경희대학교 의과대학·의학전문대학원

전체 글

(1)

악성 혈액질환의 분류

Classification of Hematologic Malignancies

경희의대 종양혈액내과

(2)

Hematologic Malignancies

• Uncontrolled clonal proliferation of hematologic

cells :

– Stem cells or progenitor cells :

– Acute or chronic : blasts in BM --- 20%

• Lymphoid

• Myeloid

• Mixed

(3)

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

(4)

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

(5)

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

(6)

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

(7)

• 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)

(8)
(9)
(10)

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)

(11)

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

(12)

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

(13)

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)

(14)

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

(15)
(16)

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

(17)

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

(18)

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

(19)

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)

(20)

Lymphoid neoplasms

• Precursor lymphoid neoplasms

• Mature B-cell neoplasms

• Mature T-cell and NK-cell neoplasms

• Hodgkin Lymphoma

• Post-transplant lymphoproliferative disor

ders (PTLD)

(21)

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)

(22)

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

(23)

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

(24)

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

(25)

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

(26)

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

(27)

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

(28)

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

(29)

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

*

(30)

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

(31)

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

(32)

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

(33)

Myeloproliferative Neoplasm

s (MPN)

경희의대 종양혈액내과

(34)

MPN(CMPD)

• Multipotent hematopoietic progenitor cell

• Overproduction of blood cells without signific

ant dysplasia (effective production)

• Predilection to extramedullary hematopoiesis

• Myelofibrosis

(35)

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

(36)

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↓ +++ + +++

-

(37)

---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

(38)

Other Symptoms of MPN

• Fatigue :

81 %

• Pruritus :

52 %

• Night sweats : 49 %

• Bone pain :

44 %

• Fever :

14 %

• Weight loss :

13 %

(39)

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

(40)

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

(41)

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

(42)

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

(43)

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%)

(44)

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

(45)

Differential diagnosis

• Secondary erythrocytosis

• Stress or spurious erythrocytosis

(Geisböck’s sy

ndrome)

• Microcytic erythrocytosis :

– β-thalassemia trait – Hypoxic erythrocytosis – PV

• Normal Hct PV

(46)
(47)
(48)
(49)

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

(50)

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

(51)

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).

(52)

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

(53)

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

(54)
(55)

Lab findings

• Thrombocytosis, giant hypogranular,

abnormal function(epinephrine)

• BM: large numbers of hyperploid mega

karyocytes, progressing fibrosis

• JAK2 V617F mutation : 50 %

• Cytogenetic abnormalities: uncommo

(56)

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

(57)

Causes of thrombocytosis(I)

• Iron-deficiency anemia

• Hyposplenism

• Postsplenectomy

• Malignancy

• Collagen vascular diseases

• Inflammatory bowel disease

• Infection

• Hemolysis

• Hemorrhage

• PV

(58)

Causes of thrombocytosis(II)

• Primary myelofibrosis

• ET

• CML

• Idiopathic sideroblastic anemia

• Myelodysplasia (5q- syndrome)

• Postsurgery

• Rebound: cessation of ethanol intake,

correction of vitamin B

12

or folate def

iciency

(59)

Therapy

• Myelosuppression:

hydroxyurea

, alkyl

ating agents,

32

P

• IFN-alpha

• Anagrelide

• Emergency plateletpheresis

• Platelet transfusion

• Aspirin and dipyridamole: protect thro

(60)

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%)

(61)

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,

(62)

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)

(63)

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

(64)

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

(65)

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

(66)

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

(67)

Diagnosis

• Bone marrow biopsy: essential

• May be difficult to distinguish from

other MPN

• Rule out other causes of myelofibr

osis

• Acute myelofibrosis: M7

(68)
(69)
(70)

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)

(71)

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

(72)

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

(73)
(74)
(75)
(76)

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

(77)

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

(78)

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

(79)
(80)

Symptoms and signs

• Splenomegaly, hepatomegaly, rare lym

phadenopathy

• Hypermetabolism: weight loss, fatigue, f

ever elevated uric acid

• Bone pain, arthralgia, pain from splenic

infarction

(81)

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

(82)

Lab findings

• Leukocytosis: left shift, eosinophilia,

basophilia

• Thrombocytosis: normal morphology and

function

• Increased vitamin B

12

and binding capacity

• Reduced LAP score

• Hyperuricemia

• Gaucher cells or see-blue histiocytes in BM

• Ph : chromosome analysis or FISH

(83)

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

(84)
(85)
(86)
(87)

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)

(88)
(89)

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

(90)
(91)

SCT and DLI

• Allogeneic SCT

– HLA-matched sibling

– Mismatched relatives

– Matched unrelatives

– Cord blood

• Autologous SCT

• DLI

• NMAST (mini-transplantation)

(92)
(93)
(94)
(95)
(96)

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

(97)
(98)

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

• Bcr-Abl amplification

• Enhanced expression of multidrug exporter proteins

• Alternative signaling pathway

(99)

Strategies to treat resistance

• Dose escalation : 300 – 400 mg bid

my

elosuppression, fluid retention

• Novel Bcr-Abl inhibitors :

dasatini

b (thiazolcarboxamide),

nilotinib (am

inopyrimidine)

• SCT

• Upfront combination therapy :

IFN,

ara-C, farnesyltransferase inhibitor (lona

farnib), rapamycin

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