modul tutor sk 4
TRANSCRIPT
-
7/27/2019 Modul Tutor Sk 4
1/33
Tim Kurikulum Pendidikan Preklinik
Fakultas Kedokteran
Universitas Islam Malang
2 0 13
MODUL TUTORSKENARIO KEEMPAT
NAMA MAHASISWA : .... .. ... .... ...
KELOMPOK : .................
-
7/27/2019 Modul Tutor Sk 4
2/33
SKENARIO KEEMPATDemam & Berat badan
URAIAN S K EN ARIO
Tn Marijo, 48 tahun, Karyawan BUMN, pergi berobat ke
Poliklinik karena demam, sesak napas dan tidak nafsu
makan. Dua bulan terakhir pasien mengalami penurunan
berat badan yang tidak direncanakan serta berkeringat di
malam hari.
Hasil pemeriksaan fisik dokter menunjukkan pasien
mengalami pembesaran limpa, hepar dan kelenjar limfe di
inguinal serta purpura pada bagian ekstremitas inferior. Apa
yang terjadi pada Tn. Marijo ?
1. Apa diagnosa banding demam pada kasus Tn. Marijo ?
2. Bagaimana penegakan diagnosa demam pada kasus
Tn. Marijo ?
3. Bagaimana penatalaksanaan pada kasus Tn. Marijo ?
-
7/27/2019 Modul Tutor Sk 4
3/33
I. IDENTIFIKASI KATA SULIT & ADDITIONAL DATA
ANAMESA
- Identitas
a. Nama/Umur : Tn. Marijo, 48 tahun (TB = 170 cm / BB=70 kg saat ini)
b. Suku/Bangsa : Madura/Indonesia
c. Pekerjaan : Karyawan
d. Pendidikan : Sarjana
- History of present Illness : (1 minggu yang lalu)
o Demam (38-39C)
o Sesak napas saat beraktifitas berat
o Luka memar tanpa alasan yang jelas terutama di bagian kaki
o Benjolan di selangkangan
o Mudah lelah
o Tidak nafsu makan
- History of past Illness (2 bulan yang lalu)
o
Common coldso Penurunan nafsu makan
-
7/27/2019 Modul Tutor Sk 4
4/33
o Dalam sebulan terakhir, pasien mengalami penurunan berat badan yang tidak
direncanakan dan lebih dari 10 % (80 kg 70 kg)
o Riwayat merokok (sehari 2 bungkus) dan minum kopi
o Riwayat penggunaan jamu disangkal.
o Riwayat MRS disangkal
o Tidak ada riwayat penyalahgunaan obat terlarang
- History of Treatment & Medical
o Obat penurun demam mengandung Parasetamol
o Multivitamin untuk meningkatkan nafsu makan
- History of Family illness
Tidak diketahui
PEMERIKSAAN FISIK
a. Vital Sign : Tampak sakit sedang
Kesadaran : Compos mentis
Tensi : 110/90 mm hg
Nadi : 85 x/min, (N : 60 80 x / min)
RR : 24 x/min (N ; 16-20 x/ min)
T.Ax : 38,5C
b. Kepala/Leher/thorax/ :
-Wajah pucat & konjuctiva anemis
- Gusi bengkak dan mengalami perdarahan
- Pulmo (dbn) suara pernafasan vesikuler, tidak dijumpai ronkhi
- Cor (dbn), murmur (-)
c. Abdomen :
Soefl, meteorismus (-)
Pembesaran Limpa (S-1) disertai nyeri tekan perut pada bagian kiri atas
Pembesaran Hepar 2 cm di bawah arcus costae (teraba saat pemeriksaan)
- Pembesaran kelenjar getah bening inguinal (bilateral, immobile, konsistensi padat,
multiple, ka =3 cm, ki =2).
d. Ekstremitas Superior/Inferior
- Kaki : Purpura, Refleks fisologik normal, refleks patologik (-), tidak dijumpai edema
DIFERENTIAL DIAGNOSADEMAM :
- Fever e.c Infeksi m.o
-Fever e.c malignancy
-
7/27/2019 Modul Tutor Sk 4
5/33
- Fever e.c drug induced
- Limfadenopathy
PEMERIKSAAN TAMBAHAN
a. LAB DARAH LENGKAP
Erytrocyte counts 4,0 x 106/mm3 (N: 4,2 4,9 x 106/mm3)
Leucocytes counts 20.000/mm3 (N:6000 10800/mm3)
Trombosit 100.000/mm3 (N: 130.000 400.000/mm3)
Hemoglobin 9,2 mg/dl (N in female 12 16,5mg/dl)
Mean corpuscular hemoglobin (MCH) 27 pg/cell (N: 28 -33pg/cell)
Mean corpuscular hemoglobin concentration (MCHC) 30g/dL (N: 32 -36pg/cell)
Mean corpuscular volume (MCV) 85 m3 (N: 86-98 m3)
Hematocrit 35 % (N: 37 48%)
Diff eo/ba/stab/seg/lym/mo = 6/1/4/50/35/4 (N:0-7/0-2/0-4/45-74/16-45/4-10) Reticulosit 60.000 /ml3 (N : 50.000/ ml3)
TIBC 3500 g / L (W = 2500-3500g / L )
Saturasi Iron 20 % (N,W= 20-25)
Saturasi Transferin 17 % (N ; > 16 %)
Feritin 16 ug/l (N ; > 15 ug/L)
Serum transferin receptor concentration (TfR) 10 mg/L (N ; > 8.5 mg/L)
Coombs Test direct (-)
Evaluasi Hapusan darah:
Eritrosit : Kesan Jumlah menurun, Hipokrom, Normositer,
Leukosit : Kesan Jumlah meningkat & tampak sel blast kurang lebih 30 %
Trombosit : Kesan Jumlah menurun
FAAL PEMBEKUAN
PTT 14 detik (N < 11,3 detik)
APTT 40 detik (N < 27.8 detik )
BT 6 menit (N : 2-5 menit)
TT 20 detik (N : 15-17 detik)
FDP (D-dimer) 0.4 % (N< 0.5%)
b. URINE LENGKAP
Warna/keadaan = kuning/jernih
BJ/pH = 1,005 /6,0
Albumin , Urobilin,Reduksi,Bilirubin = (-)
Sedimen : Silinder hialin, granuler,
Eritrosit : (-)
Lekosit : (-)
Protein : (-) (N < 30 mg/dl)
-
7/27/2019 Modul Tutor Sk 4
6/33
c. KIMIA DARAH
GDS = 110 mg/dl
Ureum = 40,4 mg/dl
Creatinin = 0,85 mg/dl
Uric acid = 5,0 mg/dl SGOT = 50 U/L, SGPT = 45 U / L
LDH =
PEMERIKSAAN SUMSUM TULANG
Sumsum tulang hiposeluler
Peningkatan jumlah leukoblast 30 %
Peningkatan megakariosit
Auer rods di sitoplasma sel blast (khas untuk AML)
SEROLOGI
Ig M (-)
ANA test (-)
WORKING DIAGNOSA
- Acute Myeloid Leukemia (AML)
1. IDENTIFIKASI KATA SULIT/KUNCI1. Leukosit
2. Leukoblast3. Auer rods
4. LDH
5. Purpura
2. PENENTUAN PROBLEM LIST
1. Mengapa Tn. Marijo demam, sesak napas dan tidak nafsu makan ?
2. Mengapa Tn. Marijo mengalami penurunan berat badan dan berkeringat di malam
hari ?
3. Mengapa pemeriksaan fisik pada Tn. Marijo terdapat pembesaran limpa, hepar danKGB ringan serta purpura di ekstremitas inferior ?
4. Apa diagnosa banding demam pada kasus Tn. Marijo ?
5. Bagaimana penegakan diagnosa demam pada kasus Tn. Marijo ?
6. Bagaimana interpretasi hasil laboratorium Tn. Marijo ?
7. Bagaimana penatalaksanaan pada kasus Tn. Marijo ?
3. BRAIN STORMING1. Baca Tentang : Biologi Molekular Neoplasma
2. Baca Tentang : Keganasan pada hematologi
3. Baca Tentang kausa AML4. Baca tentang patofisologi AML
http://en.wikipedia.org/wiki/Auer_rodshttp://en.wikipedia.org/wiki/Auer_rods -
7/27/2019 Modul Tutor Sk 4
7/33
5. Baca tentang alur penegakan diagnosa pada AML
6. Baca tentang Penatalaksanaan AML
7. Baca Maping Konsep
8. Baca Maping Kasus
-
7/27/2019 Modul Tutor Sk 4
8/33
4.MAPPING KONSEP
HEMATOPOESIS JALUR MYELOID & LYMPHOID
-
7/27/2019 Modul Tutor Sk 4
9/33
WBC DISORDERS
Disorder Type Target
Granulosit Neurophilia Proliferasi Progenitor SelInefektif granulopoesis
Apoptosis
Fungsi Fagosit Congenital abnormality CorticosteroidLeukemic cell
Chemotaxis Defect Opsonisasi
-
7/27/2019 Modul Tutor Sk 4
10/33
Hipogamaglobulinemia, Complement
Defect Killing & Digestionbacteri
MyeloperoksidaseChediak-Higashi syndrome
Defect Digestion
KLASIFIKASI GANGGUANSISTEM LIMFATIKA
CAUSES OF
PENEGAKAN DIAGNOSA GANGGUAN SISTEMLIMFATIKA
LYMPHADENOPATHY
MALIGNANCY Storagediseases(e.g.,
Gaucher's
INFEKSI
a. Bacterial (e.g. allpyogenic bacteria, cat-
scratch disease, syphilis,tularemia)
b. Mycobacterial (e.g.,tuberculosis, leprosy)
c. Fungal (e.g.,histoplasmosis,coccidioidomycosis)
d. Chlamydial (e.g.,lymphogranulomavenereum)
e. Parasitic (e.g.,
Other
malignancies(e.g.,breastca,melanoma,head &neckcancer,gastro-intestinalmalignan
Benign disorder
of the immunesystem (e.g., RA,SLE, serumsickness, drugreactions such asto phenytoin,Castleman'sdisease, sinushistiocytosis withmassivelymphadenopathy, Langerhans
Malignant
disorders ofImmune system(e.g., AML, CML,ALL, CLL, non-Hodgkin'slymphoma,Hodgkin'sdisease,angioimmunoblastic-like T-celllymphoma,Waldenstrm's
Endocrinopathies (e.g.thyroiditis,hyperthyroidi
Miscellaneous (e.g.,sarcoidosis,amyloidosis,
METHODS OF LYMPH NODE EVALUATION
PhysicalexaminationVitals, GeneralExams
Imaging
Chest radiography *
Lymphangiography
Ultrasono ra h * Com uted
Sampling
Needle
aspiration
Cuttin needle
AN APPROACH TO A PX WITH LYMPHADENOPATHY
HOW TO DIAGNOSE LYMPHADENOPATHY
Does the patient have a known illness that
causes lymphadenopathy ? Treat and monitorfor resolution.
Is there an obvious infection to explain the
lymphadenopathy (e.g., infectious
mononucleosis) ? Treat and monitor forresolution.
Are the nodes very large and/or very firm and
thus suggestive of malignancy ? Perform abiopsy.
Is the patient very concerned about
malignancy and unable to be reassured that
FACTORS TO CONSIDER IN THEDIAGNOSIS OF LYMPHADENOPATHY
Associated systemic symptoms
Patient's age
History of infection, trauma, medications,
travel experience, previous malignancy, etc.
Location: cervical, supraclavicular,
epitrochlear, axillary, intrathoracic (hilar vs.mediastinal), intra-abdominal(retroperitoneal vs. mesenteric vs. other),iliac, inguinal, femoral
Localized vs. disseminated
Tenderness / inflammation
-
7/27/2019 Modul Tutor Sk 4
11/33
Proses Penegakan Diagnosa Pasien dg Febris menggigil
PROSES PENEGAKAN DIAGNOSA PASIEN
DENGAN FEBRIS/DEMAM AKUT
-
7/27/2019 Modul Tutor Sk 4
12/33
-
7/27/2019 Modul Tutor Sk 4
13/33
INISIASI & METASTASIS TUMOR
FAB CLASIFICATION OF AML
JALUR LIMFOIDJALUR MYELOID
SELPLASMA
SINDROMAMYELODISPLASIA
LEUKEMIALIMFOBLASTIKLEUKEMIA
MYELOID
-
7/27/2019 Modul Tutor Sk 4
14/33
Type Name Cytogenetics Percentage of adult AMLpatients
M0 minimally differentiated acute
myeloblastic leukemia
5%
M1 minimally differentiated acute
myeloblastic leukemia
15%
M2 acute myeloblastic leukemia, without
maturation
t(8;21)(q22;q22), t(6;9) 25%
M3promyelocytic, or acute promyelocytic
leukemia(APL)
t(15;17) 10%
M4 acute myelomonocytic leukemia inv(16)(p13q22), del(16q) 20%
M4eo myelomonocytic together with bonemarroweosinophilia
inv(16), t(16;16) 5%
M5 acute monoblastic leukemia (M5a) oracute monocytic leukemia (M5b)
del (11q), t(9;11), t(11;19) 10%
M6 erythroleukemia (M6a) and very rarepure erythroid leukemia (M6b)
5%
M7 acute megakaryoblastic leukemia t(1;22) 5%
Sub Type AML Description ICD-O
Acute myeloid leukemia
with recurrent genetic
abnormalities
AML with translocations betweenchromosome 8 and
21 [t(8;21)] (ICD-O 9896/3); RUNX1/RUNX1T1
AML with inversions inchromosome 16[inv(16)]
(ICD-O 9871/3); CBFB/MYH11
APL with translocations betweenchromosome 15and
17 [t(15;17)] (ICD-O 9866/3);RARA;PML
AML with translocations in chromosomes 9 and 11
[t(9;11)]; MLLT3-MLL
Patients with AML in this category generally have a highrate of remission and a better prognosis compared to other
types of AML.
Multiple
AML with multilineage
dysplasia
This category includes patients who have had a priormyelodysplastic syndrome (MDS) ormyeloproliferative
disease (MPD) that transforms into AML. This categoryof AML occurs most often in elderly patients and often
has a worse prognosis.
M9895/3
AML and MDS, therapy-
related
This category includes patients who have had prior
chemotherapy and/or radiation and subsequently developAML or MDS. These leukemias may be characterized byspecific chromosomal abnormalities, and often carry a
worse prognosis.
M9920/3
AML not otherwise
categorized
Includes subtypes of AML that do not fall into the abovecategories
M9861/3
MAPPING KASUSCausa :
AktifasiSitokin
ATP + Panas
http://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_without_maturationhttp://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_without_maturationhttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_myelomonocytic_leukemiahttp://en.wikipedia.org/wiki/Eosinophilhttp://en.wikipedia.org/wiki/Eosinophilhttp://en.wikipedia.org/wiki/Acute_monoblastic_leukemiahttp://en.wikipedia.org/wiki/Acute_monocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_megakaryoblastic_leukemiahttp://en.wikipedia.org/wiki/ICD-Ohttp://en.wikipedia.org/wiki/Chromosome_8http://en.wikipedia.org/wiki/Chromosome_8http://en.wikipedia.org/wiki/RUNX1http://en.wikipedia.org/wiki/RUNX1T1http://en.wikipedia.org/wiki/RUNX1T1http://en.wikipedia.org/wiki/Chromosome_16http://en.wikipedia.org/wiki/Chromosome_16http://en.wikipedia.org/wiki/Chromosome_16http://en.wikipedia.org/wiki/CBFBhttp://en.wikipedia.org/wiki/MYH11http://en.wikipedia.org/wiki/MYH11http://en.wikipedia.org/wiki/Chromosome_15http://en.wikipedia.org/wiki/Chromosome_15http://en.wikipedia.org/wiki/Chromosome_15http://en.wikipedia.org/wiki/Retinoic_acid_receptor_alphahttp://en.wikipedia.org/wiki/Retinoic_acid_receptor_alphahttp://en.wikipedia.org/wiki/Retinoic_acid_receptor_alphahttp://en.wikipedia.org/wiki/Promyelocytic_leukemia_proteinhttp://en.wikipedia.org/wiki/Myelodysplastic_syndromehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I98953/http://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I99203/http://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I98613/http://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_without_maturationhttp://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_without_maturationhttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_myelomonocytic_leukemiahttp://en.wikipedia.org/wiki/Eosinophilhttp://en.wikipedia.org/wiki/Acute_monoblastic_leukemiahttp://en.wikipedia.org/wiki/Acute_monocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_megakaryoblastic_leukemiahttp://en.wikipedia.org/wiki/ICD-Ohttp://en.wikipedia.org/wiki/Chromosome_8http://en.wikipedia.org/wiki/RUNX1http://en.wikipedia.org/wiki/RUNX1T1http://en.wikipedia.org/wiki/Chromosome_16http://en.wikipedia.org/wiki/CBFBhttp://en.wikipedia.org/wiki/MYH11http://en.wikipedia.org/wiki/Chromosome_15http://en.wikipedia.org/wiki/Retinoic_acid_receptor_alphahttp://en.wikipedia.org/wiki/Promyelocytic_leukemia_proteinhttp://en.wikipedia.org/wiki/Myelodysplastic_syndromehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I98953/http://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I99203/http://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I98613/ -
7/27/2019 Modul Tutor Sk 4
15/33
Sitostatika
Radiasi : X-Ray
Chemical : Benzene
Infeksi
Bone marrow transplant
Antigen (Ag)
Tn. MarijoAg inducing
NF KB & Mutasi DNAMyeloblast
Innate/Adaptive Immun Cells Activated
Sel Myeloma
Gen Supresor Tumor (p53)
Gen Apoptosis
(bcl-2 >>)
DNA Repair
Aktivasi Oncogen(V-ONC, C-ONC)
Invasi ke Pembuluh Limfatika
ImunoTolerance
Infiltrasike Gums
Pembesaran KGB inguinal
Diagnosa
Anamnesa : Usia, Pekerjaan, RPD, RPS
Pemeriksaan Fisik :
Inspeksi & Palpasi Limpa, Hepar
Inspeksi & Palpasi Kelenjar Limfe
Radiologi : X-Ray, USG, MRI, CT Scan
Hematologi : CBC, WBC, Platelet, Hb
Uji Biopsi : KGB inguinal (neoplasma)
Bone Marrow aspiration : Sel blast leukemic
Sitogenetik :
Auer rod (+) AML,
Translocation Chr : t(8:21), t (6:9)
Ag : CD 13 & CD 33
Penatalaksanaan
Tx Farmakologi
Chemotherapy
Radiotherapy
Antibiotic (fight infection)
Tx Non Farmakologi
Transfusion : Platelet, RBC
Bone marrow transplantation
Stem Cell transplantationNecrotic Tissue
-
7/27/2019 Modul Tutor Sk 4
16/33
LDH, AST, ALT BleedingPtechiae
Produksi
abnormalHematopoesis
inefektifLeukosit (blast )
Eritrosit
RentanInfeksi
AnemiaSesak
Trombosit
Sel Leukemic
(blast)Systemic Sign (B)
Fever
Apetite Loss
Weight LossInteraksi dg
Limfosit Host
Proliferasi CompLimfonodi
Emboli
LimfatikaLymphedema
Hiper
metabolism
Complication :
Bleeding
DIC
Infeksi berat
Metastase
Relapse of ALL
Organ damage
Rentan
InfeksiRisk Factor :
- Down syndrome
- Genetic disorder
- Family
Hepatomegali
Swelling
Gums
5. LEARNING OBJECTIVE
-
7/27/2019 Modul Tutor Sk 4
17/33
1. Mampu menjelaskan hematopoesis pada jalur lymphoid dan myeloid
2. Mampu menjelaskan jenis-jenis keganasan sistem hematology (ALL, AML, MM,
CLL, CML)
3. Mampu menjelaskan Patogenesa keganasan hematologi (AML)
4. Mampu menjelaskan alur diagnosa keganasan hematologi (AML)
5. Mampu menjelaskan penatalaksanaan keganasan hematologi (AML)
6. Mampu menjelaskan pencegahan keganasan hematologi
7. Mampu menjelaskan komplikasi keganasan hematologi
Acute Leukemia
-
7/27/2019 Modul Tutor Sk 4
18/33
Essentials of Diagnosis
Short duration of symptoms, including fatigue, fever, and bleeding.
Cytopenias or pancytopenia.
More than 20% blasts in the bone marrow.
Blasts in peripheral blood in 90% of patients.
Classify as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).
General Considerations
Acute leukemia is a malignancy of the hematopoietic progenitor cell. These cells proliferate
in an uncontrolled fashion and replace normal bone marrow elements. Most cases arise with
no clear cause. However, radiation and some toxins (benzene) are leukemogenic. In addition,
a number of chemotherapeutic agents (especially cyclophosphamide, melphalan, other
alkylating agents, and etoposide) may cause leukemia. The leukemias seen after toxin or
chemotherapy exposure often develop from a myelodysplastic prodrome and are often
associated with abnormalities in chromosomes 5 and 7, and those related to etoposide may
have abnormalities in chromosome 11q23.
Much has been learned about the molecular biology of the leukemias. One subtype, acutepromyelocytic leukemia (APL), is characterized by chromosomal translocation t(15;17),
which produces the fusion genePML-RAR which interacts with the retinoic acid receptor to
produce a block in differentiation that can be overcome with pharmacologic doses of retinoic
acid (see below).
Most of the clinical findings in acute leukemia are due to replacement of normal bone
marrow elements by the malignant cell. Less common manifestations result from organ
infiltration (skin, gastrointestinal tract, meninges). Acute leukemia is potentially curable with
combination chemotherapy.
Acute lymphoblastic leukemia (ALL) comprises 80% of the acute leukemias of childhood.
The peak incidence is between 3 and 7 years of age. It is also seen in adults, causingapproximately 20% of adult acute leukemias. Acute myeloid leukemia (AML) is primarily an
adult disease with a median age at presentation of 60 years and an increasing incidence with
advanced age.
Clinical Findings
Symptoms and Signs
Most patients have been ill only for days or weeks. Bleeding (usually due to
thrombocytopenia) occurs in the skin and mucosal surfaces, with gingival bleeding, epistaxis,
or menorrhagia. Less commonly, widespread bleeding is seen in patients with disseminated
intravascular coagulation (DIC) (in APL and monocytic leukemia). Infection is due to
neutropenia, with the risk of infection rising as the neutrophil count falls below 500/mcL;
with neutrophil counts less than 100/mcL, infection within days is the rule. The mostcommon pathogens are gram-negative bacteria (Escherichia coli, Klebsiella, Pseudomonas)
or fungi (Candida, Aspergillus). Common presentations include cellulitis, pneumonia, and
perirectal infections; death within a few hours may occur if treatment with appropriate
antibiotics is delayed.
Patients may also seek medical attention because of gum hypertrophy and bone and joint
pain. The most dramatic presentation is hyperleukocytosis, in which a markedly elevated
circulating blast count (usually > 200,000/mcL) leads to impaired circulation, presenting as
headache, confusion, and dyspnea. Such patients require emergent leukapheresis and
chemotherapy.
On examination, patients appear pale and have purpura and petechiae; signs of infection maynot be present. Stomatitis and gum hypertrophy may be seen in patients with monocytic
-
7/27/2019 Modul Tutor Sk 4
19/33
leukemia, as may rectal fissures. There is variable enlargement of the liver, spleen, and lymph
nodes. Bone tenderness may be present, particularly in the sternum, tibia, and femur.
Laboratory Findings
The hallmark of acute leukemia is the combination of pancytopenia with circulating blasts
(see micrograph). However, blasts may be absent from the peripheral smear in as many as
10% of cases ("aleukemic leukemia"). The bone marrow is usually hypercellular anddominated by blasts. More than 20% blasts are required to make a diagnosis of acute
leukemia.
A number of other laboratory abnormalities are noted. Hyperuricemia may be seen. If DIC is
present, the fibrinogen level will be reduced, the prothrombin time prolonged, and fibrin
degradation products or fibrin D-dimers present. Patients with ALL (especially T cell) may
have a mediastinal mass visible on chest radiograph. Meningeal leukemia will have blasts
present in the spinal fluid, seen in approximately 5% of cases at diagnosis; it is more common
in monocytic types of AML.
The Auer rod, an eosinophilic needle-like inclusion in the cytoplasm, is pathognomonic of
AML (see micrograph) and, if seen, secures the diagnosis. Leukemia cells retain properties ofthe lineages from which they are derived. Thus, histochemistry will demonstrate peroxidase
in myeloid cells and butyrate esterase in monocytic cells, whereas ALL cells will not contain
either of these enzymes. The phenotype of leukemia cells is usually demonstrated by flow
cytometry. AML cells usually express myeloid antigens such as CD 13 or CD 33. ALL cells
of B lineage will express CD19, common to all B cells, and most cases will express CD10,
formerly known as the "common ALL antigen." ALL cells of T lineage will usually not
express mature T-cell markers, such as CD 3, 4, or 8, but will express some combination of
CD 2, 5, and 7 and do not express surface immunoglobulin. Almost all ALL cells express
terminal deoxynucleotidyl transferase (TdT). The uncommon Burkitt type of ALL has a
"lymphoma" phenotype, expressing CD19. CD20 and surface immunoglobulin but not TdT
AML has been characterized in several ways. The "FAB," (French, American, British)classification was based on morphology and histochemistry as follows: acute undifferentiated
leukemia (M0), acute myeloblastic leukemia (M1), acute myeloblastic leukemia with
differentiation (M2), acute promyelocytic leukemia (APL) (M3), acute myelomonocytic
leukemia (M4), acute monoblastic leukemia (M5), erythroleukemia (M6), and
megakaryoblastic leukemia (M7). The World Health Organization (WHO) has sponsored a
classification of the leukemias and other hematologic malignancies that incorporates
cytogenetic, molecular, and immunophenotype information.
ALL is most usefully classified by immunologic phenotype as follows: common, early B
lineage, and T cell.
In considering the various types of AML, APL is now considered separately because of its
unique biologic features and unique response to non-chemotherapy treatments. APL is
characterized by the cytogenetic finding of t(15;17) and the fusion genePML-RAR alpha.
Among the other types of AML, cytogenetic studies are the most powerful prognostic factors.
Favorable cytogenetics such as t(8;21) and inv(16)(p13;q22) are seen in 15% of cases and
are, termed the "core-binding factor" leukemias because of common genetic lesions affecting
DNA-binding elements. These patients have a higher chance of achieving both short- and
long-term disease control. The majority of cases of AML are of intermediate risk and have
either normal cytogenetics or abnormalities that do not confer strong prognostic significance.
Within this large subgroup, a relatively favorable group of patients has been defined based on
a molecular signature that includes mutations of nucleophosmin 1 (NPM1) and lacks the
internal tandem duplication of theFLT3 gene. A poor prognosis is conferred by the
-
7/27/2019 Modul Tutor Sk 4
20/33
cytogenetics finding of monosomy 5 or 7, or complex cytogenetics with more than three
separate abnormalities.
In ALL, the hyperdiploidy (with more than 50 chromosomes) is associated with a better
prognosis, but is seldom seen in adults. Unfavorable cytogenetics in ALL are the Philadelphia
chromosome t(9;22) and t(4;11), which has fusion genes involving theMLL gene at 11q23.
Differential DiagnosisAML must be distinguished from other myeloproliferative disorders, chronic myeloid
leukemia, and myelodysplastic syndromes. Acute leukemia may also resemble a left-shifted
bone marrow recovering from a previous toxic insult. If the question is in doubt, a bone
marrow study should be repeated in several days to see if maturation has taken place. ALL
must be separated from other lymphoproliferative disease such as chronic lymphocytic
leukemia, lymphomas, and hairy cell leukemia. It may also be confused with the atypical
lymphocytosis of mononucleosis and pertussis
AML
Most patients with AML are treated with a combination of an anthracycline (daunorubicin or
idarubicin) plus cytarabine, either alone or in combination with other agents. This therapywill produce complete remissions in 80% of patients under age 60 years and in 5060% of
older patients (see Tables 393 and 394). APL is treated differently from other forms of
AML. Induction therapy should include an anthracycline plus all-trans-retinoic acid. With
this approach 9095% of patients will achieve complete remission. For patients with high-
risk APL based on an initial white blood cell count > 10,000/mcL, the addition of arsenic
trioxide may be beneficial, and the addition of this biologic agent may be helpful in other
cases as well.
Once a patient has entered remission, postremission therapy should be given with curative
intent whenever possible. Options include standard chemotherapy and autologous and
allogeneic transplantation. The optimal treatment strategy depends on the patient's age and
clinical status, and the risk factor profile of the leukemia. Significant advances have beenmade in the treatment of APL. With the use of all-trans retinoic acid, arsenic trioxide, and
chemotherapy, 90% of patients remain in long-term remission. Only the uncommon group of
high-risk patients (based on initial white blood cell count > 10,000/mcL) have not shared in
this favorable outcome, but studies of the potentially synergistic combination of retinoic acid
and arsenic trioxide may improve results here. For intermediate-risk patients with AML, cure
rates for postremission therapy are 3540% for chemotherapy, 4050% for autologous
transplantation, and 5060% for allogeneic transplantation. Some types of AML whose
cytogenetics involved core-binding factors have a more favorable prognosis, with cure rates
of 5060% with chemotherapy and 7080% with autologous transplantation. Patients who do
not enter remission or who have high-risk cytogenetics (such as monosomy 7 and complex
cytogenetics) do far more poorly and are rarely cured with chemotherapy. Allogeneictransplantation is the treatment of choice, but cure rates are only 2030%.
Once leukemia has recurred after initial chemotherapy, the prognosis is much more guarded.
For patients in second remission, transplantation (autologous or allogeneic) offers a 2040%
chance of cure. For those patients with APL who relapse, arsenic trioxide can produce second
remissions in 90% of cases, and autologous transplant in second remission produces cure
rates of 6070%.
AML
Acute myeloid leukemia (AML), also known as acute myelogenous leukemia oracute
nonlymphocytic leukemia (ANLL), is a cancerof the myeloid line of blood cells,
characterized by the rapid growth of abnormalwhite blood cells that accumulate in thebonemarrow and interfere with the production of normal blood cells. AML is the most common
http://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Myeloidhttp://en.wikipedia.org/wiki/White_blood_cellhttp://en.wikipedia.org/wiki/White_blood_cellhttp://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/wiki/Haematopoiesishttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Myeloidhttp://en.wikipedia.org/wiki/White_blood_cellhttp://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/wiki/Haematopoiesis -
7/27/2019 Modul Tutor Sk 4
21/33
acute leukemiaaffecting adults, and its incidence increases with age. Although AML is a
relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United
States,[1] its incidence is expected to increase as the population ages.
The symptoms of AML are caused by replacement of normal bone marrow with leukemic
cells, which causes a drop in red blood cells,platelets, and normal white blood cells. These
symptoms include fatigue, shortness of breath, easy bruising and bleeding, and increased riskof infection. Several risk factorsand chromosomal abnormalitieshave been identified, but the
specific cause is not clear. As an acute leukemia, AML progresses rapidly and is typically
fatal within weeks or months if left untreated.
AML has several subtypes; treatment and prognosis varies among subtypes. Five-year
survival varies from 1570%, and relapse rate varies from 3378%, depending on subtype.
AML is treated initially withchemotherapy aimed at inducing a remission; patients may go
on to receive additional chemotherapy or a hematopoietic stem cell transplant. Recent
research into the genetics of AML has resulted in the availability of tests that can predict
which drug or drugs may work best for a particular patient, as well as how long that patient is
likely to survive.
World Health Organization
The World Health Organization (WHO) classification of acute myeloid leukemia attempts to
be more clinically useful and to produce more meaningful prognostic information than the
FAB criteria. Each of the WHO categories contains numerous descriptive subcategories of
interest to the hematopathologist and oncologist; however, most of the clinically significant
information in the WHO schema is communicated via categorization into one of the subtypes
listed below.
The WHO subtypes of AML are:[2]
Name Description ICD-O
Acute myeloid
leukemia with
recurrent genetic
abnormalities
Includes: AML with translocations between chromosome 8and
21 [t(8;21)] (ICD-O 9896/3); RUNX1/RUNX1T1
AML with inversions in chromosome 16[inv(16)]
(ICD-O 9871/3); CBFB/MYH11
APL with translocations between chromosome 15and
17 [t(15;17)] (ICD-O 9866/3); RARA;PML
AML with translocations in chromosomes 9 and 11
[t(9;11)]; MLLT3-MLL
Patients with AML in this category generally have a high rate
of remission and a better prognosis compared to other types ofAML.
Multiple
AML with
multilineage
dysplasia
This category includes patients who have had a prior
myelodysplastic syndrome (MDS) ormyeloproliferative
disease (MPD) that transforms into AML. This category of
AML occurs most often in elderly patients and often has a
worse prognosis.
M9895/3
AML and MDS,
therapy-related
This category includes patients who have had prior
chemotherapy and/or radiation and subsequently develop AML
or MDS. These leukemias may be characterized by specific
chromosomal abnormalities, and often carry a worse prognosis.
M9920/3
AML not otherwise
categorized
Includes subtypes of AML that do not fall into the above
categories.M9861/3
http://en.wikipedia.org/wiki/Acute_leukemiahttp://en.wikipedia.org/wiki/Acute_leukemiahttp://en.wikipedia.org/wiki/Incidence_(epidemiology)http://en.wikipedia.org/wiki/Rare_diseasehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-cancerstats-1http://en.wikipedia.org/wiki/Red_blood_cellhttp://en.wikipedia.org/wiki/Platelethttp://en.wikipedia.org/wiki/Risk_factorshttp://en.wikipedia.org/wiki/Risk_factorshttp://en.wikipedia.org/wiki/Chromosome_abnormalityhttp://en.wikipedia.org/wiki/Chromosome_abnormalityhttp://en.wikipedia.org/wiki/Chemotherapyhttp://en.wikipedia.org/wiki/Chemotherapyhttp://en.wikipedia.org/wiki/Remission_(medicine)http://en.wikipedia.org/wiki/Hematopoietic_stem_cell_transplanthttp://en.wikipedia.org/wiki/World_Health_Organizationhttp://en.wikipedia.org/wiki/Hematopathologisthttp://en.wikipedia.org/wiki/Oncologisthttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-Vardiman-2http://en.wikipedia.org/wiki/ICD-Ohttp://en.wikipedia.org/wiki/Chromosome_8http://en.wikipedia.org/wiki/Chromosome_8http://en.wikipedia.org/wiki/RUNX1http://en.wikipedia.org/wiki/RUNX1T1http://en.wikipedia.org/wiki/Chromosome_16http://en.wikipedia.org/wiki/Chromosome_16http://en.wikipedia.org/wiki/CBFBhttp://en.wikipedia.org/wiki/MYH11http://en.wikipedia.org/wiki/Chromosome_15http://en.wikipedia.org/wiki/Chromosome_15http://en.wikipedia.org/wiki/Retinoic_acid_receptor_alphahttp://en.wikipedia.org/wiki/Promyelocytic_leukemia_proteinhttp://en.wikipedia.org/wiki/Myelodysplastic_syndromehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I98953/http://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I99203/http://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I98613/http://en.wikipedia.org/wiki/Acute_leukemiahttp://en.wikipedia.org/wiki/Incidence_(epidemiology)http://en.wikipedia.org/wiki/Rare_diseasehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-cancerstats-1http://en.wikipedia.org/wiki/Red_blood_cellhttp://en.wikipedia.org/wiki/Platelethttp://en.wikipedia.org/wiki/Risk_factorshttp://en.wikipedia.org/wiki/Chromosome_abnormalityhttp://en.wikipedia.org/wiki/Chemotherapyhttp://en.wikipedia.org/wiki/Remission_(medicine)http://en.wikipedia.org/wiki/Hematopoietic_stem_cell_transplanthttp://en.wikipedia.org/wiki/World_Health_Organizationhttp://en.wikipedia.org/wiki/Hematopathologisthttp://en.wikipedia.org/wiki/Oncologisthttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-Vardiman-2http://en.wikipedia.org/wiki/ICD-Ohttp://en.wikipedia.org/wiki/Chromosome_8http://en.wikipedia.org/wiki/RUNX1http://en.wikipedia.org/wiki/RUNX1T1http://en.wikipedia.org/wiki/Chromosome_16http://en.wikipedia.org/wiki/CBFBhttp://en.wikipedia.org/wiki/MYH11http://en.wikipedia.org/wiki/Chromosome_15http://en.wikipedia.org/wiki/Retinoic_acid_receptor_alphahttp://en.wikipedia.org/wiki/Promyelocytic_leukemia_proteinhttp://en.wikipedia.org/wiki/Myelodysplastic_syndromehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I98953/http://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I99203/http://en.wikipedia.org/wiki/ICD-Ohttp://www.progenetix.net/progenetix/I98613/ -
7/27/2019 Modul Tutor Sk 4
22/33
Acute leukemias of ambiguous lineage (also known as mixed phenotype orbiphenotypic
acute leukemia) occur when the leukemic cells can not be classified as either myeloid or
lymphoid cells, or where both types of cells are present.
French-American-British
The French-American-British (FAB) classification system divides AML into eight subtypes,M0 through to M7, based on the type of cell from which the leukemia developed and its
degree of maturity. This is done by examining the appearance of the malignant cells with
light microscopy and/or by using cytogenetics to characterize any underlying chromosomal
abnormalities. The subtypes have varying prognoses and responses to therapy. Although the
WHO classification (see above) may be more useful, the FAB system is still widely used.
Eight FAB subtypes were proposed in 1976.[3]
Type Name Cytogenetics
Percentage of
adult AML
patients
M0minimally differentiated acute myeloblastic
leukemia 5%[4]
M1acute myeloblastic leukemia, without
maturation15%[4]
M2acute myeloblastic leukemia, with
granulocytic maturation
t(8;21)(q22;q22),
t(6;9)25%[4]
M3promyelocytic, oracute promyelocytic
leukemia (APL)t(15;17) 10%[4]
M4 acute myelomonocytic leukemiainv(16)(p13q22),
del(16q)20%[4]
M4eo
myelomonocytic together with bone marrow
eosinophilia inv(16), t(16;16) 5%[4]
M5acute monoblastic leukemia (M5a) oracute
monocytic leukemia (M5b)
del (11q), t(9;11),
t(11;19)10%[4]
M6
acute erythroid leukemias, including
erythroleukemia (M6a) and very rare pure
erythroid leukemia (M6b)
5%[4]
M7 acute megakaryoblastic leukemia t(1;22) 5%[4]
The morphologic subtypes of AML also include rare types not included in the FAB system,
such as acute basophilic leukemia, which was proposed as a ninth subtype, M8, in 1999.[5]
Signs and symptomsMost signs and symptoms of AML are caused by the replacement of normal blood cells with
leukemic cells. A lack of normal white blood cell production makes the patient susceptible to
infections; while the leukemic cells themselves are derived from white blood cell precursors,
they have no infection-fighting capacity.[6]A drop in red blood cell count (anemia) can cause
fatigue, paleness, and shortness of breath. A lack ofplateletscan lead to easy bruising or
bleeding with minor trauma.
The early signs of AML are often vague and nonspecific, and may be similar to those of
influenza or other common illnesses. Some generalized symptoms include fever, fatigue,
weight loss orloss of appetite, shortness of breath, anemia, easy bruising or bleeding,
petechiae(flat, pin-head sized spots under the skin caused by bleeding), bone and joint pain,and persistent or frequent infections.[6]
http://en.wikipedia.org/wiki/Biphenotypic_acute_leukemiahttp://en.wikipedia.org/wiki/Biphenotypic_acute_leukemiahttp://en.wikipedia.org/wiki/Biphenotypic_acute_leukemiahttp://en.wikipedia.org/wiki/French-American-British_classificationhttp://en.wikipedia.org/wiki/Malignanthttp://en.wikipedia.org/wiki/Light_microscopyhttp://en.wikipedia.org/wiki/Cytogeneticshttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-3http://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_without_maturationhttp://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_without_maturationhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_with_granulocytic_maturationhttp://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_with_granulocytic_maturationhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_myelomonocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Eosinophilhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_monoblastic_leukemiahttp://en.wikipedia.org/wiki/Acute_monocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_monocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_erythroid_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_megakaryoblastic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_basophilic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-5http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-symptoms-6http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-symptoms-6http://en.wikipedia.org/wiki/Anemiahttp://en.wikipedia.org/wiki/Platelethttp://en.wikipedia.org/wiki/Platelethttp://en.wikipedia.org/wiki/Influenzahttp://en.wikipedia.org/wiki/Feverhttp://en.wikipedia.org/wiki/Fatigue_(physical)http://en.wikipedia.org/wiki/Fatigue_(physical)http://en.wikipedia.org/wiki/Weight_losshttp://en.wikipedia.org/wiki/Loss_of_appetitehttp://en.wikipedia.org/wiki/Dyspneahttp://en.wikipedia.org/wiki/Petechiahttp://en.wikipedia.org/wiki/Petechiahttp://en.wikipedia.org/wiki/Infectionshttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-symptoms-6http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-symptoms-6http://en.wikipedia.org/wiki/Biphenotypic_acute_leukemiahttp://en.wikipedia.org/wiki/Biphenotypic_acute_leukemiahttp://en.wikipedia.org/wiki/French-American-British_classificationhttp://en.wikipedia.org/wiki/Malignanthttp://en.wikipedia.org/wiki/Light_microscopyhttp://en.wikipedia.org/wiki/Cytogeneticshttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-3http://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Minimally_differentiated_acute_myeloblastic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_without_maturationhttp://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_without_maturationhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_with_granulocytic_maturationhttp://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia,_with_granulocytic_maturationhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_myelomonocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Eosinophilhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_monoblastic_leukemiahttp://en.wikipedia.org/wiki/Acute_monocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_monocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_erythroid_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_megakaryoblastic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-medscape-4http://en.wikipedia.org/wiki/Acute_basophilic_leukemiahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-5http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-symptoms-6http://en.wikipedia.org/wiki/Anemiahttp://en.wikipedia.org/wiki/Platelethttp://en.wikipedia.org/wiki/Influenzahttp://en.wikipedia.org/wiki/Feverhttp://en.wikipedia.org/wiki/Fatigue_(physical)http://en.wikipedia.org/wiki/Weight_losshttp://en.wikipedia.org/wiki/Loss_of_appetitehttp://en.wikipedia.org/wiki/Dyspneahttp://en.wikipedia.org/wiki/Petechiahttp://en.wikipedia.org/wiki/Infectionshttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-symptoms-6 -
7/27/2019 Modul Tutor Sk 4
23/33
Enlargement of the spleen may occur in AML, but it is typically mild and asymptomatic.
Lymph node swelling is rare in AML, in contrast to acute lymphoblastic leukemia. The skin
is involved about 10% of the time in the form ofleukemia cutis. Rarely, Sweet's syndrome, a
paraneoplasticinflammation of the skin, can occur with AML.[6]
Some patients with AML may experience swelling of the gums because of infiltration of
leukemic cells into the gum tissue. Rarely, the first sign of leukemia may be the developmentof a solid leukemic mass or tumor outside of thebone marrow, called a chloroma.
Occasionally, a person may show no symptoms, and the leukemia may be discovered
incidentally during a routineblood test.[7]
CausesA number of risk factors for developing AML have been identified, including: other blood
disorders, chemical exposures, ionizing radiation, and genetics.
Preleukemia
"Preleukemic" blood disorders, such as myelodysplastic syndrome ormyeloproliferative
disease, can evolve into AML; the exact risk depends on the type of MDS/MPS.[8]
Chemical exposure
Exposure to anticancer chemotherapy, in particularalkylating agents, can increase the risk of
subsequently developing AML. The risk is highest about three to five years after
chemotherapy.[9]Other chemotherapy agents, specificallyepipodophyllotoxinsand
anthracyclines, have also been associated with treatment-related leukemia. These treatment-
related leukemias are often associated with specific chromosomal abnormalities in the
leukemic cells.[10]
Occupational chemical exposure tobenzeneand other aromatic organic solventsis
controversial as a cause of AML. Benzene and many of its derivatives are known to be
carcinogenicin vitro. While some studies have suggested a link between occupationalexposure to benzene and increased risk of AML,[11] others have suggested the attributable
risk, if any, is slight.[12]
Radiation
Ionizing radiation exposure can increase the risk of AML. Survivors of the atomic bombings
of Hiroshima and Nagasaki had an increased rate of AML,[13]as didradiologists exposed to
high levels ofX-rays prior to the adoption of modern radiation safety practices. [14]
Genetics
A hereditary risk for AML appears to exist. Multiple cases of AML developing in a family at
a rate higher than predicted by chance alone have been reported. [15][16][17][18]The risk ofdeveloping AML is increased threefold in first-degree relatives of patients with AML.[19]
Several congenital conditions may increase the risk of leukemia; the most common is
probably Down syndrome, which is associated with a 10- to 18-fold increase in the risk of
AML.[20]
DiagnosisThe first clue to a diagnosis of AML is typically an abnormal result on a complete blood
count. While an excess of abnormal white blood cells (leukocytosis) is a common finding,
and leukemic blasts are sometimes seen, AML can also present with isolated decreases in
platelets, red blood cells, or even with a low white blood cell count (leukopenia).[21] While a
presumptive diagnosis of AML can be made via examination of theperipheral blood smear
http://en.wikipedia.org/wiki/Splenomegalyhttp://en.wikipedia.org/wiki/Asymptomatichttp://en.wikipedia.org/wiki/Lymphadenopathyhttp://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemiahttp://en.wikipedia.org/wiki/Chloromahttp://en.wikipedia.org/wiki/Sweet's_syndromehttp://en.wikipedia.org/wiki/Sweet's_syndromehttp://en.wikipedia.org/wiki/Paraneoplastic_syndromehttp://en.wikipedia.org/wiki/Paraneoplastic_syndromehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-symptoms-6http://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/wiki/Chloromahttp://en.wikipedia.org/wiki/Asymptomatichttp://en.wikipedia.org/wiki/Blood_testhttp://en.wikipedia.org/wiki/Blood_testhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-7http://en.wikipedia.org/wiki/Myelodysplastic_syndromehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-8http://en.wikipedia.org/wiki/Chemotherapyhttp://en.wikipedia.org/wiki/Alkylating_antineoplastic_agenthttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-9http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-9http://en.wikipedia.org/wiki/Podophyllotoxinhttp://en.wikipedia.org/wiki/Podophyllotoxinhttp://en.wikipedia.org/wiki/Podophyllotoxinhttp://en.wikipedia.org/wiki/Anthracyclinehttp://en.wikipedia.org/wiki/Anthracyclinehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-10http://en.wikipedia.org/wiki/Benzenehttp://en.wikipedia.org/wiki/Benzenehttp://en.wikipedia.org/wiki/Solventhttp://en.wikipedia.org/wiki/Solventhttp://en.wikipedia.org/wiki/Carcinogenichttp://en.wikipedia.org/wiki/Carcinogenichttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-11http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-11http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-12http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-12http://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Atomic_bombings_of_Hiroshima_and_Nagasakihttp://en.wikipedia.org/wiki/Atomic_bombings_of_Hiroshima_and_Nagasakihttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-13http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-13http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-13http://en.wikipedia.org/wiki/Radiologisthttp://en.wikipedia.org/wiki/Radiologisthttp://en.wikipedia.org/wiki/X-rayhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-14http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-15http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-16http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-17http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-18http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-18http://en.wikipedia.org/wiki/First_degree_relativehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-19http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-19http://en.wikipedia.org/wiki/Congenitalhttp://en.wikipedia.org/wiki/Down_syndromehttp://en.wikipedia.org/wiki/Down_syndromehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-20http://en.wikipedia.org/wiki/Complete_blood_counthttp://en.wikipedia.org/wiki/Complete_blood_counthttp://en.wikipedia.org/wiki/Leukocytosishttp://en.wikipedia.org/wiki/Platelethttp://en.wikipedia.org/wiki/Red_blood_cellhttp://en.wikipedia.org/wiki/Leukopeniahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-21http://en.wikipedia.org/wiki/Blood_filmhttp://en.wikipedia.org/wiki/Splenomegalyhttp://en.wikipedia.org/wiki/Asymptomatichttp://en.wikipedia.org/wiki/Lymphadenopathyhttp://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemiahttp://en.wikipedia.org/wiki/Chloromahttp://en.wikipedia.org/wiki/Sweet's_syndromehttp://en.wikipedia.org/wiki/Paraneoplastic_syndromehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-symptoms-6http://en.wikipedia.org/wiki/Bone_marrowhttp://en.wikipedia.org/wiki/Chloromahttp://en.wikipedia.org/wiki/Asymptomatichttp://en.wikipedia.org/wiki/Blood_testhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-7http://en.wikipedia.org/wiki/Myelodysplastic_syndromehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/Myeloproliferative_diseasehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-8http://en.wikipedia.org/wiki/Chemotherapyhttp://en.wikipedia.org/wiki/Alkylating_antineoplastic_agenthttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-9http://en.wikipedia.org/wiki/Podophyllotoxinhttp://en.wikipedia.org/wiki/Anthracyclinehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-10http://en.wikipedia.org/wiki/Benzenehttp://en.wikipedia.org/wiki/Solventhttp://en.wikipedia.org/wiki/Carcinogenichttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-11http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-12http://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Atomic_bombings_of_Hiroshima_and_Nagasakihttp://en.wikipedia.org/wiki/Atomic_bombings_of_Hiroshima_and_Nagasakihttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-13http://en.wikipedia.org/wiki/Radiologisthttp://en.wikipedia.org/wiki/X-rayhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-14http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-15http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-16http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-17http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-18http://en.wikipedia.org/wiki/First_degree_relativehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-19http://en.wikipedia.org/wiki/Congenitalhttp://en.wikipedia.org/wiki/Down_syndromehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-20http://en.wikipedia.org/wiki/Complete_blood_counthttp://en.wikipedia.org/wiki/Complete_blood_counthttp://en.wikipedia.org/wiki/Leukocytosishttp://en.wikipedia.org/wiki/Platelethttp://en.wikipedia.org/wiki/Red_blood_cellhttp://en.wikipedia.org/wiki/Leukopeniahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-21http://en.wikipedia.org/wiki/Blood_film -
7/27/2019 Modul Tutor Sk 4
24/33
-
7/27/2019 Modul Tutor Sk 4
25/33
properties may cause the "differentiation arrest".[31] For example, in acute promyelocytic
leukemia, the t(15;17) translocation produces a PML-RARfusion protein which binds to the
retinoic acid receptor element in the promoters of several myeloid-specific genes and inhibits
myeloid differentiation.[32]
The clinical signs and symptoms of AML result from the growth of leukemic clone cells,
which tends to displace or interfere with the development of normal blood cells in the bonemarrow.[33]This leads to neutropenia, anemia, and thrombocytopenia. The symptoms of AML
are, in turn, often due to the low numbers of these normal blood elements. In rare cases,
patients can develop a chloroma, or solid tumor of leukemic cells outside the bone marrow,
which can cause various symptoms depending on its location.[6]
TreatmentFirst-line treatment of AML consists primarily ofchemotherapy, and is divided into two
phases: induction and postremission (orconsolidation) therapy. The goal of induction
therapy is to achieve a complete remission by reducing the number of leukemic cells to an
undetectable level; the goal of consolidation therapy is to eliminate any residual undetectable
disease and achieve a cure.[34]Hematopoietic stem cell transplantation is usually considered ifinduction chemotherapy fails or after a patient relapses, although transplantation is also
sometimes used as front-line therapy for patients with high-risk disease.
Induction
All FAB subtypes except M3 are usually given induction chemotherapy with cytarabine(ara-
C) and an anthracycline(such as daunorubicin oridarubicin).[35] This induction chemotherapy
regimen is known as "7+3" (or "3+7"), because the cytarabine is given as a continuous IV
infusion for seven consecutive days while theanthracyclineis given for three consecutive
days as an IV push. Up to 70% of patients will achieve a remission with this protocol. [36]
Other alternative induction regimens, including high-dose cytarabine alone or investigational
agents, may also be used.[37][38]Because of the toxic effects of therapy, including
myelosuppression and an increased risk of infection, induction chemotherapy may not be
offered to the very elderly, and the options may include less intense chemotherapy or
palliative care.
The M3 subtype of AML, also known as acute promyelocytic leukemia(APL), is almost
universally treated with the drug all-trans-retinoic acid (ATRA ) in addition to induction
chemotherapy, usually an anthracycline.[39][40][41] Care must be taken to prevent disseminated
intravascular coagulation (DIC), complicating the treatment of APL when the promyelocytes
release the contents of their granules into the peripheral circulation. APL is eminently
curable, with well-documented treatment protocols.
The goal of the induction phase is to reach a complete remission. Complete remission doesnot mean the disease has been cured; rather, it signifies no disease can be detected with
available diagnostic methods.[35] Complete remission is obtained in about 50%75% of newly
diagnosed adults, although this may vary based on the prognostic factors described above.[42]
The length of remission depends on the prognostic features of the original leukemia. In
general, all remissions will fail without additional consolidation therapy.[43]
Consolidation
Even after complete remission is achieved, leukemic cells likely remain in numbers too small
to be detected with current diagnostic techniques. If no further postremission or consolidation
therapy is given, almost all patients will eventually relapse.[44]Therefore, more therapy is
necessary to eliminate nondetectable disease and prevent relapse that is, to achieve a cure.
http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-31http://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Fusion_proteinhttp://en.wikipedia.org/wiki/Fusion_proteinhttp://en.wikipedia.org/wiki/Retinoic_acidhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-32http://en.wikipedia.org/wiki/Medical_signhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-33http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-33http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-33http://en.wikipedia.org/wiki/Neutropeniahttp://en.wikipedia.org/wiki/Anemiahttp://en.wikipedia.org/wiki/Thrombocytopeniahttp://en.wikipedia.org/wiki/Thrombocytopeniahttp://en.wikipedia.org/wiki/Chloromahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-symptoms-6http://en.wikipedia.org/wiki/Chemotherapyhttp://en.wikipedia.org/wiki/Chemotherapyhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-34http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-34http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-34http://en.wikipedia.org/wiki/Cytarabinehttp://en.wikipedia.org/wiki/Cytarabinehttp://en.wikipedia.org/wiki/Anthracyclinehttp://en.wikipedia.org/wiki/Anthracyclinehttp://en.wikipedia.org/wiki/Daunorubicinhttp://en.wikipedia.org/wiki/Idarubicinhttp://en.wikipedia.org/wiki/Idarubicinhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-treatment-35http://en.wikipedia.org/wiki/Cytarabinehttp://en.wikipedia.org/wiki/Anthracyclinehttp://en.wikipedia.org/wiki/Anthracyclinehttp://en.wikipedia.org/wiki/Anthracyclinehttp://en.wikipedia.org/wiki/IV_pushhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-36http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-36http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-37http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-38http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-38http://en.wikipedia.org/wiki/Myelosuppressionhttp://en.wikipedia.org/wiki/Palliative_carehttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/ATRAhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-39http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-40http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-41http://en.wikipedia.org/wiki/Disseminated_intravascular_coagulationhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-treatment-35http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-42http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-42http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-42http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-43http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-44http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-44http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-44http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-31http://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/Fusion_proteinhttp://en.wikipedia.org/wiki/Retinoic_acidhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-32http://en.wikipedia.org/wiki/Medical_signhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-33http://en.wikipedia.org/wiki/Neutropeniahttp://en.wikipedia.org/wiki/Anemiahttp://en.wikipedia.org/wiki/Thrombocytopeniahttp://en.wikipedia.org/wiki/Chloromahttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-symptoms-6http://en.wikipedia.org/wiki/Chemotherapyhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-34http://en.wikipedia.org/wiki/Cytarabinehttp://en.wikipedia.org/wiki/Anthracyclinehttp://en.wikipedia.org/wiki/Daunorubicinhttp://en.wikipedia.org/wiki/Idarubicinhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-treatment-35http://en.wikipedia.org/wiki/Cytarabinehttp://en.wikipedia.org/wiki/Anthracyclinehttp://en.wikipedia.org/wiki/IV_pushhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-36http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-37http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-38http://en.wikipedia.org/wiki/Myelosuppressionhttp://en.wikipedia.org/wiki/Palliative_carehttp://en.wikipedia.org/wiki/Acute_promyelocytic_leukemiahttp://en.wikipedia.org/wiki/ATRAhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-39http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-40http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-41http://en.wikipedia.org/wiki/Disseminated_intravascular_coagulationhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-treatment-35http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-42http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-43http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-44 -
7/27/2019 Modul Tutor Sk 4
26/33
The specific type of postremission therapy is individualized based on a patient's prognostic
factors (see above) and general health. For good-prognosis leukemias (i.e. inv(16), t(8;21),
and t(15;17)), patients will typically undergo an additional three to five courses of intensive
chemotherapy, known as consolidation chemotherapy.[45][46] For patients at high risk of relapse
(e.g. those with high-risk cytogenetics, underlying MDS, or therapy-related AML), allogeneic
stem cell transplantationis usually recommended if the patient is able to tolerate a transplantand has a suitable donor. The best postremission therapy for intermediate-risk AML (normal
cytogenetics or cytogenetic changes not falling into good-risk or high-risk groups) is less
clear and depends on the specific situation, including the age and overall health of the patient,
the patient's personal values, and whether a suitable stem cell donor is available.[46]
For patients who are not eligible for a stem cell transplant, immunotherapy with a
combination of histamine dihydrochloride (Ceplene) and interleukin 2 (Proleukin) after the
completion of consolidation has been shown to reduce the absolute relapse risk by 14%,
translating to a 50% increase in the likelihood of maintained remission. [47]
Relapsed AML
For patients with relapsed AML, the only proven potentially curative therapy is ahematopoietic stem cell transplant, if one has not already been performed.[48][49][50] In 2000, the
monoclonal antibody-linked cytotoxic agent gemtuzumab ozogamicin(Mylotarg) was
approved in the United States for patients aged more than 60 years with relapsed AML who
are not candidates for high-dose chemotherapy.[51]
Since treatment options for relapsed AML are so limited,palliative care may be offered.
Clinical trials
Patients with relapsed AML who are not candidates for stem cell transplantion, or who have
relapsed after a stem cell transplant, may be offered treatment in a clinical trial, as
conventional treatment options are limited. Agents under investigation include cytotoxic
drugs such as clofarabine, as well as targeted therapies, such as farnesyl transferaseinhibitors, decitabine, and inhibitors of MDR1 (multidrug-resistance protein).
Chronic Myeloid Leukemia
Essentials of Diagnosis
Elevated white blood count.
Markedly left-shifted myeloid series but with a low percentage of promyelocytes and
blasts.
Presence of Philadelphia chromosome orbcr/ablgene.
General Considerations
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized byoverproduction of myeloid cells. These myeloid cells retain the capacity for differentiation,
and normal bone marrow function is retained during the early phases.
CML is characterized by a specific chromosomal abnormality and specific molecular
abnormality. The Philadelphia chromosome is a reciprocal translocation between the long
arms of chromosomes 9 and 22. A large portion of 22q is translocated to 9q, and a smaller
piece of 9q is moved to 22q. The portion of 9q that is translocated contains abl, a
protooncogene that is the cellular homolog of the Ableson murine leukemia virus. The abl
gene is received at a specific site on 22q, the break point cluster (bcr). The fusion gene
bcr/ablproduces a novel protein that differs from the normal transcript of the ablgene in that
it possesses tyrosine kinase activity (a characteristic activity of transforming genes). Evidence
that the bcr/ablfusion gene is pathogenic is provided by transgenic mouse models in whichintroduction of the gene almost invariably leads to leukemia.
http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-45http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-nccn-46http://en.wikipedia.org/wiki/Bone_marrow_transplanthttp://en.wikipedia.org/wiki/Bone_marrow_transplanthttp://en.wikipedia.org/wiki/Bone_marrow_transplanthttp://en.wikipedia.org/wiki/Stem_cellhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-nccn-46http://en.wikipedia.org/wiki/Ceplenehttp://en.wikipedia.org/wiki/Interleukin_2http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-47http://en.wikipedia.org/wiki/Hematopoietic_stem_cell_transplanthttp://en.wikipedia.org/wiki/Hematopoietic_stem_cell_transplanthttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-relapse-48http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-49http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-50http://en.wikipedia.org/wiki/Monoclonal_antibodyhttp://en.wikipedia.org/wiki/Gemtuzumab_ozogamicinhttp://en.wikipedia.org/wiki/Gemtuzumab_ozogamicinhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-51http://en.wikipedia.org/wiki/Palliative_carehttp://en.wikipedia.org/wiki/Clinical_trialhttp://en.wikipedia.org/wiki/Clofarabinehttp://en.wikipedia.org/wiki/Targeted_therapyhttp://en.wikipedia.org/wiki/Farnesyltransferase_inhibitorhttp://en.wikipedia.org/wiki/Farnesyltransferase_inhibitorhttp://en.wikipedia.org/wiki/Multidrug_resistancehttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-45http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-nccn-46http://en.wikipedia.org/wiki/Bone_marrow_transplanthttp://en.wikipedia.org/wiki/Bone_marrow_transplanthttp://en.wikipedia.org/wiki/Stem_cellhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-nccn-46http://en.wikipedia.org/wiki/Ceplenehttp://en.wikipedia.org/wiki/Interleukin_2http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-47http://en.wikipedia.org/wiki/Hematopoietic_stem_cell_transplanthttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-relapse-48http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-49http://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-50http://en.wikipedia.org/wiki/Monoclonal_antibodyhttp://en.wikipedia.org/wiki/Gemtuzumab_ozogamicinhttp://en.wikipedia.org/wiki/Acute_myeloid_leukemia#cite_note-51http://en.wikipedia.org/wiki/Palliative_carehttp://en.wikipedia.org/wiki/Clinical_trialhttp://en.wikipedia.org/wiki/Clofarabinehttp://en.wikipedia.org/wiki/Targeted_therapyhttp://en.wikipedia.org/wiki/Farnesyltransferase_inhibitorhttp://en.wikipedia.org/wiki/Farnesyltransferase_inhibitorhttp://en.wikipedia.org/wiki/Multidrug_resistance -
7/27/2019 Modul Tutor Sk 4
27/33
Early CML ("chronic phase") does not behave like a malignant disease. Normal bone marrow
function is retained, white blood cells differentiate and, despite some qualitative
abnormalities, the neutrophils combat infection normally. However, CML is inherently
unstable, and without treatment the disease progresses to an accelerated and then acute blast
phase, which is morphologically indistinguishable from acute leukemia. In recent years,
remarkable advances in therapy have changed the natural history of the disease, and therelentless progression to more advanced stages of disease is at least greatly delayed, if not
eliminated.
Clinical Findings
Symptoms and Signs
CML is a disorder of middle age (median age at presentation is 55 years). Patients usually
present with fatigue, night sweats, and low-grade fever related to the hypermetabolic state
caused by overproduction of white blood cells. At other times, the patient complains of
abdominal fullness related to splenomegaly. In some cases, especially with the increased used
of laboratory tests, an elevated white blood count is discovered incidentally. Rarely, the
patient will present with a clinical syndrome related to leukostasis with blurred vision,
respiratory distress, or priapism. The white blood count in these cases is usually greater than
500,000/mcL.
On examination, the spleen is enlarged (often markedly so), and sternal tenderness may be
present as a sign of marrow overexpansion. In cases discovered during routine laboratory
monitoring, these findings are often absent.
Acceleration of the disease is often associated with fever in the absence of infection, bone
pain, and splenomegaly.
Laboratory Findings
The hallmark of CML is an elevated white blood count; the median white blood count at
diagnosis is 150,000/mcL, although in some cases the white blood cell count is only modestly
increased (Table 1314). The peripheral blood is characteristic (see micrograph). Themyeloid series is left-shifted, with mature forms dominating and with cells usually present in
proportion to their degree of maturation. Blasts are usually less than 5%. Basophilia and
eosinophilia of granulocytes may be present. At presentation, the patient is usually not
anemic. Red blood cell morphology is normal, and nucleated red blood cells are rarely seen.
The platelet count may be normal or elevated (sometimes to strikingly high levels .The bone
marrow is hypercellular, with left-shifted myelopoiesis (see micrograph). Myeloblasts
comprise less than 5% of marrow cells
The hallmark of the disease is that the bcr/ablgene is detected in the peripheral blood. This is
best done by the polymerase chain reaction (PCR) test, which has now supplanted
cytogenetics. A bone marrow examination is not necessary for diagnosis, although it is useful
for prognosis and for detecting additional chromosomal abnormalities in addition to the
Philadelphia chromosome.
With progression to the accelerated and blast phases, progressive anemia and
thrombocytopenia occur, and the percentage of blasts in the blood and bone marrow increases
(see micrograph). Blast phase CML is diagnosed when blasts comprise more than 30% of
bone marrow cells.
Differential Diagnosis
Early CML must be differentiated from the reactive leukocytosis associated with infection. In
such cases, the white blood count is usually less than 50,000/mcL, splenomegaly is absent,
and the bcr/ablgene is not present.
-
7/27/2019 Modul Tutor Sk 4
28/33
-
7/27/2019 Modul Tutor Sk 4
29/33
cytogenetic abnormalities in the bone marrow are characteristic of myelodysplasia. Some
patients with an indolent form of the disease have an isolated partial deletion of chromosome
5 (5q syndrome). The presence of other abnormalities such as monosomy 7 or complex
abnormalities is associated with more aggressive disease
Differential Diagnosis
In subtle cases, cytogenetic evaluation of the bone marrow may help distinguish this clonaldisorder from other causes of cytopenias. As the number of blasts increases in the bone
marrow, myelodysplasia is arbitrarily separated from acute myeloid leukemia by the presence
of less than 20% blasts
Acute Leukemia
Essentials of Diagnosis
Short duration of symptoms, including fatigue, fever, and bleeding.
Cytopenias or pancytopenia.
More than 20% blasts in the bone marrow.
Blasts in peripheral blood in 90% of patients.
Classify as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).
General Considerations
Acute leukemia is a malignancy of the hematopoietic progenitor cell. These cells proliferate
in an uncontrolled fashion and replace normal bone marrow elements. Most cases arise with
no clear cause. However, radiation and some toxins (benzene) are leukemogenic. In addition,
a number of chemotherapeutic agents (especially cyclophosphamide, melphalan, other
alkylating agents, and etoposide) may cause leukemia. The leukemias seen after toxin or
chemotherapy exposure often develop from a myelodysplastic prodrome and are often
associated with abnormalities in chromosomes 5 and 7, and those related to etoposide may
have abnormalities in chromosome 11q23.
Much has been learned about the molecular biology of the leukemias. One subtype, acutepromyelocytic leukemia (APL), is characterized by chromosomal translocation t(15;17),
which produces the fusion genePML-RAR which interacts with the retinoic acid receptor to
produce a block in differentiation that can be overcome with pharmacologic doses of retinoic
acid (see below).
Most of the clinical findings in acute leukemia are due to replacement of normal bone
marrow elements by the malignant cell. Less common manifestations result from organ
infiltration (skin, gastrointestinal tract, meninges). Acute leukemia is potentially curable with
combination chemotherapy.
Acute lymphoblastic leukemia (ALL) comprises 80% of the acute leukemias of childhood.
The peak incidence is between 3 and 7 years of age. It is also seen in adults, causing
approximately 20% of adult acute leukemias. Acute myeloid leukemia (AML) is primarily anadult disease with a median age at presentation of 60 years and an increasing incidence with
advanced age.
Clinical Findings
Symptoms and Signs
Most patients have been ill only for days or weeks. Bleeding (usually due to
thrombocytopenia) occurs in the skin and mucosal surfaces, with gingival bleeding, epistaxis,
or menorrhagia. Less commonly, widespread bleeding is seen in patients with disseminated
intravascular coagulation (DIC) (in APL and monocytic leukemia). Infection is due to
neutropenia, with the risk of infection rising as the neutrophil count falls below 500/mcL;
with neutrophil counts less than 100/mcL, infection within days is the rule. The mostcommon pathogens are gram-negative bacteria (Escherichia coli, Klebsiella, Pseudomonas)
-
7/27/2019 Modul Tutor Sk 4
30/33
-
7/27/2019 Modul Tutor Sk 4
31/33
Among the other types of AML, cytogenetic studies are the most powerful prognostic factors.
Favorable cytogenetics such as t(8;21) and inv(16)(p13;q22) are seen in 15% of cases and
are, termed the "core-binding factor" leukemias because of common genetic lesions affecting
DNA-binding elements. These patients have a higher chance of achieving both short- and
long-term disease control. The majority of cases of AML are of intermediate risk and have
either normal cytogenetics or abnormalities that do not confer strong prognostic significance.Within this large subgroup, a relatively favorable group of patients has been defined based on
a molecular signature that includes mutations of nucleophosmin 1 (NPM1) and lacks the
internal tandem duplication of theFLT3 gene. A poor prognosis is conferred by the
cytogenetics finding of monosomy 5 or 7, or complex cytogenetics with more than three
separate abnormalities.
In ALL, the hyperdiploidy (with more than 50 chromosomes) is associated with a better
prognosis, but is seldom seen in adults. Unfavorable cytogenetics in ALL are the Philadelphia
chromosome t(9;22) and t(4;11), which has fusion genes involving theMLL gene at 11q23.
Differential Diagnosis
AML must be distinguished from other myeloproliferative disorders, chronic myeloid
leukemia, and myelodysplastic syndromes. Acute leukemia may also resemble a left-shifted
bone marrow recovering from a previous toxic insult. If the question is in doubt, a bone
marrow study should be repeated in several days to see if maturation has taken place. ALL
must be separated from other lymphoproliferative disease such as chronic lymphocytic
leukemia, lymphomas, and hairy cell leukemia. It may also be confused with the atypical
lymphocytosis of mononucleosis and pertussis
AML
Most patients with AML are treated with a combination of an anthracycline (daunorubicin or
idarubicin) plus cytarabine, either alone or in combination with other agents. This therapy
will produce complete remissions in 80% of patients under age 60 years and in 5060% of
older patients (see Tables 393 and 394). APL is treated differently from other forms ofAML. Induction therapy should include an anthracycline plus all-trans-retinoic acid. With
this approach 9095% of patients will achieve complete remission. For patients with high-
risk APL based on an initial white blood cell count > 10,000/mcL, the addition of arsenic
trioxide may be beneficial, and the addition of this biologic agent may be helpful in other
cases as well.
Once a patient has entered remission, postremission therapy should be given with curative
intent whenever possible. Options include standard chemotherapy and autologous and
allogeneic transplantation. The optimal treatment strategy depends on the patient's age and
clinical status, and the risk factor profile of the leukemia. Significant advances have been
made in the treatment of APL. With the use of all-trans retinoic acid, arsenic trioxide, and
chemotherapy, 90% of patients remain in long-term remission. Only the uncommon group ofhigh-risk patients (based on initial white blood cell count > 10,000/mcL) have not shared in
this favorable outcome, but studies of the potentially synergistic combination of retinoic acid
and arsenic trioxide may improve results here. For intermediate-risk patients with AML, cure
rates for postremission therapy are 3540% for chemotherapy, 4050% for autologous
transplantation, and 5060% for allogeneic transplantation. Some types of AML whose
cytogenetics involved core-binding factors have a more favorable prognosis, with cure rates
of 5060% with chemotherapy and 7080% with autologous transplantation. Patients who do
not enter remission or who have high-risk cytogenetics (such as monosomy 7 and complex
cytogenetics) do far more poorly and are rarely cured with chemotherapy. Allogeneic
transplantation is the treatment of choice, but cure rates are only 2030%.
-
7/27/2019 Modul Tutor Sk 4
32/33
-
7/27/2019 Modul Tutor Sk 4
33/33
different, characterized by larger and more immature cells. In 510% of cases, CLL may be
complicated by autoimmune hemolytic anemia or autoimmune thrombocytopenia. In
approximately 5% of cases, while the systemic disease remains stable, an isolated lymph
node transforms into an aggressive large cell lymphoma (Richter syndrome).
Laboratory Findings
The hallmark of CLL is isolated lymphocytosis. The white blood count is usually greater than20,000/mcL and may be markedly elevated to several hundred thousand. Usually 7598% of
the circulating cells are lymphocytes. Lymphocytes appear small and mature, with condensed
nuclear chromatin, and are morphologically indistinguishable from normal small
lymphocytes, but smaller numbers of larger and activated lymphocytes may be seen. The
hematocrit and platelet count are usually normal at presentation. The bone marrow is variably
infiltrated with small lymphocytes (see micrograph); (see micrograph). The
immunophenotype of CLL demonstrates coexpression of the B lymphocyte lineage marker
CD19 with the T lymphocyte marker CD5; this finding is commonly observed only in CLL
and mantle cell lymphoma. CLL is distinguished from mantle cell lymphoma by the
expression of CD23, low expression of surface immunoglobulin and CD20, and the absence
of overexpression of cyclin D1. Patients whose CLL cells have mutated forms of the
immunoglobulin gene (which can currently be tested only in research laboratories) have a
more indolent form of disease; these cells typically express low levels of the surface antigen
CD38 and do not express the zeta-associated protein (ZAP-70). Conversely, patients whose
cells have unmutated IgV genes and high levels of ZAP-70 expression do less well. The
assessment of genomic changes by fluorescence in-situ hybridization (FISH) provides
important prognostic information. The finding of deletions of chromosome 17p or 11q
confers a poor prognosis, whereas those whose only genomic change is deletion of 13q have
a very favorable outcome.
Differential Diagnosis
Few syndromes can be confused with CLL. Viral infections producing lymphocytosis shouldbe obvious from the presence of fever and other clinical findings; however, fever may occur
in CLL from concomitant bacterial infection. Pertussis may cause a particularly high total
lymphocyte count. Other lymphoproliferative diseases such as Waldenstrm
macroglobulinemia, hairy cell leukemia, or lymphoma (especially mantle cell) in the
leukemic phase are distinguished on the basis of the morphology and immunophenotype of
circulating lymphocytes and bone