CHRONIC LEUKEMIA

KARTIKA WIDAYATI TAROENO-HARIADI

Dr. Sardjito Hospital
Div. Hematology and Medical Oncology, Department of Internal Medicine
Faculty of Medicine, Public Health and Nursing
Universitas Gadjah Mada, Yogyakarta
• Male, 39 year old
• He complained on his abdominal
discomfort, fullness in left upper
quadrant of abdomen, decreased of
appetite, and he felt fatigue since 8
months before his visit to PHC
• He looks pale
• BP 110/70 mmHg, HR100 x /min, RR 20
times/min t = 36.2C
• No lymph-nodes enlargement
• Splenomegaly, Schuffner III.
• Laboratory findings;
• Hg= 9.0 g/dL
• WBC= 87x 109/L ,
• PLT = 675.109/L
 Diagnostic Workup
Physical examination : spleen and liver size
Complete blood count
Peripheral blood morphology
Bone marrow aspiration
Cytogenetic
FISH
RT PCR BCR ABL qualitative and RT-Q-PCR
Mutational analysis
ECG
Standard biological profile with Hep-B -
serology

Hochhaus A. et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia.
Leukemia (2020) 34:966–984
CHRONIC MYELOGENIC LEUKEMIA
CML
Chronic myelogenous leukemia (CML) is an uncommon type of cancer of the bone marrow
the spongy tissue inside bones where blood cells are made.
CML causes an increased number of white blood cells in the blood.
The term "chronic" in chronic myelogenous leukemia indicates that this cancer
tends to progress more slowly than acute forms of leukemia.
The term "myelogenous" n chronic myelogenous leukemia refers to the type of cells
affected by this cancer.
Chronic myelogenous leukemia can also be called chronic myeloid leukemia and
chronic granulocytic leukemia.
It typically affects older adults and rarely occurs in children, though it can occur at any age.
SYMPTOM AND SIGN OF CML

• Pallor
• Fatigue
• Anemia
• Leukocytosis
• Thrombocytopenia or
thrombocytosis
• Splenomegaly
• Loss of appetite
• Excessive sweating
 Chronic Myelogenous Leukemia with splenic
enlargement and infarction

Case courtesy of Dr Hani Makky Al Salam,

Radiopaedia.org, rID: 9178
 Introduction
• Central to the pathogenesis of
• Incidence of CML is around 10- CML is the fusion of the
15 cases /106/year. Abelson murine leukemia
• Slight higher incidence in men (ABL) gene on chromosome 9
than women with the breakpoint cluster
• The incidence increases with age region (BCR) gene on
chromosome 22, which
• The median age of diagnosis results in expression of an
ranges between 60 and 65 years oncoprotein, termed BCR-ABL
• Very rare in children • BCR-ABL is a constitutive TK,
• The prevalence of CML is promotes growth and
steadily rising replication → leukemogenesis
Jabbour and Kantarjian. Am. J. Hematol. 2012; 87:1038–1045 Annals of Oncology 23 (Supplement 7): vii72–vii77, 2012
Hochhaus, A. et al. Annal of Oncology 28 (Supplement 4):iv4-iv5,2017 doi:10.1093/annonc/mds228
 Molecular Biology and Pathology of Chronic Myelogenous Leukemia

https://nci-media.cancer.gov/pdq/media/images/533336.jpg
J Mol Diagn. 2004 Nov; 6(4): 343–347.
Dr Sardjito Hospital, CML Registry 2010-2014

Ninety nine percent (99%) of CML patients

in Yogyakarta, Indonesia are BCR-ABL
positive, with 74.3% have b3a2 transcript,
22.4% have b2a2 trascript, 1.1% have co-
expression of b3a2 and b2a2 transcript, and
the rest (2.2%) have uncommon bands that
still need to be confirmed.

Paramita DK et al. APJCP 2020; 21 (6):1545-1550

• The natural history of chronic myeloid leukemia (CML) progresses
from a relatively benign chronic phase into a fatal blast crisis, which
resembles acute leukemia
Natural history of CML
 normal

(A–B): Chronic myeloid leukemia (CML) showing hypercellular bone marrow on H & E staining at
×100 and ×400 magnification. (C): Classical karyotype of CML translocation – t(9; 22) & (D): CML
Complex translocation 9,6,19,22
Ujjan ID et al.Pak J Med Sci 2015;31(4):936-940
RISK Stratification
Case-2
• An 85-year old man admitted to hospital due to fatigue and weak
• He losses his appetite for the last 2 weeks
• He does not have any comorbidities and started to recognize the
gradual declining of hemoglobin since 6 month ago
• The doctor found patient’s condition pale and weak. Some palpable
cervical lymph nodes were found. Splenomegaly was Schuffner II
Case courtesy of Dr Ian Bickle, Radiopaedia.org, rID: 52825
 Splenic deposit in CLL

Case courtesy of Ed Uthman, Radiopaedia.org,

rID: 77580
Laboratory findings
• Hb=8.2 g/dL
• WBC = 72.000/microL
• AT =78.000/microL
• Granulocyt: 42 %; Lymphocyte : 66 % monosit 1% eosinophil 1 %
basophil 1 %
• Doctor then ordered Peripheral blood examination and bone marrow
aspiration
 CHRONIC LYMPHOCYTIC LEUKEMIA

• The most common leukemia in western world. Its incidence 4.2:100 000
/year.
• It is very rare in Asian, incidence is up to 10 lower than Caucasian
• Not top 5 most common cancer in both sexes in Indonesia
• Median age at diagnosis is 72 years. CLL is a disease of the elderly
• Incidence is higher in family with CLL
 Overview CLL in the Past
• progressive accumulation of • Management
lymphocytes. • When asymptomatic: wait and
• CLL lymphocytes are watch regimen
morphologically • Initiation of treatment:
indistinguishable from a normal
mature lymphocyte chlorambucil ± steroid
• CLL lymphocytes are functionally cyclophosphamide ±
inert, their life-span is longer steroid
than of normal lymphocytes. irradiation
• CLL lymphocytes are not rapidly
proliferating.
Diagnosis and Molecular Biology
• Lymphocytosis, monoclonal B Cell >
5000 B lymphocytes/µl
• small, mature-appearing lymphocytes
with a narrow border of cytoplasma
• dense nucleus
• lacking discernible nucleoli, and
• having partially aggregated chromatin
• CD 5, CD 19, CD 20, CD 23

AFIP Atlas of Tumor Pathology.

 Pretreatment Evaluation of Pts With CLL
Tests to Establish the Diagnosis Assessment Before Treatment Additional Tests Before Treatment
▪ History and physical, performance
▪ Complete blood count and status ▪ Cytogenetics (FISH) for del(13q),
differential count ▪ Complete blood count and del(11q), del(17p), trisomy 12*
▪ Immunophenotyping of differential ▪ del(6q) in the peripheral blood
lymphocytes ▪ Marrow aspirate and biopsy* lymphocytes
▪ Serum chemistry, serum ▪ IGVH mutational status, ZAP-70†,
immunoglobulin, direct antiglobulin and CD38†
test ▪ CT scan of chest, abdomen, and
▪ Chest radiograph pelvis†
▪ Infectious disease status ▪ MRI, lymphangiogram, gallium
Hep B and C, CMV, HIV scan, PET scans†
▪ Abdominal ultrasound‡

*Desirable in clinical practice.

†Not generally indicated in clinical practice.
‡Used in some countries to monitor lymphadenopathy and organomegaly.

Hallek M, et al. Blood. 2008;111:5446-5456. Slide credit: clinicaloptions.com

 CLL Clinical Staging

Rai system Binet system

Stage Description Modified Stage Description

Risk Status A Hemoglobin ≥ 10 g/dL, platelets ≥ 100.000/µL, <3
Lymphocytosis, lymphocyte in blood low enlarged area
0
5x109 /L clonal B cells, B Hemoglobin ≥ 10 g/dL, platelets ≥ 100.000/µL, ≥3
> 40% lymphocytes in bone marrow enlarged area
I Stage 0 with enlarged lymph node(s) intermediate C Hemoglobin < 10 g/dL, platelets < 100.000/µL, any
enlarged area
II Stage 0-I with splenomegaly or intermediate
hepatomegaly or both
III Stage 0-II with Hg < 11.0 g/dL or high
hematocrit <33%
IV Stage 0-III with platelets < 100.000/µL high

NCCN Guideline Version 3.2020

RISK STRATIFICATION

CLL-IPI working group. Lancet Oncol. 17, 779–790 (2016).

Parikh. Blood Cancer Journal (2018) 8:93
DOI 10.1038/s41408-018-0131-2
 Prognostic Factor in CLL
Older Prognostic Factor Poor Prognostic Factor
Clinical staging—Rai and Binet Advanced clinical stage
Lymphocyte doubling time (LDT) Short LDT <6 months (only when lymphocyte counts above
30,000/mL)
Bone marrow infiltration Diffuse pattern of infiltration
CD38 expression on CLL cells High CD38 expression (≥30%)
Zap-70 expression on CLL cells High Zap-70 expression (≥20%)
IGHV mutation status U-CLL (2%)
Serum Beta 2-microglobulin Elevated (3.5 mg L-1)
Serum thymidine kinase Elevated (>10 U L-1)
FISH cytogenetics Del17p, del11q with high FISH%
VH3-21 gene usage With subset 2
Newer Prognosis
Stereotypy of BCR, Specific subsets, VH4-39 gene usage
Gene mutations TP53, NOTCH1, BIRC3, SF3B1, or ATM
microRNA (miR) 155 Poor response and disease progression
CD49d Expression High (30%)
CCL3, CCL4 serum levels Elevated levels with advanced disease and poor outcome
MRD assessment MRD Positive disease
Blood Cancer Journal (2018) 8:93