CHAPTER 1 INTRODUCTION The body is made up of hundreds of millions of living cells.

Normal body cells grow, divide, and die in an orderly fashion. During the early years of a person's life, normal cells divide faster to allow the person to grow. After the person becomes an adult, most cells divide only to replace worn-out or dying cells or to repair injuries. !ancer begins when cells in a part of the body start to grow out of control. There are many "inds of cancer, but they all start because of out-of-control growth of abnormal cells. !ancer cell growth is different from normal cell growth. #nstead of dying, cancer cells continue to grow and form new, abnormal cells. !ancer cells can also invade $grow into% other tissues, something that normal cells cannot do. &rowing out of control and invading other tissues are what ma"es a cell a cancer cell. Acute myeloblastic leu"emia $A'(% is a group of malignant bone marrow neoplasms of myeloid precursors of white blood cells. Acute myeloblastic leu"emia is a common type of pediatric A'(. )owever, the condition is rare and represents appro*imately +, of all leu"emias during childhood and has an incidence of -,---, per million per year..,/, A'( starts in the bone marrow $the soft inner part of the bones, where new blood cells are made%, but in most cases it 0uic"ly moves into the blood. #t can sometimes spread to other parts of the body including the lymph nodes, liver, spleen, central nervous system $brain and spinal cord%, and testicles $in males%. 1ther types of cancer can start in these organs and then spread to the bone marrow. 2ut these cancers that start elsewhere and then spread to the bone marrow are not leu"emia..,/,

CHAPTER II THEORY 2.1 Definition6,7 Acute myeloblastic leu"emia $A'(% goes by many names, including acute myelocytic leu"emia, acute myelogenous leu"emia, acute granulocytic leu"emia, and acute non lymphocytic leu"emia. 3Acute3 means that the leu"emia can progress 0uic"ly, and if not treated, would probably be fatal in a few months. Acute myeloid leu"aemia is a type of cancer that affects immature blood cells on the myeloid cell line. A'( causes an overproduction of abnormal blast cells $immature white cells%, which crowd the bone marrow and prevent it from ma"ing normal blood cells. 2ecause the bone marrow cannot function properly, it cannot produce ade0uate numbers of red cells, normal white cells and platelets. This ma"es people with A'( more susceptible to anaemia, recurrent infections and to bruising and bleeding easily. The abnormal blast cells $leu"aemic blasts% eventually spill out into the blood stream and can accumulate in various organs li"e the spleen and liver. 2.2 Epidemiolog
1,!,",6,7

The incidence of acute leu"emia in the first year of life in the 4nited 5tates is +6 cases per million live births. The annual incidence of A(( $76 per million% is almost twice the rate of A'( $-6./ per million%. 8hile 7.9, to 9, of pediatric A(( occurs in infants, A'( in infants comprises /, to -., of pediatric A'(. The pea" annual incidence of pediatric A'( of -6./ per million occurs during the first year of life. #n contrast, the pea" annual incidence of pediatric A(( of /./ per million occurs between two and three years of age. 2oth A(( and A'( occur more fre0uently in female than male infants. The rates of A(( and A'( in white infants are higher than the rates for blac"s. :ach year in Australia around 7,7;6 adults and 779 children are diagnosed with leu"emia. 1f these around /66 adults and around 96 children ar diagnosed with A'(. A'( is a relatively rare type of cancer but it is the most common type of acute leu"aemia diagnosed in Australian adults. A'( can also affect children but it more commonly occurs in adults. Acute lymphoblastic leu"aemia $A((% is more common in children than in adults. Around - 9 Australian children are diagnosed with A(( each year ma"ing it the most
2

common type of cancer in children aged 6 to -. years. 1verall, chronic leu"aemias are more common in adults than acute leu"emias. They rarely occur in children. !hronic lymphocytic leu"emia $!((% is about twice as common as chronic myeloblastic leu"emia $!'(%. #ncidence of acute myeloblastic leu"emia in children in )aji Adam 'ali" )ospital 'edan during <anuary 766- = December 766/, the diagnosis of A'( was established based on morphology and there were .9 children meet the criteria.

2.! Etiolog

!,",6,7

Although ;6, children with A'( have no "nown ris" factors, a number of predisposing constitutional disorders have been indentified in the remaining -6, of children. The following factors are important in pathogenesis of leu"emia.

R#di#tion e$po%&'e )igh-dose radiation e*posure $such as being a survivor of an atomic bomb blast or nuclear reactor accident% increases the ris" of developing A'(. <apanese atomic bomb survivors had a greatly increased ris" of developing acute leu"emia, usually within / to > years after e*posure. The possible ris"s of leu"emia from e*posure to lower levels of radiation, such as from radiation therapy, *-rays, or !T scans, is not well-defined. #f a fetus is e*posed to radiation within the first months of development, it may carry an increased ris" of leu"emia, but the e*tent of the ris" is not clear. #f there is an increased ris" it is li"ely to be small, but to be safe, most doctors try to limit a person's e*posure to radiation as much as possible. Ce't#in ()emi(#l e$po%&'e% The ris" of A'( may be increased by e*posure to certain chemicals. (ong-term e*posure to high levels of ben?ene is a ris" factor for A'(. 2en?ene is a solvent used in the rubber industry, oil refineries, chemical plants, shoe manufacturing, and gasoline related industries, and is also present in cigarette smo"e, and some glues, cleaning products, detergents, art supplies, and paint strippers. @atients with other cancers who are treated with certain chemotherapy drugs are more li"ely to develop A'(. 5ome of the drugs lin"ed with these secondary $treatment related% leu"emias include mechlorethamine, procarba?ine, chlorambucil, melphalan, etoposide, teniposide and cyclophosphamide. !ombining these
3

drugs with radiation therapy further increases the ris". 'ost secondary cases of A'( occur within -6 years after treatment of )odg"in disease, non-)odg"in lymphoma, or childhood acute lymphocytic leu"emia $A((%. 5econdary leu"emias also sometimes occur after treatment of breast, ovarian, or other cancers. *mo+ing The only proven lifestyle-related ris" factor for A'( is smo"ing. 'any people "now that smo"ing is lin"ed to cancers of the lungs, mouth, throat, and laryn* $voice bo*%, but few reali?e that it can also affect cells that don't come into direct contact with smo"e. !ancer causing substances in tobacco smo"e are absorbed by the lungs and spread through the bloodstream to many parts of the body. Ce't#in ,lood di%o'de'% @atients with certain blood disorders seem to be at increased ris" for getting A'(. These include chronic myeloproliferative disorders such as polycythemia vera, essential thrombocytopenia, and idiopathic myelofibrosis. !hronic myeloblastic leu"emia $!'(% is another type of myeloproliferative disorder, and some patients with !'( later develop a form of A'(. The ris" of developing A'( is increased further if treatment for these disorders includes some types of chemotherapy or radiation. 5ome patients who have a myelodysplastic syndrome $a pre-leu"emic condition% may develop A'(. These conditions cause defects in blood cell formation, and over a period of years may evolve into leu"emia. @atients who have a myelodysplastic syndrome and develop A'( typically have a poor prognosis. Congenit#l % nd'ome% -p'e%ent #t ,i't). Aor the most part, acute myeloid leu"emia does not appear to be an inherited disease. #t is rare for it to run in families, so a person's ris" is not usually increased if a family member has the disease. 2ut there are some congenital syndromes with genetic changes that seem to raise the ris" of A'(. These include Down syndrome, Aanconi anemia, 2loom syndrome, Ata*ia-telangiectasia, and 2lac"fan-Diamond syndrome H#/ing #n identi(#l t0in 0it) A12 This ris" is largely confined to the first year of life. As mentioned above, most cases of A'( are not thought to have a strong genetic lin". 'any doctors feel the increased ris"
4

among identical twins may be due to leu"emia cells being passed from one fetus to the other while still in the womb. 3ende' A'( is more common in males than in females, but the reasons for this are not clear. Un(e't#in, &np'o/en o' (ont'o/e'%i#l 'i%+ f#(to'% 1ther factors that have been studied for a possible lin" to A'( include e*posure to electromagnetic fields $such as living near power lines%, wor"place e*posure to diesel, gasoline, and certain other chemicals and solvents, and e*posure to herbicides or pesticides. 5o far, none of these factors has been lin"ed conclusively to A'(. Besearch in these areas is on going. 2." Cl#%%ifi(#tion!,",7 Acute leu"emia can be classified based on morphologic characteristic and cytochemical features imunologic charateristic and cytogenetic and molecular characteristics. Table 7.-. 'orphologic !haracteristic of (ymphoblasts and 'yeloblasts !harateristic 5i?e Nucleus 5hape !hromatin Bound or oval 5mooth, homogenenous Bound or oval 5pongy,loose, finely developed meshwor" Nucleoli Nuclear membrane Nuclear-cytoplasmic !ytoplasm !olor Amount 2lue Thin rim 2lue-gray 6-7 and indistinct 5mooth, round )igh 7-9 and distinct CpunchedoutD #regular (ow (ymphoblasts -6-76 um 'yeloblasts -.-76 um

&ranules Auer rods

Absent Absent

'ore abundant @resent @resent

C to()emi(#l 'e#(tion% @ero*idase 5udan blac" @eriodic acid-5chiff :sterase Terminal deo*ynucleotidyl transferase Ea
-

EE E E EFEF-b

a 1ften negative in (+ morphology; b Also may be positive in acute monocytic leu"emia

#n the -; 6s, a group of Arench, American, and 2ritish leu"emia e*perts divided acute myeloid leu"emias into subtypes, '6 through ' , based on the type of cell from which the leu"emia developed and how mature the cells are. This was based largely on how the leu"emia cells loo"ed under the microscope after routine staining. Table 7.7 The Arench-American-2ritish $AA2% classification of A'( '6 ''7 '+ '. 4ndifferentiated acute myeloblastic leu"emia Acute myeloblastic leu"emia with minimal maturation Acute myeloblastic leu"emia with maturation Acute promyelocytic leu"emia $A@(% 5ubdivided '. Acute myelomonocytic leu"emia '.:6 Acute myerlomonocytic leu"emia with eosinophilia '9 5ubdivided '9A Acute monocytic leu"emia without differentiation '92 Acute monocytic leu"emia with differentiation
6

'/ '

Acute erythroid leu"emia Acute mega"aryoblastic leu"emia

Table 7.+ Arench-American-2ritish $AA2% classification of myeloblasts in microscopic A12 4A5 11 A12 4A5 12

A12 4A5 1!

A12 4A5 1"

A12 4A5 16A

A12 4A5 165

A12 4A5 16

A12 4A5 17

The AA2 classification system is useful and is still commonly used to group A'( into subtypes. 2ut it doesn't ta"e into account many of the factors that are "nown to impact prognosis $outloo"%. The 8orld )ealth 1rgani?ation $8)1% has proposed a newer system that includes some of these factors to try to help better classify cases of A'( based on a patient's outloo". Not all doctors use this new system. The 8)1 classification system divides A'( into several broad groupsG Table 7.. 8)1 !lassification of Acute 'yeloblastic (eu"emia A(&te m elo,l#%ti( le&+emi# 0it) 'e(&''ent geneti( #,no'm#litie% H Acute myeloblastic leu"emia with t$>I7-%$077I077%, $A'(-F:T1% H Acute myeloblastic leu"emia with abnormal bone marrow eosinophils and inv$-/%$p-+077% or t$-/I-/%$p-+I077%, $!2A-JF'K)--% H Acute promyelocytic leu"emia with t$-9I- $077I0-7%, $@'(FBAB-J%, and variants H Acute myeloid leu"emia with --07+ $'((% abnormalities A(&te m elo,l#%ti( le&+emi# 0it) m&ltiline#ge d %pl#%i# H Aollowing 'D5 or 'D5F'@D H 8ithout antecedent 'D5 or 'D5F'@D, but with dysplasia in at least 96, of cells in two or more myeloid lineages A(&te m elo,l#%ti( le&+emi# #nd m elod %pl#%ti( % nd'ome%, t)e'#p 'el#ted H Al"ylating agentFradiation=related type H Topoisomerase ## inhibitor=related type $some may be lymphoid% H 1thers A(&te m elo,l#%ti( le&+emi#, not ot)e'0i%e (#tego'i7ed !lassify asG H Acute myeloblastic leu"emia, minimally differentiated H Acute myeloblastic leu"emia without maturation H Acute myeloblastic leu"emia with maturation H Acute myelomonocytic leu"emia H Acute monoblasticFacute monocytic leu"emia H Acute erythroid leu"emia $erythroidFmyeloid and pure erythroleu"emia% H Acute mega"aryoblastic leu"emia H Acute basophilic leu"emia H Acute panmyelosis with myelofibrosis H 'yeloid sarcoma AbbreviationsG A'(-F:T1G acute myeloid leu"emia oneFeight twenty one, !2A-JF'K)--G core binding factor alphaFsmooth muscle myosin heavy chain --, 'D5G myelodysplastic syndrome, '((G mi*ed lineage leu"emia, '@DG myeloproliferative disorder, @'(FBAB-JG promyelocytic leu"emiaFretinoic acid receptor alpha. 2.6 P#t)ogene%i%18,11

The pathogenesis of A'( can be e*plained by ac0uired genetic changes in bone marrow stem cells that cause a complete or partial bloc" in normal hematopoietic stem cell maturation. The genetic changes may involve mutations that lead to activation of growthpromoting proto-oncogenes, inactivation of tumor suppressor genes, or alterations in transcription factors. 'utations in codons -7, -+, or /- of the N -ras gene encoding a 7- "d guanosine nucleotide binding protein involved in signal transduction have been noted in up to +6, of those with A'(. 5uch abnormalities may be more common in the monocytic subtypes of A'(. 1ver e*pression of the fit-+ growth factor receptor has been reported, suggesting the possible role of autocrine stimulation. 'utations of the tumor suppressor gene RbLMand p53LN have been observed and appear to confer an inferior prognosis. The greatest insight regarding A'( pathogenesis has been provided by their identification of genes at cytogenetic brea"points involved in balanced translocation. The fusion proteins generated by the translocation generally results in disruption of transcription factors believed to be critical in myeloid differentiation. 'any of theses chromosomal abnormalities Oe.g., t$>I7-%, t $-9I- %, inv -/P are associated with specific A'( subtypes and carry prognostic importance. :ach will be discussed in turn later in this chapter. )owever, the genetic changes that account for poor prognosis when loss of all orparts of chromosomes occur remain to be elucidated. Although the ac0uired genetic lesions that lead to leu"emia are being rapidly defined, DNA damage from a "nown cause account for a small fraction of patients with A'(. None the less, leu"emias clearly occur with increased fre0uency after military or therapeutic radiation e*posure, after certain types of chemotherapy, and with heavy and continuous occupational e*posures to ben?ene. #t is now recogni?ed that there are two types of chemotherapy related leu"emiasG $a% the classic al"ylating agent induced type in which the leu"emia is preceded by a myelodysplastic prodrome and is characteri?ed byclonal abnormalities of chromosome 9 andFor and $b% anepipodophyilloto*in-associated type with shorter $7-yr vs 9-yr% incubation period that is associated with myelomonocytic or monocytic differentiation and abnormalities at the --07+ region. There have been a number of large, survey type epidemiologic studies that have attempted to lin" a variety of environmental e*posures to leu"emia incidence. 'any of these studies contain relatively small sample si?es and identify modest, if any, increases in ris" ratio.
9

#n addition, older and retrospective studies may be somewhat suspectin that the pathologic diagnoses have usually not been reviewed and classified using contemporary criteria, and therefore the distinctions between myeloid, lymphoid, and perhaps even acute versus chronic leu"emia may not be accurate. Aurthermore, as in many epidemiologic studies, it is difficult to 0uantify the degree of e*posure to various environmental insults. There may be a small increased ris" associated with cigarette smo"ing, where as e*posure to electromagnetic radiation seems an unli"ely cause of A'(. )owever, occupational e*posures, particularly to ben?ene- or petro chemicals have been implicated in the development of A'(. Al"aylating agents used in )odg"inQs disease, multiple myeloma, ovarian cancer, and colon cancer have been associated with =9F= chromosome type, where as tenoposide use in childhood acute lymphoblastic leu"emia $A((% and high dose anthracyclineFcyclophosphamide combinations have caused --07+-associated disease. 8ith the few e*ceptions noted above, however, there is no clear relationship between environmental e*posures and the occurrence of acute leu"emia. Nor are the acute leu"emias a familial or inherited disorder. :*cept for the increased incidence of acute leu"emia occurring during the first / months after diagnosis in the identical twin of an affected child, the occurrence of multiple cases of acute leu"emia in a given family is e*tremely rare. #ndeed, it is 0uite important to reassure family membersin this regard because this is often an unas"ed 0uestion when leu"emiais first diagnosed in a relative. A few families have been described in which leu"emia incidence is increased. #n some of these families,multiple different types of leu"emias and other cancers have been found. #n other, potentially more informative families, the morphologicor clinical characteristics of the leu"emia have been similar, suggestinga common, heritable genetic mutation. A large family has recently been described in which seven cases of erythroleu"emia or myelodysplasia have been noted in three successive generations. 'ost of these cases antedated current molecular biologic techni0ues, and the available cytogenetic data did not suggest a common chromosomal abnormality. There was no association of leu"emia with specific )(A types in this family, a finding similar to that noted in large surveys of )(A typing among patients with leu"emia. 2.6 Di#gno%i% #nd Clini(#l 1#nife%t#tion!,",6,6,7 The diagnosis of A'( is made on bone marrow aspirate and biopsy with the presence of greater than +6, blasts. 'arrow should be obtained cytochemical stains, flow cytometry, and cytogenetics. Although the morphologic diagnosis of A'( is straight forward, others
10

malignancies may mimic A'(. 'ost notably, metastatic alveolar rhabdomyosarcoma, undifferentiated leu"emia or (7 A(( may appear morphologically li"e mega"aryoblastic $' % A'(. Neuroblastoma and alveolar rhabdomyosarcoma may also loo" li"e monoblastic $'9% A'(. The clinical presentations of A'( stem from leu"emia cells crowding out normal hematopoietic cells in the bone marrow and invading e*tramedullary sites. Thus, patients present with signs and symptoms of diminished numbers of normal red blood cells, white blood cells, and platelets, as well as the presence of malignant cells. @atients with peripheral blast counts greater than 766,666Fmm+are atris" for central nervous system $!N5% stro"e due to hyperviscosity. )epatosplenomegaly and adenopathy are also common. @eripheral collections of malignant cells cause chloromas, which can be locatedin the soft tissues, s"in $leu"emia cutis%, gingiva, orbit, or elsewhere. 'arrow replacement causes neutropenia that places patients at ris" for invasive bacterial infections. Thus, patients often have fever or other signs of a focal or systemic infection. @atients may also present with anemia, which gives rise to fatigue and loss of energy, pallor, and, in e*treme cases, hemodynamic insta-bility. Thrombocytopenia may cause petechiae, purpura, mucosal bleeding, or, rarely, !N5 hemorrhage. Thrombocytopenia maybe e*acerbated by coagulopathy, especially in the '+ and '9 subtypes. Although the mechanism for disseminated intravascular coagulation $D#!% is not "nown in '9 A'(, there is convincing evidence thate*pression of anne*in ##, a receptor for fibrinolytic proteins, facilitates plasminogen activation by associating plasminogen and its activator, t-@A, at the A@( $'+% leu"emic blast cell surface. About 9, of patients with A'( will have !N5 yvdisease at diagno-sis and a smaller percentage will present with !N5 chloromas. These patients may present with headaches, cranial nerve palsies,focal neurologic deficits, or, rarely, sei?ures. 2.7 Diffe'enti#l Di#gno%i%9 1ther malignancies that should be differentiated from A'( are acute lymphphocytic leu"emia $A((%, myelodysplastic syndrome $'D5, chronic myeloblastic leu"emia $!'(% including juvenile chronic myelomonocytic leu"emia, bone marrow metastases of solid tumors such as neuroblastoma, rhabdomyosarcoma, and :wing sarcoma, bone marrow by

11

Non-)odg"in lymphoma $N)(%. Differential diagnosis also includes non-malignant disorders such ad transiet leu"emoid reactions, transiet myeloproliferative syndrome, juvenile chronic arthritis, viral induced bone marrow suppresion, aplastic anemia, congenital or ac0uired neutropenia and autoimmune cytopenia.

Table 7.9 Differential diagnosis of acute leu"emia in children and adolescents. Disease Aplastic anemia and other marrow failure syndromes $e.g., Aanconi disease% Difference (ess common than leu"emia, marrow aspiration, trephine biopsy and di epo*y butane test

Bheumatic disease $e.g., 5till disease, rheumatic fever%

Bare, bone marrow aspiration

1steomyelitis

Badiography, s"eletal scintigraphy, bone marrow aspiration

2one marrow dissemination of different malignancies $e.g., neuroblastoma, rhabdomyosarcoma%

Tumor mar"ers, immunophenotyping, bone marrow aspiration, immunohistochemistry, trephine biopsy

'yeloproliferativeFmyelodysplastic syndrome

2one marrow aspiration, trephine biopsy, marrow cytogenetics, hemoglobin A level

Riral and other infection $e.g., infectious

5pecific serology, bone marrow aspiration

12

mononucleosis, cytomegalovirus and Leishmania%

(eu"emoid reaction $e.g., in whooping cough, sepsis%

2one marrow aspiration

Normal platelet and granulocyte count, bone Transient erythroblastopenia of childhood marrow aspiration

#diopathic thrombocytopenic purpura

Normal neutrophil and red blood cell count, bone marrow aspiration

2.9 T'e#tment!,",6,6,7 @ediatric A'( protocols begin with a remission induction regimen and !N5 prophyla*is and continue with consolidation and intensification therapy. The 2erlinAran"furt-'unster $2A'% group adds a maintenance phase similar to pediatric A(( therapy. #nduction therapy has two goalsG $-% to reduce the leu"emic blast bone marrow percentage to less than 9, andFor eliminate e*tramedullary disease and $7% to restore normal hematopoiesis. !ytarabine $Ara-!% and anthracyclines play central roles in induction. :ach pediatric cooperative group uses a different dose and schedule of these two drugs with the addition of /-thioguanine andFor etoposide although the optimal combination is not "nown. !urrent induction regimens are becoming increasingly intensive. Although more intensive induction regimens have been shown to induce more durable remissions and better overall survival, the more intensive induction regimens also have mortality in the range of / to over-6,. Thus, overall gains in remission induction by increasing induction dose and schedule intensity may be limited by to*icity. 5ince durable remission induction is a prere0uisite for cure, future clinical trials need to attempt to improve remission induction outcomes. The pediatric cooperative group suse various strategies for postinduction therapy. 'ultiple trials have demonstrated that matched related bone marrow transplantation $'BD2'T% significantly improves event free survival and overall survival compared to intensive chemotherapy or autologous bone marrow transplant. Thus, in the !hildrenQs !ancer
13

&roup $!!&%, the @ediatric 1ncology &roup $@1&%, the Arench !ooperative A'( &roup, and others, intensive induction therapy with appropriately matched related donor transplantation is now frontline therapy for patients in first remission. The conditioning, source of stems cells, and graft versus host disease $&R)D% prophyla*is vary. )owever, most centers use either cyclophosphamide or other chemotherapy agents and total body irradiation $T2#% or busulfan and cyclophosphamide as conditioning regimens. These different conditioning regimens have three goalsG $-% the eradication of residual leu"emia, $7% to ma"e space for the donor marrow, and $+% immune suppression to prevent donor graft rejection. #f bone marrow transplantation is not available, then consolidation and intensification chemotherapy regimens are given. All chemotherapy consodilation and intensification chemotherapy regimens heavenly on Ara-! in high doses. Although the various pediatric cooperative oncology group use Ara-! in consolidation and intensification, they differ in the use of autologous bone marrow transplant and maintenance therapy. Although !!&, @1&, and others have shown no benefit ti autologous bone marrow transplant, the most recent 2ritish trial, the Tenth 'edical Besearch !ouncil on Acute 'yeloid (eu"emia Trial $'B! A'(-6%, demonstrated a significant benefit to autologous bone marrow transplant compared to no further therapy after four courses of intensive chemotherapy. 8here as the 2A' group relies heavily on maintenance therapy !!& and (A': have shown that maintenance therapy may decrease free survival and overall survival. The chemotherapeutic agents used in induction, 'BD2'T, and the intensive consolidation and intensification chemotherapy regimens all cause mar"ed to*icity. 'ucositis, emesis, and bone marrow suppression occur with all intensive consolidation regimens and 2'T. 2one marrow suppression predisposes patients to infections that remain the leading cause of morbidity and mortality. Additionally, 2'T involving T2# may cause multiple short and long term side effects. 5hort term side effects include nephritis and an acute pneumonitis that is usually fatal. 2oth cyclophosphamide and T2# cause infertility and T2# may cause growth retardation, endocrine dysfunction, and pulmonary and cardiac dysfunction. The effects of these agents individually and together on neuropsychological function are an area of active investigation. #n newly diagnosed patients with A'(, the goal of induction therapy is to achieve what has been termed complete remission $!B%, which then permits the administration of
14

subse0uent therapy that, in most treatment protocols, is designed to ma*imi?e therate of disease free survival and cure. !urrently, !B is defined primarily on morphologic grounds and includes the development of a morphologically normal bone marrow containing less than 9, blast elements, absence of any signs of e*tramedullary leu"emia, and return of normal neutrophil $S -,966FTl% and platelet $S -96,666FTl% counts.

2.: P'e/ention%7 A ris" factor is something that increases a person's chance of getting a disease. 5ome ris" factors, li"e smo"ing, can be controlled. There is no way to prevent leu"emia at this time. A ris" factor is something that affects your chance of getting a disease such as cancer. Aor e*ample, e*posing s"in to strong sunlight is a ris" factor for s"in cancer. 5mo"ing is a ris" factor for a number of cancers. 2ut ris" factors don't tell us everything. )aving a ris" factor, or even several ris" factors, does not mean that you will definitely get the disease. And many people who get the disease may not have had any "nown ris" factors. :ven if a person has a ris" factor and develops cancer, it is often very hard to "now how much that ris" factor might have contributed to the cancer.

2.18 Compli(#tion6,7 Death may occur in patients with A'( as a conse0uence of uncontrolled infection or hemorrhage. This may happen even after use of appropriate blood product and antibiotic support. The most common complication in A'( patients is failure of the leu"emia to respond to chemotherapy. The prognosis for these patients is poor because their disease usually does not respond to other chemotherapy regimens.

2.11 P'ogno%i%2,6,7,: As mentioned before, A'( remains a difficult disease to treat. 5ome but small progress has been made during the last 7-+ decades. (ess than 76, of the patients with a recurrence can be cured in the long term. Aive year overall survival generally does not e*ceed /6,. 8hen a bone marrow donor is not available, the overall survival drops to +9-/6,. These prognostic factors include the cytogenetic test results $showing chromosome or gene changes%, the patient's age, and the white blood cell count. 1ther important factors include pre-e*isting blood disorders

15

$such as a myelodysplastic syndrome% and a history of treatment with chemotherapy andFor radiation therapy for an earlier cancer. C)'omo%ome #,no'm#litie% !hromosome changes give one clue to prognosis. Not all patients have these abnormalities. Those listed below are the most common, but there are many others. @atients without any of these usually have an outloo" that is between favorable and unfavorable. Aavorable abnormalitiesG U Translocation between chromosomes > and 7- $seen most often in patients with '7% U #nversion of chromosome -/ $seen most often in patients with '. eos% U Translocation between chromosomes -9 and - $seen most often in patients with '+% 4nfavorable abnormalitiesG U Deletion $loss% of part of chromosome 9 or $no specific A'( type% U !omple* changes - those involving several chromosomes $no specific A'( type% 3ene m&t#tion% Newer tests allow doctors to find changes within specific genes on chromosomes. @eople who have certain gene mutations may have a better or worse outloo". Aor instance, about - patient out of + with A'( has a mutation in the A(T+ gene. These people tend to have a poorer outcome, but new drugs that target this abnormal gene are now being studied, which may lead to better outcomes. 1n the other hand, people with changes in the N@'gene $and no other abnormalities% seem to have a better prognosis than people without this change. #n the coming years, doctors will use newer lab tests to learn more about the underlying genetic defects that cause A'( and how they can be used to predict a patient's prognosis. These genetic defects might also form the basis for treating the leu"emias. Age 1lder patients $over /6% generally do not fare as well as younger patients. 5ome of this may be because they are more li"ely to have unfavorable chromosome abnormalities. #t is also harder to treat them with more intense chemotherapy regimens. ;)ite ,lood (ell (o&nt
16

A high white blood cell count $S-66,666% at the time of diagnosis is lin"ed to a worse outloo". P'io' ,lood di%o'de'% o' (#n(e'% )aving a prior blood disorder such as a myelodysplastic syndrome or having A'( that develops after treatment for another cancer tends to lead to a worse prognosis, as these types of A'( are often harder to treat. *t#t&% of #(&te m eloid le&+emi# #fte' t'e#tment Not surprisingly, how well a leu"emia responds to treatment also has an effect on longterm prognosis. A remission $complete remission% is usually defined as having no evidence of disease after treatment. This means the bone marrow contains fewer than 9, blast cells, the blood cell counts are within normal limits, and there are no signs or symptoms of the disease. A molecular complete remission means there is no evidence of leu"emia cells in the bone marrow, even when using very sensitive tests, such as @!B. 'inimal residual disease is a term used after treatment when leu"emia cells can't be found in the bone marrow using standard tests $such as loo"ing at cells under a microscope%, but more sensitive tests $such as flow cytometry or @!B% find evidence that leu"emia cells remain in the bone marrow. Active disease means that either there is evidence that the leu"emia is still present during treatment or that the disease has come bac" after treatment $relapsed%. Aor a patient to be in relapse, they must have more than 9, blast cells present in the bone marrow.

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CHAPTER " DI*CU**ION < *U11ARY

".1 Di%(&%%ion 'A, a 9 years old boy, with body weight and body height of 76 "g and -6+ cm respectively, was admitted to the non-infectious unit of )aji Adam 'ali" &eneral )ospital on <uni 9th 76-- at - .+6 pm with the main complaint was continuing for chemotherapy. )e is regular patient from )emato-1ncology 4nit in B5)A' with the diagnose of Acute 'yeloblastic (eu"aemia and had started chemoteraphy since -;th Aebruary 76--. )e will continuity his following /th chemoteraphy with the medicine Rincristine, !yclophospamide, and Adriamycine. )e is complaining of flu symptom since + days ago. Aever $-%, cough$-%, history of bleeding $-%. @atient was born spontaneously, aided by a widwife, cried immediately at birth, cyanosis was not found. )istory of maternal conditionsG fever $-%, hypertension $-%, diabetes mellitus $-%, drugs $-%, and herbal medicine $-%.

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Acute myeloid leu"aemia is a type of cancer that affects immature blood cells on the myeloid cell line. A'( causes an overproduction of abnormal blast cells $immature white cells%, which crowd the bone marrow and prevent it from ma"ing normal blood cells. 2ecause the bone marrow cannot function properly, it cannot produce ade0uate numbers of red cells, normal white cells and platelets. This ma"es people with A'( more susceptible to anaemia, recurrent infections and to bruising and bleeding easily. The abnormal blast cells $leu"aemic blasts% eventually spill out into the blood stream and can accumulate in various organs li"e the spleen and liver. #n this case, the patient was admitted the main complain history of anaemia and always get transfusion while in hospital, recurrent infections li"e cough, flu, often fever and also have history of bleeding li"e epista*is. The diagnosis of A'( is made on bone marrow aspirate and biopsy with the presence of greater than +6, blasts. 'arrow should be obtained cytochemical stains, flow cytometry, and cytogenetics. #n this case, the patient has A'( because he has bone marrow aspirate on -9th Aebruary 76-- and presence of an e*cessive number of blast cells.

A child with A'( should assessed for anaemia, increased bleeding or bruising, fre0uent or repeated infections. #n this case, the patient was got transfusion for his anaemia and covered his history of bleeding and also got antibiotic for his recurrent infection. This patient should continuing his chemotherapy but his AN! $Absolute Neutrophil !ount% less than 966. @rognosis of childhood acute myeloid leu"emia $A'(% has improved significantly over the past decades, from nearly no child surviving to a present probability of cure of appro*imately /6,. )owever, this can only be achieved using very intensive chemotherapy which results in relatively high rates of treatment related deaths and significant late effects. #n this case, the patient was not continuing his chemmotherapy because his AN! less than 966. ".2 *&mm#' #t has been reported that a case of a 9 years old boy diagnosed as Acute 'yeloblastic (eu"emia. The diagnosis was established based on history tal"ing, clinical manifestation, laboratory finding and bone marrow aspiration. The treatment of this patient are #ARD D9, Na!l 6,.9,, Ami"acin injection, !otrimo*a?ole, @aracetamol, diet -966 ccal with .6 gr of
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protein and chemotherapy with the medicine $Rincristine, !yclophosphamide, and Adriamycin%.

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