악성 혈액질환의 분류
Classification of Hematologic Malignancies
경희의대 종양혈액내과
Hematologic Malignancies
• Uncontrolled clonal proliferation of hematologic
cells :
– Stem cells or progenitor cells :
– Acute or chronic : blasts in BM --- 20%
• Lymphoid
• Myeloid
• Mixed
Classification of Hematologic malignanc
ies
• Gall and Mallory classification
• Rappaport classification
• Kiel classification
• Lukes-Collins classification
• Working Formulation
• Revised European-American classification (REAL)
• French-American-British system
• World Health Organization (WHO) classification 200
1
Previous classification of hematologic n
eoplasms
• Clinical features
• Morphology
• Leukemia
:
– Acute, chronic ; Myeloid, lymphoid :
AML, CML, AL
L, CLL
– FAB classification : AML(M0-7), ALL(L1-3)
• Myelodysplastic syndrome (MDS) : FAB class.
• CMPD (MPN) : PV, ET, IMF
• Lymphoma
: HD, NHL
Bases of WHO classification
• Morphology
: most important part but sometimes not obj
ective
• Immunophenotype
: lineage, objective, target (ex. CD20)
• Genetic abnormalities
: objective
– Specific : BCR-ABL, PML-RARA,
– Characteristic but not specific : MYC, CCND, BCL2 rearrangeme nt, JAK2 mutation
– Prognostic : TP53 mutation or FLT3-ITD
• Clinical features
: age, nodal versus extranodal presentati
on,
specific anatomic site and history of cytotoxic and o
ther therapies
Stratification according to
• Lineages
:
– myeloid, lymphoid, and histiocytic/dendritic cell – Lineage plasticity
– FGFR1, PDGFA, and PDGFB rearrangement
• Maturation
: precursor, mature
• Biologic features
: MPN, MDS
• Clinical presentation
: mature lymphoid
– Disseminated, extranodal, indolent, aggressive – Stage of differentiation
• Myeloid neoplasms
• Lymphoid neoplasms
• Neoplasms with myeloid and lymphoid d
ifferentiation
• Histiocytic and dendritic cell neoplasms
WHO Classification of Tumors of Hematopoietic
and Lymphoid Tissues (2008)
Myeloid neoplasms
• Acute : blasts ≥ 20%
–
Acute myeloid leukemia (AML : 급성골수성백혈병 )
• Chronic : blasts < 20%
– Dysmyelopoiesis :
Myelodysplastic syndro
me (MDS : 골수이형성증후군 )
– No dysplasia :
Myeloproliferative neoplas
ms (MPN : 골수증식성종양 )
– Atypical :
Melodysplastic/Myeloproliferative ne
oplasms (MDS/MPN)
Acute myeloid leukemia (AML) and related
precursor neoplasms
• AML with recurrent genetic abnormalities
• AML with myelodysplasia-related changes
• Therapy-related myeloid neoplasms
• Acute myeloid leukemia, NOS
• Myeloid sarcoma
• Myeloid proliferations related to Down syndr
ome
AML with recurrent genetic abnormalities
• AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
• AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
• Acute promyelocytic leukemia with t(15;17)(q22;q12); PML-RARA
• AML with t(9;11)(q22;q23); MLLT3-MLL
• AML with t(6;9)(p23;q34); DEK-NUP214
• AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
• AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
• AML with mutated NPM1
Acute myeloid leukemia, NOS
• AML with minimal differentiation
• AML without maturation
• AML with maturation
• Acute myelomonocytic leukemia
• Acute monoblastic and monocytic leukemia
• Acute erythroid leukemia
• Acute megakaryoblastic leukemia
• Acute basophilic leukemia
• Acute panmyelosis with myelofibrosis
• (Myeloid sarcoma)
Acute myeloid leukemia (AML) and related
precursor neoplasms
• AML with myelodysplasia-related changes
• Therapy-related myeloid neoplasms
• Myeloid sarcoma
• Myeloid proliferations related to Down syndrome
– Transient abnormal myelopoiesis
– Myeloid leukemia with Down syndrome
• Blastic plasmacytoid dendritic cell
neopl
asm
Myelodysplastic syndrome
• Refractory cytopenia with unilineage dysplasia
– Refractory anemia
– Refractory neutropenia
– Refractory thrombocytopenia
• Refractory anemia with ring sideroblasts
• Refractory cytopenia with multineage dysplasia
• Refractory anemia with excess blasts
• Myelodysplastic syndrome associated with isolated del(5q)
• Myelodysplastic syndrome, unclassifiable
• Childhood myelodysplastic syndrome
Myeloproliferative neoplasms (MPN)
• Chronic myelogenous leukemia, BCR-ABL 1 positive
• Polycythemia vera • Primary myelofibrosis
• Essential thrombocythemia • Chronic neurophilic leukemia
• Chronic eosinophilic leukemia, NOS (CEL/hypereosinophilic synd.) • Mastocytosis
– Cutaneous mastocytosis – Systemic mastocytosis – Mast cell leukemia – Mast cell sarcoma
– Extracutaneous matocytoma
Melodysplastic/Myeloproliferative neoplasms
• Chronic myelomococytic leukemia
• Atypical chronic myeloid leukemia,
(
BCR-ABL1
negative)
• Juvenile myelomonocytic leukemia
• Myelodysplastic/Myeloproliferative
n
eoplasms, unclassifiable
–
Refractory anemia with ring sideroblasts ass
WHO Classification of Tumors of Hematopoietic
and Lymphoid Tissues (2008)
• Lymphoid neoplasms
– Precursor lymphoid neoplasms
– Mature B-cell neoplasms
– Mature T-cell and NK-cell neoplasms
– Hodgkin Lymphoma
– Post-transplant lymphoproliferative disorder
s (PTLD)
Lymphoid neoplasms
• Precursor lymphoid neoplasms
• Mature B-cell neoplasms
• Mature T-cell and NK-cell neoplasms
• Hodgkin Lymphoma
• Post-transplant lymphoproliferative disor
ders (PTLD)
Precursor lymphoid neoplasms
• B lymphoblastic leukemia/lymphoma
– B lymphoblastic leukemia/lymphoma, NOS
– B lymphoblastic leukemia/lymphoma, with recurrent genetic ab
normalities
• B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2); BCR-ABL1 • B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
• B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22); TEL-AML1(ET
V6-RUNX1)
• B lymphoblastic leukemia/lymphoma with hyperdiploidy
• B lymphoblastic leukemia/lymphoma with hypodiploidy (hypodiploid ALL) • B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32); IL3-IGH
• B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); E2A-PBX1(TC
F3-PBX1)
Mature B-cell neoplasms
• Chronic lymphocytic leukemia/small lymphocyt
ic lymphoma
• B-cell prolymphocytic leukemia
• Splenic marginal zone lymphoma
• Hairy cell leukemia
•
Splenic B-cell lymphoma/leukemia, unclassifiab
le
–
Splenic diffuse red pulp small B-cell lymphoma
Mature B-cell neoplasms
• Lymphoplasmacytic lymphoma
– Waldenström macroglobulinemia
• Heavy chain diseases
– Alpha heavy chain disease
– Gamma heavy chain disease
– Mu heavy chain disease
• Plasma cell myeloma
• Solitary plasmacytoma of bone
• Extraosseous plasmacytoma
Mature B-cell neoplasms
• Extranodal marginal zone lymphoma of mucos
a-associated lymphoid tissue (MALT lymphom
a)
• Nodal marginal zone lymphoma
–
Pediatric nodal marginal zone lymphoma
• Follicular lymphoma
–
Pediatric follicular lymphoma
• Primary cutaneous follicle centre lymphoma
• Mantle cell lymphoma
Mature T-cell and NK-cell neoplasms
• T-cell prolymphocytic leukemia
• T-cell large granular lymphocytic leukemia
•
Chronic lymphoproliferative disorder of NK-cell
• Aggressive NK cell leukemia
• Systemic EBV positive T-cell lymphoproliferative
dis
ease of childhood
• Hydroa vacciniforme-like lymphoma
• Adult T-cell leukemia/lymphoma
Mature T-cell and NK-cell neoplasms
• Enteropathy-associated T-cell lymphoma
• Hepatosplenic T-cell lymphoma
• Subcutaneous panniculitis-like T-cell lymphoma
• Mycosis fungoides
• Sezary syndrome
• Primary cutaneous CD30 positive T-cell lymphoprolifer
ative disorders
– Lymphomatoid papulosis
Mature T-cell and NK-cell neoplasms
• Primary cutaneous gamma-delta T-cell lymphoma
•
Primary cutaneous CD8 positive aggressive epidermotr
opic cytotoxic T-cell lymphoma
•
Primary cutaneous CD4 positive small/medium T-cell ly
mphoma
• Peripheral T-cell lymphoma, NOS
• Angioimmunoblastic T-cell lymphoma
• Anaplalstic large cell lymphoma,
ALK
positive
Hodgkin Lymphoma
• Nodular lymphocyte predominant Hodgkin lymp
homa
• Classical Hodgkin lymphoma
– Nodular sclerosis classical Hodgkin lymphoma
– Lymphocyte-rich classical Hodgkin lymphoma
– Mixed cellularity classical Hodgkin lymphoma
– Lymphocyte-depleted classical Hodgkin lymph
Post-transplant lymphoproliferative
dis
orders (PTLD)
• Early lesions
– Plasmacytic hyperplasia
– Infectious mononucleosis-like PTLD
• Polymorphic PTLD
• Monomprphic PTLD (B- and T/NK-cell ty
pes) *
• Classical Hodgkin lymphoma type PTLD
*
Myeloid and lymphoid neoplasms with eosinophilia and
abnormalities of
PDGFRA, PDGFRB
or
FGFR1
• Myeloid and lymphoid neoplasms with
PDGFRA
rearrangement
• Myeloid neoplasms with
PDGFRB
rearra
ngement
• Myeloid and lymphoid neoplasms with
Acute leukemias of ambiguous lineage
• Acute undifferntiated leukemia
• Mixed phenotype acute leukemia
with t(9;
22)(q34;q11.2); BCR-ABL1
• Mixed phenotype acute leukemia
with t(v;
11q23); MLL rearranged
• Mixed phenotype acute leukemia, B/myeloid, NOS
• Mixed phenotype acute leukemia, T/myeloid, NOS
•
Natural killer (NK) cell lymphoblastic
leukemia
/lymphoma
Histiocytic and dendritic cell neoplasms
• Histiocytic sarcoma
• Langerhans cell histiocytosis
• Langerhans cell sarcoma
• Interdigitating dendritic cell sarcoma
• Follicular dendritic cell sarcoma
• Fibroblastic reticular cell tumour
• Indeterminate dendritic cell tumour
Myeloproliferative Neoplasm
s (MPN)
경희의대 종양혈액내과
MPN(CMPD)
• Multipotent hematopoietic progenitor cell
• Overproduction of blood cells without signific
ant dysplasia (effective production)
• Predilection to extramedullary hematopoiesis
• Myelofibrosis
Myeloproliferative neoplasms (MPN)
• Chronic myelogenous leukemia, BCR-ABL 1 positive
• Polycythemia vera • Primary myelofibrosis
• Essential thrombocythemia
• Chronic neurophilic leukemia
• Chronic eosinophilic leukemia, NOS (CEL/hypereosinophilic synd.) • Mastocytosis
– Cutaneous mastocytosis – Systemic mastocytosis – Mast cell leukemia – Mast cell sarcoma
– Extracutaneous matocytoma
Characteristics of CMPD
Disease Hct WBC Platelet Splenomegaly JAK2 (m) MF Ph1 or bcr/abl
---CML N or↓ ↑↑↑ ↑to↓ +++ - ± + PV ↑↑ ↑ ↑ + ++ ± - ET N N ↑↑↑ + + ± - PMF ↓ ↑to↓ ↑to↓ +++ + +++
-
---3 major complications of MPN
• Clonal evolution : CML
– AML/MDS
• Thrombosis : PV, ET
– Arterial, venous
– Erythromelalgia : aspirin
• Bleeding : PV, ET
– Platelet function : qualitative and qua
ntitative
Other Symptoms of MPN
• Fatigue :
81 %
• Pruritus :
52 %
• Night sweats : 49 %
• Bone pain :
44 %
• Fever :
14 %
• Weight loss :
13 %
Polycythemia vera
• Definition:
– Myeloproliferative disorder resulting from
clonal
expasion of a transformed hematopoietic stem
cell associated with prominent over-production
of erythrocytes and to lesser extent expansion
of granulocytic and megakaryocytic elements
• Gradual in onset and runs a chronic but usually slowl
y progressive
• Generally benign in late middle life, slightly more co
Etiology
• Unknown
• 20q-, trisomy 8, 9 : 30%
• JAK2 mutation (V617F; val617phe) :
nonreceptor ty
rosine kinase : gain of function
30% homozygosity
• Impaired posttranslational process of
Mpl(thrombop
oietin receptor)
• Hypersensitivity to IGF-I, IL-3, GM-CSF : PV, ET
• Up-regulation of bcl-X
L: antiapoptotic
Clinical features(Sx)
• Nonspecific complaints :
– Headache (48%), Weakness (47%), Dizziness (43%) e xcessive sweating (33%)
• Acute gouty arthritis --- 5 to 20% • Pruritus --- 31%
• Erythromelalgia • Thrombosis
– CVA, MI, superficial thrombophlebitis, DVT, RE
– Budd-Chiari syndrome, and portal, splenic, or mesenteric ve in thrombosis
– Transient visual disturbances (eg, amaurosis fugax, scintillat ing scotomata, ophthalmic migraine)
• Gastrointestinal symptoms
Clinical features(PE)
• Splenomegaly (70%)
• facial plethora (ruddy cyanosis) (67%) • Hepatomegaly (40 percent)
• Injection of the conjunctival small vessels and/or en gorgement of the veins of the optic fundus
• Excoriation of the skin, which might be extensive, su ggesting the presence of severe pruritus
• Stigmata of a prior arterial or venous thrombotic event (eg, stroke, deep vein thrombosis, superficial thrombophlebitis)
• Gouty arthritis and tophi • Hypertension(1/3): systolic
Lab findings
• Elevated Hb, normocytic normochromic, polychro
masia, nucleated RBC
• Leukocytosis, basophilia, increased LAP, serum vit amin B12, and binding capacity
• Thrombocytosis, defective platelet function
• BM: erythroid hyperplasia or panhyperplasia, ir
on may be absent, mild fibrosis
• Cytogenetic abnormalities (up to 30%): trisomy 1, 8,or 9 and
20q-• Low Epo level : normal 4-26 mU/mL • JAK2 mutation
– Exon 14 : JAK2 V617F (97%)
PV
진단 (WHO 2008)
Criteria PVSG (1967) WHO (2008)
Major M1: increased red cell mass (>36ml/kg in men, >32ml/kg in women) M2: Normal oxygen saturation (>92%) M3: Splenomegaly;
A1: Elevated red cell mass >25% or Hb > 18.5g/dL (men), 16.5g/dL (women) or
17g/dL (men),
15g/dL (women), if increase of ≥ 2g/dL
A2: Presence of JAK2 V617F mutation or similar mutation such as JAK2 exon 12
mutation Minor thrombocytosis (>400,000/L) and leukocytosis (12,000/L) LAP Vit B12, binding capacity B1: BM hypercullarity
B2: Low serum EPO
B3: EEC(endogenous erythroid colony)
formation
Differential diagnosis
• Secondary erythrocytosis
• Stress or spurious erythrocytosis
(Geisböck’s sy
ndrome)
• Microcytic erythrocytosis :
– β-thalassemia trait – Hypoxic erythrocytosis – PV• Normal Hct PV
Therapy
• No therapy: 6 – 18 months
• Phlebotomy: 10-12 years
• Myelosuppression:
– Phlebotomy should be used initially
– RT: 32P : 6-24 months remission, 2nd Leukemia – Chemotherapy:
• Hydroxyurea
• alkylating agent: busulfan, melphalan, chrlorabucil • IFN-alpha
• Anagrelide for thrombocytosis • Pipobroman
• JAK2 inhibitors (?)
• Cyproheptadine, hydroxyzine, cimetidine for pruritus • Allopurinol for hyperuricemia
Course and prognosis
• Vascular complication: majority
• Post-PV MF(15-20%): marrow fibro
sis, marked splenomegaly, anemia
• Secondary hematologic neoplasm:
acute leukemia(1-2%), NHL, MM
• Increased secondary leukemia with
Course and prognosis
• The median survival of untreated symptomatic patients with PV was initially estimated at 6 to 18 months from the time of diagn osis.
• Whereas current survival of treated patients is 10 years or more. • The overall mortality in treated patients is 1.6 to 1.7 times that o
f an age- and sex-matched normal population.
• Cardiovascular mortality, solid tumors, and hematologic transf ormation accounted for 45, 20, and 13% of the deaths, respec tively.
• The median survival varied from 9.1 to 12.6 years with different therapies. The most common causes of death were thrombosis (29 percent), hematologic malignancies (23 percent), nonhem atologic malignancies (16 percent), hemorrhage (7 percent), a nd myelofibrosis/myeloid metaplasia (3 percent).
Essential thrombocythemia
• Markedly elevated platelet production in t
he absence of recognizable stimuli
• Blood platelet counts above 600,000 may re
ach levels of 3 to 4 million/ L
µ
• Clinical involvement of hematopoietic lineag
es other than megakaryocytic line is unusual
• Clonal disorder of pluripotent hematopoieti
c stem cell
• Autonomous in vitro megakaryocytic colony
Clinical features
• 2/3: asymptomatic at diagnosis
• Vasomotor symptoms
– Headache
– Lightheadedness
– Syncope
– Atypical chest pain
– Acral paresthesia
– Livedo reticularis
– Erythromelalgia
– Transient visual disturbances
• Thrombosis
• Bleeding
Lab findings
• Thrombocytosis, giant hypogranular,
abnormal function(epinephrine)
• BM: large numbers of hyperploid mega
karyocytes, progressing fibrosis
• JAK2 V617F mutation : 50 %
• Cytogenetic abnormalities: uncommo
Diagnosis
• A consistently elevated platelet count >450,000/microL.
• Megakaryocytic hyperplasia on bone marrow aspiration and biopsy.
• Absence of the Philadelphia chromosome on routine cyt ogenetic study. Molecular studies of the BCR/ABL gene re arrangement are now recommended to exclude cytogenetic ally masked cases of CML.
• Absence of causes for reactive thrombocytosis.
• Absence of peripheral blood, bone marrow, and karyotypic evidence for a myelodysplastic (MDS) disorder or for PMF. • Normal iron stores, as evidenced by normal serum ferritin and
normal red cell mean corpuscular volume (MCV). • JAK2 V617F mutation
Causes of thrombocytosis(I)
• Iron-deficiency anemia
• Hyposplenism
• Postsplenectomy
• Malignancy
• Collagen vascular diseases
• Inflammatory bowel disease
• Infection
• Hemolysis
• Hemorrhage
• PV
Causes of thrombocytosis(II)
• Primary myelofibrosis
• ET
• CML
• Idiopathic sideroblastic anemia
• Myelodysplasia (5q- syndrome)
• Postsurgery
• Rebound: cessation of ethanol intake,
correction of vitamin B
12or folate def
iciency
Therapy
• Myelosuppression:
hydroxyurea
, alkyl
ating agents,
32P
• IFN-alpha
• Anagrelide
• Emergency plateletpheresis
• Platelet transfusion
• Aspirin and dipyridamole: protect thro
Course and prognosis
• Survival will be at least as good as for t
hose of PV
• Transform to a more aggressive or fran
kly leukemic phase (5%)
Primary myelofibrosis(PMF)
Idiopathic myelofibrosis (IMF, AMM/MF)
• Clonal disorder of the hematopoietic
stem cell characterized by BM fibr
osis and extramedullary hematopoiesi
s
• In the late middle life, gradual onset,
Etiology
• 9p, 20q–, 13q–, trisomy 8 or 9, or partial trisomy 1q
are common
• Fibrosis in this disorder is associated with
overprod
uction of
transforming growth factor β
and
tissue inh
ibitors of metalloproteinases
, osteosclerosis is associat
ed with overproduction of
osteoprotegerin
,
an os
teoclast inhibitor
• Marrow angiogenesis occurs due to increased
pr
oduction of
vascular endothelial growth factor
(VEG
F)
Clinical features
• Vague constitutional symptoms associated with
anemia, fatigue, weight loss, night sweat
• Splenomegaly, hepatomegaly, lymphadenopathy
• Thrombocytopenia: petechia, bleeding
• Extramedullary hematopoiesis : jaundice, ascite
s, bone pain, portal, pulmonary, intracranial hyp
ertension, intestinal or ureteral obstruction
• Splenic infarction : fever, pleuritic chest pain
• Hyperuricemia, secondary gout
Clinical features
• Generalized Sx : fatigue, wt loss, mild fever, night sweat • Thrombotic events : incidence is same as ET
• Splenomegaly : sometimes massive
• Hepatomegaly : sometimes potal hypertension • Extramedulary hematopoiesis : in any organ
– In or surrounding the vertebral column (especially thoracic) – Lymph nodes
– Retroperitoneum – Lungs or pleura
– Genitourinary system – Skin
– Other sites (thalamus, right atrium, mouth, muscle, bowel)
• Bone and Joint involvement : osteosclerosis, periosteitis, pa
Lab findings(I)
• RBC: teardrop cell (dacrocyte), fragmented cells
an
d nucleated red cell, initially mild anemia but progres
sing(ineffective erythropoiesis
and decreased red
cell survival
• WBC: leukopenia (25%) to leukocytosis, shifting to le
ft and circulating blasts, basophilia, variable LAP score
• Increased circulating CD34+ cells
• Platelet: normal or elevated but eventually thrombo
cytopenia, giant form platelets or megakaryocytes, a
bnormal platelet function
Lab findings(II)
• Bone sclerosis (50%)
• Spleen: massive enlargement
• Extramedullary hematopoiesis: spleen, kidney, lu
ng, adrenal gland, LN
• BM: dry tap, progressive fibrosis and osteosclero
sis
• Cytogenetic abnormalities: 9p, 20q-, 13q-, triso
Diagnosis
• Bone marrow biopsy: essential
• May be difficult to distinguish from
other MPN
• Rule out other causes of myelofibr
osis
• Acute myelofibrosis: M7
Therapy
• BMT (allogeneic stem cell transplantation)
• Androgens, danazol (anemia)
• Blood transfusions with or without erythropoietin (anemia)
• Hydroxyurea (splenomegaly, thrombocytosis, leukocytosis, bone pain, consti tutional symptoms, pruritus)
• Alkylating agents (splenomegaly, thrombocytosis, leukocytosis)
• Thalidomide plus prednisone (systemic symptoms, anemia, splenomegaly, re fractory cytopenias)
• Lenalidomide (symptomatic patient with 5q-) • Etanercept (systemic symptoms)
• Ruxolitinib : JAK2 inhibitor (debilitating constitutional symptoms or severely sy mptomatic splenomegaly)
• Splenic irradiation (painful splenomegaly)
• Radiation therapy (symptomatic areas of extramedullary hematopoiesis, cord compression)
Course and prognosis
• Median survival: 4-5 years, 25% 15 years
• Major causes of death: infection, CHF, renal fail
ure, portal hypertension, hemorrhage
• Acute leukemia: 5-10%
• IPSS prognostic factor
–
Presence of constitutional symptoms (ie, weight
loss >10 percent, night sweats, or fever)
– Age >65 years
– Hemoglobin <10 g/dL
– Leukocyte count >25,000/microL
– Circulating blast cells ≥1 percent
Chronic myeloid leukemia
(CML, also known as chronic myelocytic, chronic myelogenous, or chronic granulocytic leukemia)
• Definition: Clonal myeloproliferative disorder of a pluri
potent hematopoietic stem cell with a specific cytogen
etic abnormalities,
Philadelphia Chromosome (P
h) t(9;22)(q34;q11)
•
BCR-ABL1
fusion gene results in the formation of a uni
que gene product, the
BCR-ABL1
fusion protein.
• Chronic, accelerated, and blastic phases
Pathophysiology
Philadelphia chromosome:
t(9;22)(q34;q11)
bcr-abl fusion gene :
BCR/ABL
mRNA
Bcr/Abl fusion protein (p210
BCR-ABL)
normal abl gene: p145, tyrosine kinase
Functional change
Active tyrosine kinase : prevent apoptosis
Attenuated DNA protein-binding activity
Natural course of CML
• Chronic phase
– uncontrolled production of mature and maturing
granulocytes, predominantly neutrophils, but also
basophils and eosinophils
• Intermediate, accelerated phase
– neutrophil differentiation becomes progressively i
mpaired and leukocyte counts are more difficult t
o control with treatment
• Blastic (acute transforming) phase
– a condition resembling acute leukemia in which m
yeloid or lymphoid blasts proliferate in an uncontr
olled manner
Chronic phase
• Excessive proliferation and accumulation of gra
nulocytes and their precursors; WBC often mo
re than 200,000/mm
3; myeloblast less than
5% in peripheral blood
• 20-50% asymptomatic: incidentally diagnosed
• Transformation rate: after first 6 to 12 months,
25% per year (if untreated)
• 85% die in blastic phase
• Over all survival: >5 years
Symptoms and signs
• Splenomegaly, hepatomegaly, rare lym
phadenopathy
• Hypermetabolism: weight loss, fatigue, f
ever elevated uric acid
• Bone pain, arthralgia, pain from splenic
infarction
Late stage
• Accelerated phase:
– Increasing resistance to therapy
– Progressive organomegaly
– Worsening anemia, fever, myelofibrosis
– Thrombocytosis or thrombocytopenia
• Blastic phase:
– Signs and symptoms of acute leukemia
Lab findings
• Leukocytosis: left shift, eosinophilia,
basophilia
• Thrombocytosis: normal morphology and
function
• Increased vitamin B
12and binding capacity
• Reduced LAP score
• Hyperuricemia
• Gaucher cells or see-blue histiocytes in BM
• Ph : chromosome analysis or FISH
D Dx
• Leukemoid reactions associated with infectio
n or neoplasms
• Juvenile myelomonocytic leukemia
• Chronic myelomonocytic leukemia
• Atypical CML
• Chronic eosinophilic leukemia
• Chronic neutrophilic leukemia
• Other MPN
• Other Philadelphia chromosome-positive malig
nancies
– ALL – AML
Prognostic scoring system
• Sokal prognostic score
– spleen size, percent blasts, age, and platelet
count >700,000/microL
• Hasford or Euro score
– adds eosinophilia and basophilia
• EUTOS score
– after imatinib (glivec)
Treatment
• TKI : tyrosine kinase inhibitor
– Imatinib mesylate (Glivec®) :
– Dasatinib, Nilotinib (2nd generation)
• Allogeneic stem cell transplantation :
• Palliative therapy
– IFN-α: sometimes cytogenetic remission – Other cytoreductive chemotherapy:
• Hydroxyurea • Busulfan
• Cytosine arabinoside • HHM
– Splenectomy or splenic irradiation – Blastic phase:
• Induction chemotherapy for acute leukemia, SCT
SCT and DLI
• Allogeneic SCT
– HLA-matched sibling
– Mismatched relatives
– Matched unrelatives
– Cord blood
• Autologous SCT
• DLI
• NMAST (mini-transplantation)
Defining treatment result
• Optimal response
– Complete hematologic response by 3 m – Any cytogenetic response by 6 m
– Partial cytogenetic response by 12 m – Complete cytogenetic response by 18 m
• Suboptimal response
– No complete hematologic or cytogenetic response by 3 m – Less than a partial cytogenetic response by 6 m
– Less than a complete cytogenetic response by 12 m – Less than a major molecular response by 18 m
– Loss of major molecular response at any time during treatment – BCR-ABL kinase mutations that are poorly sensitive to imatinib
• Treatment failure : inability to reach
– Complete hematologic response by 3 m – Any cytogenetic response by 6 m
– Partial cytogenetic response by 12 m – Complete cytogenetic response by 18 m
Resistance to imatinib
• Bcr-Abl mutation
– The T315I mutation has shown resistance to all currently avai lable TKIs. Such patients should either proceed to transplantat ion or try an investigational agent as part of a clinical trial.
– The Y253H, E255K/V, and F359V/C/I mutations are resistant t
o imatinib and nilotinib but sensitive to dasatinib.
– The F317L/V/I/C, V299L, and T315A mutations are sensitive to
nilotinib but shows intermediate sensitivity to imatinib and
dasatinib