCES

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6. Schrappe M, Reiter A, Ludwig WD, et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. Blood 2000;95:3310-3322. 7. Gilliland DG, Tallman MS. Focus on acute leukemias. Cancer Cell 2002;1:417-420. 8. Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 2003;3:639-649.