Transcript White Blood Cell Disease

National Taiwan University Hospital
Department of Internal Medicine
Division of Hematology
陳建源
WHITE BLOOD CELL DISEASE
Non-malignant Disorder of
Leukocyte
 1.Variations of leukocytes in disease
 2.Neutropenia
 3.Qualitative disorder of leukocytes
 4.Abnormal monocyte-macrophage system
 5.Langerhans cell histocytosis X
 6.Infectious Mononucleosis
 7.Hematology aspects of HIV and AIDS
 8.Disorder of spleen
Wintrobe’s Clinical Hematology 10th ed
Variations of leukocytes in
disease
Wintrobe’s Clinical Hematology 10th ed
Neutropenia-acquired
 The most common cause of acquired
neutropenia is infection. HBV, EBV, and HIV.
 The second most common is medication exposur
e: beta-lactam antibiotics, anti-thyroid drug, anti
-tuberculosis, ticlopidine, baktar, carbamazepine,
captopril, digitals, indomethacin
Wintrobe’s Clinical Hematology 10th ed
Neutropenia-congenital
 Kostmann syndrome
Severe congenital neutropenia
 Cyclic neutropenia
 Ela2 gene
 HAX1 is a ubiquitously expressed
mitochondrial protein with weak homology to
bcl-2
 Wiskott-Aldrich syndrome protein (WASp)
 Gfi-1 zinc-finger protein, transcriptional
repressor
Nancy Berliner Blood 2008
Qualitative disorder of leukocytes
 Pelger Huet Anomaly: AD, bilobed PMN
 Alder-Reilly Anomaly: AR, Large azurophil
granules
 May-Hegglin Anomaly: AD, inclusion in
granulocytes, giant platelets with
thrombocytopenia
 Chediak-Higashi Anomaly: AR, lysosome-like
inclusion body, children with pale hair
Wintrobe’s Clinical Hematology 10th ed
Abnormal monocyte-macrophage
system
 Fabry disease: X-linked, glycosphingolipid
anemia, decreased serum iron concentration,
platelet aggregation. Lipid-laden foamy
macrophage in BM
 Gaucher disease: AR, Glycocerebroside
 Niemann-Pick disease: sphingomyelin and
cholesterol accumulation
Wintrobe’s Clinical Hematology 10th ed
Langerhans cell histocytosis X
 Hand-Schuller-Christian Disease
 Clinical Triad: defect in membranous bone,
exophthalmos and polyuria
 Pathology: granulomatosis, histocytes,
mature eosinophil, and lymphocytes
 Birbeck granules
Wintrobe’s Clinical Hematology 10th ed
Infectious Mononucleosis
 Sorethroat and dysphagia (80-85%)
 Lymphadenopathy
 Hepatosplenomegaly
 Fever, malaise
 Lymphocytosis
 Abnormal liver function
 Hyperbilirubinemia
Wintrobe’s Clinical Hematology 10th ed
Infectious Mononucleosis
 Polyclonal T cell, CD8 subset
 Hematological complications
Immune hemolytic anemia
Immune thrombocytopenia
Granulocytopenia
Marrow aplasia
Virus-associated hemophagocytic syndrome
Acquired immune Deficiency
 Non-Hematological complication
Splenic rupture, Neurological complication, Cardiac complication,
Respiratory complications, Liver failure, Pancreatitis, Renal Failure
Hematology aspects of HIV
and AIDS: anemia

Decreased Production

Drugs

Zidovudine, Trimethoprim-sulfamethoxazole

Amphotericin B, Ganciclovir, Dapsone, Delavirdine

Deficiencies

Erythropoietin, Iron, Folate, Vitamin B12

Infection

HIV, Parvovirus B19, Mycobacterium avium complex
(MAC), Mycobacterium tuberculosis, Histoplasma
capsulatum

Neoplasia

Non-Hodgkin’s lymphoma, Multiple myeloma,

Castleman’s disease, Hodgkin’s disease

Miscellaneous

Anemia of chronic disease

Preexisting condition (sickle cell disease, thalassemia,
Increased Loss
Hemolysis
Thrombotic thrombocytopenic purpura
Glucose-6-phosphate dehydrogenase deficiency
trimethoprim-sulfamethoxazole, dapsone,
primaquine,
Autoimmune hemolytic anemia
Idiopathic
Drugs (ceftriaxone, indinavir, “Ecstasy”)
Infection (cytomegalovirus [CMV])
Gastrointestinal bleeding
Kaposi’s sarcoma
Non-Hodgkin’s lymphoma
Infection (CMV, Candida)
Hypersplenism
Infection
Lymphoma
Hemophagocytosis
Cirrhosis (hepatitis B virus, hepatitis C virus)
Hematology Am Soc Hematol Educ Program. 2003:294-313
Hematology aspects of HIV
and AIDS: thrombocytopenia
Decreased Production
Increased Loss
Drugs: Trimethoprim-sulfamethoxazole, Pentamidine,
Pyrimethamine, Ganciclovir, Fluconazole, Alpha-interferon,
Rifabutin, Clarithromycin, Didanosine, Amphotericin B,
Indinavir, Ritonavir, Delavirdine, Nelfinavir
Neoplasia Non-Hodgkin’s lymphoma
Infection HIV, Parvovirus B19,Mycobacterium avium complex
(MAC), Mycobacterium tuberculosis,Histoplasma capsulatum,
Bartonella henselae (bacillary angiomatosis)
Immune thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Hypersplenism
Infection
Deficiencies Folate, Vitamin B12
Hemophagocytosis
Cirrhosis
Preexisting condition
Drugs
Saquinavir
Miscellaneous
Interferon
Hematology Am Soc Hematol Educ Program. 2003:294-313
Hematology aspects of HIV
and AIDS: neutropenia

Decreased Production

Drugs
Ganciclovir
Zidovudine
Trimethoprim-sulfamethoxazole
Pentamidine
Rifabutin
Antineoplastic chemotherapy
Dapsone
Amphotericin B
Ritonavir
Delavirdine
Nelfinavir
Deficiencies
Folate
Vitamin B12
Infection
Human immunodeficiency virus (HIV)
Mycobacterium avium complex (MAC)
Mycobacterium tuberculosis
Histoplasma capsulatum
Neoplasia
Non-Hodgkin’s lymphoma
Multiple myeloma
Increased Loss
Autoimmune neutropenia
Hypersplenism
Infection
Hemophagocytosis
Cirrhosis
Hematology Am Soc Hematol Educ Program. 2003:294-313
Disorder of spleen
Mechanism
Causative disease
Immune response work hypertrophy
Subacute bacterial endocarditis
Infectious mononucleosis
Felty’s syndrome
RBC destruction work hypertrophy
Spherocytosis
Congestive (Venous outflow obstrcution)
Thalassemia major
Pyruvate kinase deficiency
Infiltrative
Sarcoidosis
Amyloidosis
Neoplastic
Lymphoma
Chronic lymphocytic leukemia
Hairy cell leukemia
Metastatic carcinoma
Myeloproliferative
Chronic myeloid leukemia
Myeloid metaplasia
Miscellaneous
Trauma
Splenic cyst
Hemangioma
Wintrobe’s Clinical Hematology 10th ed
Malignant hematopoietic
disorder
Normal
AML
CML
Differentiation
(++)
(-)
(+/-)
Proliferation
(+/-)
(++)
(+++)
Stem cell
MDS
MPD
Tumor suppressor gene?
Mutation of
proliferation,
survival gene
Mutation of
transcriptional
factor/ cofactor
Ex: FLT3, PTPN11,
RAS, Kit, JAK2,
PDGF gene
Ex: PML/RARa,
AML1, CEBPA,
CBFB, NPM, MLL
Acute
leukemia
Mutation of transcriptional factor and proliferation gene
(NTUH 1995-2003)
Class I mutation (No of Patients with the mutation)
Pt no
KIT
FLT3/
ITD
FLT3/
TKD
NRAS
KRAS
PTPN11
JAK2
Total*
AML1/ETO
t(8;21)
33
7
2
2
4
1
0
2
16
PML/RARA
t(15;17)
24
0
7
5
4
1
0
0
14
CBFB/MYH11
inv(16)
9
1
0
1
2
1
0
0
5
MLL
t(11q23)
13
0
1
1
2
1
0
0
4
6
0
1
0
2
2
0
0
3
AML1
31
0
7
1
2
0
3
0
11
MLL/PTD
13
0
9
0
1
0
1
0
10
CEBPA
45
1
7
2
2
0
0
0
11
NPM1
63
0
33
9
9
0
6
0
49
96
1
16
4
11
2
4
1
36
324
10
78
24
39
8
14
3
155
Class II mutation
NUP98/HOXA9
t(7;11)
Others**
Total*
* Some patients had more than one mutations.
** Excluding patients with the Class II gene mutation shown above.
NTUH 1995-2003
Class I Gene: Proliferation and Survival
FLT3/ITD
AML1/ETO
t(8;21)
NRAS
KRAS
PTPN11
P=0.011
PML/ RARα
t(15;17)
Class II
Gene:
Differen
-tiation
FLT3/TKD
JAK2
KIT
P=0.028
P<0.001
P=0.024
CBFβ /MYH11
inv(16)
MLL 11q23
NUP98HOXA9 t(7;11)
NPM1
P=0.008
P<0.001
P=0.03
P=0.035
CEBPA
AML1
MLL/ PTD
P<0.001
: Negative association
: Positive association
NTUH 1995-2003
Minimal residual disease
Flow cytometry for MRD
detection
Leukemia-associated Aberrant Immunophenotypes
(LAIP) Classification
 Cross-lineage expression of lymphoid antigens
CD33+CD2+CD34+
CD34+CD13+CD19+
 Over-expression
HLA-DR++CD33++CD34++
CD64++CD4++CD45++
 Lack of expression of antigen
HLA-DR-CD33+CD34+
 Asynchronous expression of antigens
CD15+CD33+CD34+
CD65+CD33+CD34+

+ indicates expression; ++, over-expression; -, no expression.
Kern W et al. Cancer 2008 112(1):4-16
Myeloproliferative disorder
 ET, PV, MF,
 MPD, unclassified
 JAK2 mutation
 mpl W515L(5% MF, 1%ET)
 PTPN11:JMML
 PDGFR: CMML, HES
The frequency of JAK2 V617 mutation in hematopoietic disorders
Diagnosis
Frequency of JAK2 V617F(%)
MPD PV
>90
24-27
ET
～50
3-4
MF
≧50
6-18
CML
Rare
ND
aCML
<20
ND
HES
<2
ND
Rare
ND
MPD/MDS CMMoL
<5
ND
JMMoL
<20
ND
～5
ND
1
ND
≦50
ND
ALL
None
ND
Hodgkin
None
ND
NHL
None
ND
mastocytosis
MDS
AML De novo AML
AML from MPD
Frequency of JAK2 V617F
homozygosity(%)
Human Pathology 2008(39):795–810
PV: 2001 WHO criteria and the
proposed 2007 WHO criteria
2001 WHO criteria
Diagnosis requires:
Both 1 and 2 of the A criteria, plus 1 additional A criteria, or 2 B
criteria
A-criteria:
1.Increased red cell mass 1. >25% above mean normal predicted
value, or >18.5 g/dL in men. >16.5 g/dL in women, or >99th
percentile of method-specific reference range for age, sex,
altitude of residence
2. No cause of secondary erythrocytosis, including:
Absence of familial erythrocytosis, No elevation of EPO
caused by: i.Hypoxia arterial PO2 ≤92%, ii. High oxygen
affinity hemoglobin, iii. Truncated EPO receptor ,iv.
Inappropriate EPO production by tumor
Proposed 2007 WHO criteria
Diagnosis requires:
Both major criteria and one minor criteria, or the first major
criterion and 2 minor criteria
Major criteria: 1. Hemoglobin >18.5 g/dL in men,
Hemoglobin >16.5 g/dL in women, or
Other evidence of increased red cell volume
2. Presence of JAK2 V617F or other functionally similar
mutation such as JAK2 exon 12 mutation
Minor criteria:
1. Bone marrow biopsy showing hypercellularity for
age with trilineage growth (panmyelosis) with prominent erythroid,
granulocytic, and megakaryocytic proliferation
2. Serum EPO level below the reference range .
3. EEC growth
3. Splenomegaly
4. Clonal genetic abnormality other than Philadelphia chromosome or
BCR-ABL fusion gene in marrow cells
5. EEC formation
B-criteria:
1. Thrombocytosis >400 × 109/L
2. Leukocytosis >12 × 109/L
3. Bone marrow biopsy showing panmyelosis with prominent
erythroid and megakaryocytic proliferation
4. Low serum EPO levels
Smith CA. Human Pathology 2008:795-810
Chronic myeloid leukemia
 Philadelphia
chromosome(+)
 t(9;22)
 BCR-ABL
 Tyrosine kinase
 Glivec
 Dasatinib
 Niclotinib
Mechanism of BCR/ABL resistance
 Mechanisms of Imatinib
Resistance




Decreased intracellular drug
levels
Plasma binding by -1 acid
glycoprotein
Drug efflux from P-glycoprotein
(MDR-1) overexpression
Increased expression of BCRABL kinase from genomic
amplification
Clonal evolution (non-BCR-ABL–
dependent mechanism)
Mutations in ABL kinase of BCRABL affecting drug interaction or
kinase activity
Arch Pathol Lab Med. 2006 May;130(5):669-79.
Myelodysplastic syndrome
•Nuclear Budding
•Nuclear fragmentation
•Micro-megakaryocyte
•Nuclear-cytoplasm
differentiation disassociation
•apoptosis
Myelodysplastic syndrome
Blood. 2008 May 15;111(10):4841-51.
Myelodysplastic syndrome
 Ringed sideroblasts and associated with marked
thrombocytosis (RARS-T), JAK2 V617F mutation
 5-Azacytidine was approved for the treatment of
MDS in 2004
 Azacytidine prolonged survival, delayed progression
to AML, and improved quality of life. Complete
response (CR) rate 7%, 16%PRs and 37%
hematologic improvement also seen.
 Decitabine was also evaluated in a phase 3 trial, and
a 35% overall response rate was seen (9% CR, 8%
PR, 18% hematologic improvement).
Blood. 2008 May 15;111(10):4841-51.
Acute Myeloid Leukemia
Favorable-Risk Group
Balanced structural rearrangements
t(15;17)(q22;q12-21), t(8;21)(q22;q22)
inv(16)(p13q22)/t(16;16)(p13;q22)
Intermediate-Risk Group
Normal karyotype
Balanced structural rearrangements
t(9;11)(p22;q23)
Unbalanced structural rearrangements
del(7q), del(9q), del(11q), del(20q)
Numerical aberrations:
–Y, +8, +11, +13, +21
Unfavorable-Risk Group
Complex karyotype
Balanced structural rearrangements
inv(3)(q21q26)/t(3;3)(q21;q26)
t(6;9)(p23;q34), t(6;11)(q27;q23)
t(11;19)(q23;p13.1)
Unbalanced structural rearrangements
del(5q)
Numerical aberrations:
-5,-7
Hematology Am Soc Hematol Educ Program. 2006:169-77
Genetic alterations affecting clinical outcome of
cytogenetically normal acute myeloid leukemia (AML)
patients
Genetic Alteration
Prognostic Significance
Favorable
NPM1 mutations
Patients with NPM1 mutations who do not harbor FLT3-ITD have significantly better CR rates,
EFS, RFS, DFS, and OS than patients without NPM1 mutations and FLT3-ITD.
NPM1 mutations do not have a significant effect on prognosis of patients with FLT3-ITD.
CEBPA mutations
Patients with CEBPA mutations have CRD and OS significantly longer than patients with the
wild-type CEBPA gene.
Unfavorable
FLT3-ITD
Patients with FLT3-ITD have significantly shorter CRD, DFS and OS than patients who do not
harbor
FLT3-ITD.
Particularly poor prognosis is conferred by FLT3-ITD coupled with no expression of a FLT3 wildtype allele or a high FLT3 mutant to FLT3 wild-type allele ratio.
MLL-PTD
Patients with MLL-PTD have remission duration significantly shorter than patients without
MLL-PTD.
Kit mutation in patients with t(8;21) most studies revealed unfavorable outcome,
in patients with inv(16) no significance related to outcomes
Hematology Am Soc Hematol Educ Program. 2006:169-77
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL): incidence & biological differences
Children
Adults
Peak incidence
5 years
50 years
% of Leukemias
80-85%
15%
Ph+
3%
30%
MLL
1-2%
7%
TEL/AML1
20%
2%
Hyperdiploid
25%
5%
10-15%
20-25%
1-2%
3-5%
Chromosomes
T-cell
Mature B
Hematology Am Soc Hematol Educ Program. 2006:128-32
Acute lymphoblastic leukemia
Subgroup
Disease characteristics
Cytogenetic / Molecular
markers
Specific Poor
prognostic factors
General Poor
Prognostic factors
Pro-B-ALL (11%)
(CD10 negative)
-high WBC (>100,000/μL in 70%)
-CD13/CD33 coexpression (> 50%)
-70% t(4;11)/ALL1-AF4
-(20% Flt3 in ALL1-AF4+)
High Risk
c-ALL (49%)
pre-B-ALL (12%)
-incidence increasing with age
(75% if > 55 yrs)
-partly CD20+ (45%)
-4% t(1;19)/PBX-E2A
(pre-B only)
-WBC > 3050,000/μL
-t(9;22)/BCR-ABL
-t(1;19)/PBX-E2A (?)
-Late achievement of CR
-Poor PRED response (?)
-MRD persistence
-Increasing age
-In-vitro resistance (?)
-MDR1 function (?)
-Complex aberrant
karyotype (?)
Mature B-ALL
(4%)
(L3-ALL, Burkitt
leukemia)
-large tumor mass
(LDH increased in > 90%)
-organ involvement (32%)
-CNS involvement (13%)
-CD20+ (> 80%)
-t(8;14)/c-myc-IgH
T-ALL (25%)
-mediastinal tumor (60%)
-CNS involvement (8%)
-high WBC (> 50,000) (46%)
Subtypes:
Early T (6%)
Thymic T (12%)
Mature T (6%)
20% t(10;14)/HOX11-TCR
< 20% t(11;14/LMO/TCR
8% SIL-TAL1
4% NUP213-ABL1
33% HOX11**
5% HOX11L2**
50% Notch1**
-Early, mature T-ALL
-WBC > 100,000/μL
(?)
-HOX11L2
Chronic lymphoblastic leukemia

Prognostic factor:
Traditional staging according to Rai or Binet
IgHV mutation status,
lymphocyte doubling time morphology,
Immunophenotype characteristics,
CD23 expression,
Beta-2-microglobulin,
Cytogenetics,
ZAP-70,
Pattern of bone marrow involvement,
 Cytogenetic: 13q14 in about 50% of cases (by FISH) followed by
del 11q22–q23 (20%), trisomy 12 (15%), del 6q21 (10%) and del
17p13 (5–10%).
BJH 2007 139(5):630-634
Blood 2005 105(5):1839-1840
Surface marker of B-Cell Lymphomas
Surface Marker
MCL
FL
SLL/CLL
MZL
CD5
++
-
++
-
Surface Ig
++
+++
+
+
CD19
++
++
++
++
CD20
+++
++
+ (weak)
++
CD10
-
+ (80%)
-
-
CD23
-
+/-
+
-
+++
-
-
-
t(11:14)
t(14:18)
-
t(11:18)
Cyclin D1
Cytogenetics
36
EBV associated
lymphoproliferative disorder
Blood. 2006 Feb 1;107(3):862-9.
EBV associated
lymphoproliferative disorder
Lymphoma Follicular
Rituximab Plus Chemotherapy in First-Line Therapy of Advanced Stage Follicular
J Clin Oncol. 2005 Sep 10;23(26):6394-9
Lymphoma
Author
Regimen
P
Hiddemann et al
Response rate
Median time to treatment
failure
Marcus et al
Response rate
Median time to treatment
failure
Herold et al
Response rate
Median event-free survival
CHOP (n = 205)
90%
31 months
R-CHOP (n = 223)
96%
Not reached
.011
< .0001
CVP (n = 159)
57%
7 months
R-CVP (n = 162)
81%
27 months
< .0001
< .0001
MCP (n = 96)
75%
19 months
R-MCP (n = 105)
92%
Not reached
< .001
< .0001
Salles et al
Response rate
Median event-free survival
CHVP/IFN- (n = 175)
85%
Not reached
R-CHVP/IFN- (n = 184)
94%
Not reached
Hochster et al
Median event-free survival
CVP (n = 157)
17 months*
CVP + R (n = 148)
50 months*
< .0001
Mantle Cell Lymphoma
Surface Marker
MCL
CD5
++
Surface Ig
++
CD19
++
CD20
+++
CD10
-
CD23
-
Cyclin D1
Cytogenetics
•
Small-medium sized cells, indented nuclei;
occasional small-cell variant
•
Expresses B cell antigens (CD20); CD5
•
Over-express cyclin D1
(immunohistochemistry)
•
Genetic hallmark: t(11;14) (q13;q32)
translocation
•
Molecular: BCL1 translocation, mutated
IGH ~20-30%
+++
t(11:14)
40
NCCN Mantle Cell Lymphoma
Guidelines 2006
1st
Line
1st Line
Consolidation
Second-line
Therapy
•
•
•
•
•
•
•
Rituximab + HyperCVAD
Rituximab + CHOP
Rituximab + EPOCH
ASCT
Allogeneic transplant in the context of a clinical trial
Bortezomib
Cladribine
FCMR
FC
PCR Thalidomide + Rituximab
HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin)
FCMR (fludarabine, cyclophosphamide, mitoxantrone, rituximab)
FC (fludarabine, cyclophosphamide) ± rituximab
PCR (pentostatin, cyclophosphamide, rituximab)
Thalidomide + rituximab
41
Lymphoma MALToma
J Clin Oncol. 2005 Sep 10;23(26):6370-8
Lymphoma Follicular

Prediction of patients with follicular lymphoma outcome based on
the FLIPI
No. of
risk
factors*
FLIPI score
Proportion
of patients,
%
Overall survival
at 5 y, %
at 10 y, %
0-1
Low
36%
91
71
2
Intermediate
37%
78
51
3-5
high
27%
53
36
*Factors adversely affecting survival in the FLIPI include age greater than 60
years; Ann Arbor stage III–IV; number of nodal sites greater than 4; serum LDH
level greater than the upper limit of normal; and hemoglobin level less than 12
g/dL.
Hematology 2007:216-225
NK Lymphoma
Lymphoma ALCL
 Pleomorphic large lymphocytes, Young
adult
 CD30+ (CD 30 also expressed in CTCL, lymphomatoid
papulosis, regressing atypical histocytosis, HD and some
embryonal cell, pancreatic carcinoma)
 t(2;5)(p23;q35) NPM/ALK
 Nodal
 Extranodal: skin
PLASMA CELL DYSCRASIA
Plasma cell labeling index (PCLI)