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 ߵ̰
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 ִ.