Modul Tutor Sk 4

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Tim Kurikulum Pendidikan Preklinik

Fakultas Kedokteran

Universitas Islam Malang

2 0 13

MODUL TUTORSKENARIO KEEMPAT

NAMA MAHASISWA : .... .. ... .... ...

KELOMPOK : .................


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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 ?


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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


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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


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- 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)


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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


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5. Baca tentang alur penegakan diagnosa pada AML

6. Baca tentang Penatalaksanaan AML

7. Baca Maping Konsep

8. Baca Maping Kasus


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4.MAPPING KONSEP

HEMATOPOESIS JALUR MYELOID & LYMPHOID


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WBC DISORDERS

Disorder Type Target

Granulosit Neurophilia Proliferasi Progenitor SelInefektif granulopoesis

Apoptosis

Fungsi Fagosit Congenital abnormality CorticosteroidLeukemic cell

Chemotaxis Defect Opsonisasi


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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


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Proses Penegakan Diagnosa Pasien dg Febris menggigil

PROSES PENEGAKAN DIAGNOSA PASIEN

DENGAN FEBRIS/DEMAM AKUT


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INISIASI & METASTASIS TUMOR

FAB CLASIFICATION OF AML

JALUR LIMFOIDJALUR MYELOID

SELPLASMA

SINDROMAMYELODISPLASIA

LEUKEMIALIMFOBLASTIKLEUKEMIA

MYELOID


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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/


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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


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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


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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


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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


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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


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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
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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
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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]
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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
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ute_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


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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.
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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


Elevated white blood count.

Markedly left-shifted myeloid series but with a low percentage of promyelocytes and

blasts.

Presence of Philadelphia chromosome orbcr/ablgene.


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.
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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.


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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


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


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).


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)


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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.


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%.


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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.


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

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