Chap 109. Aplastic anemia, myelodysplasia,

and related BM failure syndromes

marrow damage õ hypoproliferative anemias

i) aplastic anemia, myelodysplasia(MDS)

ii) pure red cell aplasia(PRCA)

iii) myelophthisis ִ.

̷ ȯ鿡 normochromic, normocyticϰų macrocyticϰ low reti count

Ư¡̴.

BM failure, pancytopenia(anemia, leukopenia & thrombocytopenia) deficient

hematopoiesis ϸ, ̴ red cell(hemolytic anemia), plt(ITP or splenomegaly),

granulocytes(immune leukopenias) peripheral destruction blood count

depression ȴ.

hematopoietic stem cell syndromes dominant morphologic feature

зҼ ִ(Tab 109-1).

I. Aplastic anemia

1.

pancytopenia + BM hypocellularity Ѵ.

acquired AA intensive cytotoxic chemotherapy marrow hypocellularity ߻ϴ

iatrogenic marrow aplasia ȴ. AA Ÿ ִ(genetic disease

Fandoni's anemia).

δ blood count depression moderate or incompleteϴ. AA PNH, MDS Ѵٿ

ְ 쿡 и 谡 Ұϴ.

2.

̽󿤿 󵵴 ų 鸸 2case, ± ߱ 5-7̸

ϴ.

biphasic age distribution δ(older children & young adult, elderly)

3. Tab 109-2

κ idiopathic

radiation

marrow aplasia 缱 ֿ ޼պ̴. 缱 DNA ջŲ.

active mitosisϴ ջDZ .

chemicals

benzene BM failure ̴. leukemia߻ ü ⷮ 뷫

߿ϴ.

drugs(Tab 109-3)

ȭġ marrow suppression Ų.

ȿ 뷮 Ѵ.

ݴ idiosyncratic reaction ѷ 뷮- aplastic anemia Ű⵵

Ѵ.

chloramphenicol ̸ 1/60,000 󵵷 aplasia ǰ ִ.

న̴. posthepatitis marrow failure 1-2

ΰ ȸ ڿ . subsequent pancytopenia ſ ϴ.

seronegative(non-A, non-B, con-G)̰ ߰ߵ novel virus .

AA 幰 infectious mononucleosisĞo ִµ EBV AAȯ

߰ߵǾ.

Parvovirus B19 hemolytic anemia Ͻ aplastic crisis PRCA ̸

generalized BM failure Ű ʴ´.

blood count depression viral & bacterial infection ߵ̰

Բ ȸȴ.

immunologic disease

aplasia transfusion-associated GVHD ֿպ̸ ̴.

GVHD unirradiated blood products 鿪ȯڿ Ŀ ߻Ѵ.

AA eosinophil fasciitis θ 幮 collagen vascular syndrome ϰ ִ.

pancytopenia with marrow hypoplasia SLE ִ.

pregnancy: ӽŽ ſ 幰 и Ȥ ȸDZ⵵ Ѵ.

PNH

hematopoietic stem cell PIG-A gene acquired mutation ߻Ѵ.

PIG-A mutant stem cell ϸ GPI-linked cell surface membrane proteins

ȴ.

PNH cells Ham or sucrose lysis test granulocyte flow cytometry

(CD55 or CD59) Ȯ ˼ ִ.

PNH ۵ ȯ(Ư ȯ) ߿ frank marrow aplasia & pancytopenia

ϱ⵵ Ѵ.

congenital disorders

i) Fanconi's anemia: progressive pancytopenia, congenital developmental anomalies

malignancy risk, short stature, cafe au lait spot,

thumb, radium, genitourinary tract anomalies

mc type A Fanconi's anemia(FANCA mutation )

ii) Shwachma-Diamond syndrome: pancreatic insufficiency, malabsorption, neutropenia

4. »

BM failure hematopoietic cell compartment severe damage Ѵ.

AA BM ä ˿ ִ.

early hematopoietic cells marker CD34 Ag ũ Ѵ.

primitive progenitor cells .

1) drug injury

๰ highly reactive electrophilic compounds صǴµ ̴ toxicϴ.

2) immune-mediated injury

ALG BMT غϴ Ϻȯڿ ȸ AA immune-mediated û

Ѵ. ˻ Ұ AA immune system ߿ ޹ħѴ.

ȯڿ blood & BM cells hematopoietic progenitor cell growth ϰ AA BM

κ T cell ϸ colony formation ȣȴ.

AA activated cytotoxic T cell ǰ 鿪ġ

Ѵ. cytokine predominant TH1 immune response(IFN-, IL-2, TNF) û

Ѵ.

IFN & TNF CD34 cells Fas expression ϸ ̴ apoptotic cell death

Ų.

5. ӻƯ¡

1) History

ڱ Ȥ Ҽ ִ.

ʱ̴. Ͽ ְ , ġ, , ȣ

ϸ δ ݵȴ.

thrombocytopenia, massive hemolysis ġ CNS ҷ catastrophic

intracranial or retinal hemorrhage ų ִ. (lassitude, weakness, SOB)

ϴ.

ġ ù ̴. ü߰Ҵ pancytopenia ٸ

ؾ Ѵ. drug history, chemical exposure, ϴ ̷ ȯ ݺ

س Ѵ.

2) P/E

petechiae & ecchymosis retinal hemorrhage ̱⵵ Ѵ.

Ǻ â ϴ.

ġ ְ ִ ȯڿ ִ.

lymphadenopathy & splenomegaly A.A ſ ̴.

Cafe au lait spot & short stature Fanconi's anemia Ѵ.

6. Lab

1) Blood

PB smear: large erythrocyte ̰ , ʴ´.

MCV ǰ reticulocyte ų 幰.

lymphocyte ̰ų

immature myeloid forms ϶ leukemia or MDS ûѴ.

2) BM

Ҽ ϸ 񼮵ȴ. ׸ fatty biopsy ϴ.

"dry tap" fibrosis or myelophthisis ûѴ.

severe A.A aspirated specimen smear , residual lymphocytes, stromal

cells δ.

Bx(1cm̻ ؾ Ѵ) cellularity ϴµ ϸ ̰Ͽ fat,

hematopoietic cell ִ.(AA: marrow space 25%̸)

κ 쿡 Bx 100% fat̴. marrow cellularity & disease severity

ҿϴ.

3) Ancillary studies

chromosome breakage studies Fanconi's anemia ϱ Ǿ Ѵ.

Flow cytometric assays PNHܿ Ham test üߴ.

7.

pancytopenia + fatty, empty BM ܵȴ.

pancytopenia 2϶ primary diagnosis ° и ִ.

> massive spleen of alcoholic cirrhosis

metastatic cancer or SLE Hx, miliary Tbc

A.A hypocellular MDS ϱⰡ ƴ. ̻(Ư megakaryocytes,

myeloid precursor cells), typical cytogenetic abnormalities MDS .

8.

severe A.A ް ȭǾ ̸.

RBC & later platelet transfusion, effective antibiotics ణ DZ⵵ ڿ

ȸǴ ȯڴ . ĸ ϴ ڴ blood count̴. severe disease

2 Ҷ Ѵ.

i) absolute neutrophil count < 500/uL

ii) platelet count < 20,000/uL

iii) corrected reti count < 1%(absolute reti count < 50,000/uL)

ȯ 1 20%̴.

very severe dsȯ(absolute neutrophil count < 200/uL) .

̷ 쿡 ġ Ǿ.

9. ġ

underlying marrow failure ȸϰ pancytopenia supportive care ϴ

̴. severe acquired A.A absent hematopoietic cells replacementϰ, stem cell

transplant, ȯ residual BM function ȸϵ 鿪踦 ν ġų

ִ. hematopoietic growth factor 뼺 ѵǰ glucocorticoid ġ . ǽ

Ǵ ̳ ȭй ߴؾ , severe blood count depression ڿȸ

幰. ġ waiting period blood count ߵ Ұ ƴ϶ õ

ʴ´.

1) BMT

ִ ȯڿ ̽ ּ ġ̴. HLA typing

ؾ Ѵ. ̽ ڿ κ ؾ Ѵ.

̴ histocompatability Ag ϱ ̴.

׸ Ϲ ּȭϰ ؾ Ѵ.

allogeneic tranplant 80%̴. transplant

morbidity & mortality ο Ѵ. ̴ ַ chronic GVHD & serious infection

̴.

Graft rejection ̽ļ ̴. primary or secondary graft failure

alloimmunizationӸ ƴ϶ marrow failure »͵

. κ ȯڴ ڰ . Ȥ full phenotypic match

߰ߵɼ ִ.

unrelated but histocompatible volunteers Ȥ closely but not perfectly matched family

members alternative donors ϴ. ̷ alternative donors

conventional sibling transplants ̴.

̷ ȯڵ late complication ִ(Ư high rate of cancer).

alternative donor tranplants ϴ κ transplant-related complications

״´.

2) Immunosuppression

ALG or ATG ܵ 50% hematologic recovery Ҽ ִ. cyclosporine

߰ν 70-80% ų ְ, Ư ̿ severely neutropenic

patients Ư Ǿ. ġ severe diseaseȯڿ ǥġ

̴. hematologic response ִ.

ȣ Ϲ ġ 2 Ÿ. κ ȸȯڴ blood

count depression ϴµ MCV ϰ BM cellularity ſ õõ ȭȴ.

δ ƴϴ κп (recurrent pancytopenia) ϸ cyclosporine

ߴϸ鼭 .

鿪 ٽ ϸ ϰ Ϻ ڵ cyclosporine Ѵ.

MDS߻ ġȯ 15% ߻ϴµ pancytopenia ǵư⵵ ϰ Ϻȯ

leukemia ϱ⵵ Ѵ.

* : horse ATG(ATGAM) 40 mg/kg/d 4 daysϰ

rabbit ALG(thymoglobulin) 3.5 mg/kg/d 5 days Ѵ.

ATG anaphylaxis 幰 Ȥ ġ պ ⵵ Ѵ. allergy undiluted

solution prick skin test ˻ϰ ؾ Ѵ. desensitization Ҽ ִ.

ATG PB cells Ͽ ġ߿ ⵵ Ѵ.

serum sickness(flulike illness + cutaneous eruption & artralgias) ġ 10ϳ

߻Ѵ. κ ȯڴ heterogenous protein infusion 鿪 ȣŰ

methylprednisolone 1mg/kg/d 2ְ Ѵ.

excessive or extensive glucocorticoid tx avascular joint necrosis . ο

cyclosporine 汸 12mg/kg/d(Ҿƴ 15mg/kg/d) ϰ 2ָ Ѵ.

Trough level 150-200 ng/ml ؾ Ѵ. κ ߿ ۿ nephrotoxicity,

seizure, opportunistic infection(Ư Pneumocystis carini) ִ.

̽ ڰ A.A ȯ κ immunosuppression TOC̴.

뷮 ̽İ 鿪 .

׷ ̽ marrow failure ġŲ. ݸ 鿪 blood count

ȸ ȯڴ ߰ Ϲ߻ ִ. ̿

ִٸ allogeneic transplant ؾ Ѵ. matched family donor ִ ο

̰ neutropenia ϸ, ̽İ 鿪 ߿ ġ ؾ Ѵ.

ȯڴ ATG cyclosporine . ݸ transplant granulocytopenia

ȣȴ. ̽İ 鿪 ð Ǿ. stem cell rescue

high-dose cyclophosphamide Ⱓ ̳ MDS߻ hematologic recovery

ϴ Ǿ. ׷ ġ severe neutropenia ų

ְ ġ .

mycophenolate mofetil ̿ novel immunosuppressive drug ų

ִ.

3) other treatment

G-CSF, GM-CSF, IL-3 : initial tx ʴ´. 鿪 ġῡ ϴ

Ȯ ʾҴ. 鿪 ġῡ Ϻȯڿ growth factor Ͽ

찡 ־.

splenectomy: ϰų ȯڿ blood count Ű⵵ Ͽ.

4) supportive care

ġ ȯڿ ö ǰ ʿϴ. ߿ severe neutropenia

ﰢ ġϴ ̴(parenteral, broad-spectrum antibiotics).

ceftazidime or AG, cephalosporin, semisynthetic penicillin

oropharyngeal or anorectal abscess, pneumonia, sinusitis, typhlitis Ư foci

ִ ϴ ġ ϰ culture ٷ ȵȴ.

indwelling plastic catheter Ǿ vancomycin ߰ؾ Ѵ. ̰ų

ϴ ߿ fungal disease ǹѴ. candida or Aspergillus ϴ(Ư

antibacterial antibiotics ). ׸ Ҷ amphotericin ؾ

Ѵ.

hand washing ĸ µ ȿ õǰ ִ.

gut decomtamination Ǵ nonabsorbed antibiotics tolerable ʰ ȿ

ʾҴ. total reverse isolation mortalityҿ и ̵

.

platelet & erythrocyte Ѵ Ҽ ִ. alloimmuization

ѵǴµ single donor ϰ leukocyte ϴ , ȭ ϴ

 alloimmunization ϰų ּȭҼ ִ.

HLA-matched platelet ȿ̴.

fibrinolysis inhibitors(aminocaproic acid) mucosal oozing ȭŰ

ʴ.

"vascular stability" ϱ low-dose glucocorticoid뵵 ȿ

ʾҴ.

ϴ° , ƴϸ ʿҶ ϴ° Ĵ

Ȯ ʴ.

oral estrogen̳ nasal FSH/LH antagonist Ͽ ؾ Ѵ.

Aspirin̳ NSAID ϹǷ ؾ Ѵ. RBC ϱ

Ͽ Hbġ 7.0 g/dL(underlying cardiac or pulmonary disease ִٸ 9.0

g/dL) ؾ Ѵ: 2ָ 2 units

chronic anemia secondary hemochromatosis ϱ 15° iron

chelator deferoxamine ߰ؾ Ѵ.

II. Pure red cell aplasia

pure white cell aplasia amegakaryocytic thrombocytopenia 幰 PRCAó

destructive Ab or lymphocyte ߻ϸ 鿪ġῡ Ѵ. single

lineage failure syndrome pancytopenia leukemia 幰.

1.

anemia, reticulocytopenia, BM erythroid precursor cell Ư¡̴.

*з: Tab 109-4

i) ο acquired

ii) Diamond-Blackfan anemia(=congenital PRCA)

: or early childhood ܵǸ glucocorticoid Ѵ.

iii) temporary red cell failure: acute parvoviral infection hemolytic anemia

transient aplastic crisis

iv) ̿ transient erythroblastopenia

2. ӻ

immune system disease ݵȴ.

Ϻδ thymoma ߻ϰ ϱδ large granular lymphocytosis major

manifestationϼ ְ, CLL ߻ϱ⵵ Ѵ.

Ϻδ hypogammaglobulinemic.

agranulocytosisó ๰ idiosyncratic reaction ߻ϱ⵵ Ѵ.

aplsatic anemiaó پ ߻Ѵ.

RBC precursor ü ߰ߵ T cell inhibition immune

mechanism̴.

* persistent parvovirus B19 infection: transient aplsatic crisis߱

3. ġ

i) drug exposureȮ -> ߴ

ii) thymomaִ CXR Ȯ

ִٸ tumor excision, ׷ ݵ ȸǴ ƴϴ.

iii) Parvovirus infection: viral DNA sequence detection(IgG & IgM Ab: absent)

IV IG(0.4 g/kg/d 5 days) κ Ѵ.

߰ ġᰡ ... Ư AIDS

iv) erythroid colony

erythroid colony idiopathic PRCA 鿪ġῡ

ִ.

v) PRCA supportive careܵε long survivalѴ.

transfusion & iron chelation

vi) idiopathic PRCA κ 鿪ġῡ ´.

1st course of glucocorticoid

-> cyclosporine, ATG, azathioprine or cyclophosphamide

III. Myelodysplasia

1.

MDS peripheral cytopenia + dysmorphic & usually cellular bone marrow

ineffective blood cell production Ư¡ ϴ heterogenous group of hematologic

disorders̴(Tab 109-5).

2.

idiopathic MDS ο ߻ϴ ̴( 68).

MDS BM failure ټ ̸, ߻ Ϲα 100 35-100

Ǿ. Tx-related MDS ̿ .

׾ġ 10⳻ ȯ 15% ߻Ѵ. MDS ϴµ ǻ簡

ϰ α ȭDZ ̴.

3. »

radiation & benzene ִ.

secondary MDS cancer txĿ ߻Ѵ.

radiation + alkylating agents(busulfan, nitrosoures or procarbazine): 5-7

DNA topoisomerase inhibitors: 2

鿪ġḦ acquired A.A Fanconi's anemia Ѵ MDS Ҽ ִ.

cytogenetic abnormality ȯ ݿ ߰ߵǰ Ư frank leukemia

ȴ. deletions translocations ϴ.

cytogenetic abnormalities Ǵ ƴϸ(chr 5, 7 or κ ҽ,

trisomy 8) ΰ õDZ⵵ Ѵ(topoisomerase II inhibitors 11q23).

CMML : t(5:12) => chimeric tel-PDGF gene

cytogenetic abnormality type & number leukemic transformation & survival ϰ

ִ.

N-ras, p53 & IRF-1, Bcl-2 mutation Ǿ.

marrow cell apoptosis MDS ϴµ Ƹ acquired genetic alteration ϴ

. sideroblastic anemia mitochondrial gene mutation ִ. ineffective

erytropoiesis & disordered iron metabolism gene alterations ̴.

4. ӻƯ¡

ʱ Ұ̴. κ ִ ȯڵ ӵǴ fatigue, weakness,

dyspnea, & pallor ȣ ̰ routine blood count 쿬

ߵȴ. chemotherapy or radiation exposure ߿ ̴. fever & wt loss

myelodysplastic process myeloproliferative ؾ Ѵ.

Down's syndrome̴ MDS sideroblastic anemia hereditary form or

Fanconi's anemia ִ.

20% splenomegaly ִ.

幮 Ǻκ(sweet's syndrome=febrile neutrophilic dermatosis) MDS ִ.

5. Lab

Blood

κ 쿡 Ѵ. ̱ܵ⵵ ϰ bi- or pancytopenia κ

⵵ ϳ isolated neutropenia or thrombocytopenia 幰.

macrocytosis ϴ.

ũ, granule . ɿ, ū̻ ȯڴ

ִ.

neutrophils hypogranlated, hyposegmented, ringed or abnormally segmented nuclei

.

circulating myeloblast marrow blast ϸ з Ŀ ߿ϴ.

Total WBC count CMML ϰ ̰ų ణ .

A.Aó MDS PNH cells clonal population ݵɼ ִ.

BM

BM ̰ų hypercellular 20% hypocellularϿ aplasia ȥȴ.

marrow morphology Ư¡ Ұ MDS . ׷

Ǵ Ұ̴.

: dyserythropoietic changes(Ư nuclear abnormalities)

& ringed sideroblasts in the erythoid lineage

hypogranulation & hyposegmentation in granulocytic precursors. myeloblasts

megakayrocytes showing reduced numbers of disorganized nuclei

Ĵ marrow blasts Ѵ. cytogenetic analysis ߿ϴ.

ġ chromosome aberration ϱ ΰ ˻ FISH(fluorescent

in situ hybridization)̰, PCR gene amplification ˷ chromosomal

translocation Ҽ ִ.

6.

* vit B12 or folate deficiency

history ǽϰ װ˻ ؾ Ѵ.

vit B6 deficiency BM ringed sideroblast δٸ pyridoxine therapeutic trial

ν Ҽ ִ. marrow dysplasia acute vitral infections, drug reactions or

chemical toxicity Ͻ̴. hypocellular MDS aplasia

ϰų RAEB in transformation early acute leukemia ϴ ̴.

7.

߰ FAB type ſ پϴ.

5q- or sideroblastic anemia() RAEB or severe pancytopenia with monosomy

7() پϴ. κ ȯڴ pancytopenia պ ϸ leukemic

transformation ϴ ƴϴ. 1/3 MDS þ ٸ Ѵ.

pancytopeniaȭ, new chromosomal abnormalities, blast poor prognostic

indicators̴.

FAB type tx-related MDS İ , κ refractory

AML Ѵ.

8. ġ

Ϲ ϴ.

stem cell transplantation ġϴ.

40% Ǿ treatment-related mortality & morbidity

.

better prognostic features ȯڴ more malignant subtypes ȯں

.

õ 쿡 ϴ mathed unrelated donorκ

̽İ ϴ.

MDS cytotoxic chemotx regimen Ư ȵ´.

ο drug toxicity ġ̰ ذ ª.

cytosine arabinoside ִ ƴϴ.

etoposide & 5-azacytidine Ȱ ̴.

Amitostine(apoptosis ϴ organic thiophosphonate) blood count

ִ.

A.A ȿ ATG, cyclosporine 鿪ġ refractory anemiaȯڿ

sustained remission Ѵ. Ư hypocellular marrow or cytogenetic abnormalities

׷ϴ.

hematopoietic growth factors blood count ȣŰ κ ٸ marrow failure

stateó severe pancytopeniaȯڿ ȴ. G-CSFġܵ

Ű ߴ. G-CSF + erythropoietinġ 1/3-1/2 blood

count Ű ʾҴ.

III. Myelophthisic anemias

BM fibrosis Ư¡ PB smearҰ Ÿµ ̸ "leukoerythroblastosis" ϸ

primary hematologic ds Ÿ myelofibrosis or myeloid metaplasia ϰ,

secondary process϶ myelophthisis Ѵ.

Myelophthisis or secondary myelofibrosis ڱؿ ΰϴ. fibrosis tumor cell

invasion(Ư breast, lung prostate or neuroblastoma epithelial cancer) Ͽ

ִ. marrow fibrosis mycobacteria infection(M. tuberculosis & M. avium), fungi or

HIV, sarcoidosis ִ.

Gaucher's disease intracellular lipid deposition & congenital osteopetrosis

fibrosis ų ִ. secondary myelofibrosis RT or radiomimetic drugġ ı

պ̴.

infectious or malignant underlying process иϴ.

marrow fibrosis پ hematologic synromes Ư¡ϼ ִ.

Ư CML, multiple myeloma, lymphoma, myeloma & hairy cell leukemia

» и Ư¡ .

i) marrow space fibroblast(myelofibrosis)

ii) hematopoiesis long bone extension, Ư extramedullary sites( spleen,

liver, LN)(myeloid metaplasia)

iii) ineffective erythropoiesis

fibrosis ˷ growth factorа .

: plt-derived growth factor, TGFⰡ õȴ.

secondary myelofibrosis ε巯. normocytic & normochromicϴ.

Ư¡ leukoerythroblastic smear ǽѴ.

Erythrocyte morphology ſ ε circulating nuleated RBC, tear drops & shape

distortions

WBC : leukemoid reaction (circulating myelocytes, promyelocytes,

myeloblasts)

platelet dz: giant size

, Ư¡ "dry tap" myelophthisis Ҽ ִ.

secondary myelofibrosis ο ȴ.

ġᰡ ؾ Ѵ. Ư tuberculosis, fungus

transfusion ȭų ִ.