Diagnosis and Treatment

of Leukemia

Sahyuddin

Dept. of Int. Medicine, Faculty of Medicine , Hasanuddin Univ.

 Leukemia

▪ Is a malignant hematologic disorder characterized by a

proliferation of abnormal white cells, enhanced differentiation ,
suppression apoptosis that infiltrate the bone marrow,
peripheral blood & organs
▪ 4 main types of leukemia
▪ Acute or chronic
▪ Myelogenous or Lymphocytic
➔ AML,ALL,CML,CLL
 ALL CLL Lymphomas MM
naïve

B-lymphocytes

Plasma
Lymphoid cells
progenitor T-lymphocytes

AML Myeloproliferative disorders

Hematopoietic Myeloid Neutrophils

progenitor
stem cell
Eosinophils

Basophils

Monocytes

Platelets

Red cells
 Acute vs. Chronic Leukemia

▪ Acute Leukemia (AML and ALL)

▪ excess myeloblasts or lymphoblasts
▪ short clinical course (weeks to months)

▪ Chronic Leukemia (CML and CLL)

▪ accumulation of mature granulocytes or
lymphocytes
▪ longer clinical course (several to many years)
Acute Leukemia
Acute Myelogenous Leukemia
 I. Acute Leukemia

▪ A clonal, molecular abnormality of

hematopoietic blast cells resulting in
a block differentiation & uncontrolled cell
proliferation & suppression apoptosis

▪ Accumulation of leukemic blast cells

results in marrow replacement, organ
infiltration & metabolic effects
 Acute Leukemia:
AML versus ALL

▪ Adults ➔ 85% of acute leukemia is AML

▪ Children ➔ 85% of acute leukemia is ALL
▪ Leukemic Blast morphology
▪ AML: cytoplasmic granules, Auer rods,
more cytoplasm, 2-5 nucleoli
▪ ALL: no cytoplasmic granules, minimal
cytoplasm, 1-2 nucleoli
 II. Pathogenesis Leukemia

Penampungan air
(SST)

Pipa air
(PD)

Rumah
(Organ)
 Sel Normal vs Sel kanker

Gain of function mutations Loss of function of Loss of Apoptosis

of tyrosine kinases transcription factors
needed for differen. eg.:
eg. FLT3, c-KIT mutations
N- & K-RAS mutations eg. AML1-ETO Bcl-2 over expression
BCR-ABL CBFb-SMMHC
TEL-PDGFbR PML-RARa

enhanced
Normal enhanced
Normal Normal
Suppression
proliferation + differentiation + apoptosis

Ggn
ImunSistem
surveilence
imun
 II. Three-hit model of leukemogenesis

Acute Leukemia
Gain of function mutations Loss of function of
Loss of Apoptosis
of tyrosine kinases transcription factors
eg.:
eg. FLT3, c-KIT mutations needed for differen.
Bcl-2 over expression
N- & K-RAS mutations eg. AML1-ETO
BCR-ABL CBFb-SMMHC
TEL-PDGFbR PML-RARa

enhanced differentiation Suppression

proliferation + block + apoptosis

Acute
Leukemia
 II. Three-hit model of leukemogenesis

Chronic Leukemia
Gain of function mutations Loss of function of Loss of Apoptosis
of tyrosine kinases transcription factors eg.:
eg. FLT3, c-KIT mutations needed for differen. Bcl-2 over expression
N- & K-RAS mutations eg. AML1-ETO
BCR-ABL CBFb-SMMHC
TEL-PDGFbR PML-RARa

enhanced Normal Suppression

proliferation + differentiation + apoptosis

Acute
Leukemia
 Myeloid maturation

myeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATION

Adapted and modified from U Va website

 Acute Leukemia

▪ Accumulation of blasts in the marrow

 How to distinguish AML vs CML
from looking at peripheral blood

Myeloid cell CML AML normal

Blasts q q
Promyelocytes q
Myelocytes q
Metamyelocytes q
Bands q
Neutrophils q # q
Significance of adult acute leukemia

▪ A hematologic urgency
▪ Usually fatal within weeks to months
without chemotherapy
▪ With treatment, high mortality due to
disease or treatment-related complications
(unlike childhood acute leukemia)
▪ Notify Hematologist promptly if acute
leukemia is suspected
 Classification of AML

___________________________________
▪ M 1 : L Mieloblastik akut
▪ M 2 : L Mieloblastik akut + deferensiasi
▪ M 3 : L Promielositik akut
▪ M 4 : L Mielo-monositik akut
▪ M 5 : L Monoblastik akut
▪ M 6 : Eritroleukemia
___________________________________
III. Causes of acute leukemias

▪ Idiopathic (most)
▪ Underlying hematologic disorders
▪ Chemicals, drugs
▪ Ionizing radiation
▪ Viruses (HTLV I)
▪ Hereditary/genetic conditions
 IV. Clinical manifestations

▪ Symptoms due to :
1. Marrow failure
2. Leukostasis SST
3. Tissue infiltration
4. Constitutional symptoms PD
5. Other (DIC) →
L.Promielositik & L.Monositik Organ

▪ Usually short duration of symptoms

 1. Marrow failure

▪ Neutropenia : Infections, sepsis

▪ Anemia : Fatigue, pallor
▪ Thrombocytopenia : Bleeding
 2. Leukostasis

▪ Accumulation of blasts in microcirculation

with impaired perfusion
▪ Lungs : Dyspnea, chest pain, hypoxemia,
pulmonary infiltrates
▪ CNS : Headaches, altered mentation,
ocular symptoms, stroke
▪ Priapism
▪ Myocardial infarction
▪ Only seen with WBC >> 50 x 109/L
 3. Infiltration of tissues/organs

▪ Enlargement of liver, spleen, lymph nodes

▪ Gum hypertrophy
▪ Bone pain
▪ Other organs: CNS, skin, testis, any organ
Gum hypertrophy
Gingival Infiltration in Monocytic
(AML M4 eos) Variant of AML

▪ Mani, A, Lee, DA. Leukemic Gingival Infiltration. N Engl J Med 2008; 358(3): 274. Copyright ©2008 Massachusetts Medical Society
Chloromas

A
B
C

NEJM 1998
 Myeloid sarcoma

▪ Extramedullary disease (myeloid sarcoma)

▪ Can also have involvement of lymph nodes,
intestine, mediastinum, ovaries, uterus
4. Constitutional symptoms

▪ Fever and sweats common

▪ Weight loss less common
 Laboratory features

▪ WBC usually elevated, but can be

normal or low
▪ Blasts in peripheral blood
▪ Normocytic anemia
▪ Thrombocytopenia
▪ Neutropenia
▪ DIC
Click to edit Master title style
Click to edit Master title style
BONE MARROW
PUNCTURE
No. RM : 01010693 No. Registrasi : 2303180138
Nama : JUMRIAH Tgl. Registrasi : 18/03/2023 18:18:45
Sex / Tgl Lahir : Perempuan / 19-03-1967 Tgl. Hasil : 18/03/2023 20:11:17
No. Lab : 1011601032303180095 Unit Pengantar : Non Bedah
Diagnosa : Anemia Aplastik Dokter Perujuk : Dr. dr. HASYIM KASIM, Sp.PD, KGH

PEMERIKSAAN HASIL NILAI RUJUKAN SATUAN

Group : HEMATOLOGI

Kelompok : Hematologi Rutin

Hematologi Rutin Automatik _

WBC 1.3 4.00 - 10.0 10^3/ul
RBC 2.42 4.00 - 6.00 10^6/uL
HGB 7.8 12.0 - 16.0 gr/dl
HCT 23 37.0 - 48.0 %
MCV 97 80.0 - 97.0 fL
MCH 32 26.5 - 33.5 pg
MCHC 33 31.5 - 35.0 gr/dl
PLT 17 150 - 400 10^3/ul
RDW-SD 63.8 37.0 - 54.0 fL
RDW-CV 18.2 10.0 - 15.0 %
PDW 9.6 10.0 - 18.0 fL
MPV 11.1 6.50 - 11.0 fL
PCT 0.00 0.15 - 0.50 %
NEUT 8.5 52.0 - 75.0 %
LYMPH 82.9 20.0 - 40.0 %
MONO 7.8 2.00 - 8.00 %
EO 0.8 1.00 - 3.00 %
BASO 0.0 0.00 - 0.10 %
LED I >140 (L < 10, P <20) mm
Kelompok : Koagulasi

Waktu Prothtrombine (PT) _

INR 0.99 --
Auer rods in AML
Treatment of acute leukemias

Choice of Rx is influenced by :
1. Type (AML vs ALL)
2. Age
3. Curative vs palliative intent
 Principles of treatment

1. Combination chemotherapy
▪ First goal is complete remission
▪ Further Rx to prevent relapse
▪ Combination Daunorubicin + Cytarabin
▪ Azacitidine, decitabine, venetoclax,
gentuzumab ozogamicin
2. Supportive medical care
▪ Transfusions, antibiotics, nutrition
3. Psychosocial support
▪ Patient & family
Chemotherapy for acute leukemias

▪ Phases of ALL treatment

▪ induction
▪ intensification
▪ CNS prophylaxis Post-remission therapy

▪ maintenance
▪ Phases of AML treatment
▪ Induction remission
▪ consolidation (post-remission therapy)
Hematopoietic stem cell transplantation

▪ Permits “ Rescue ” from otherwise

excessively toxic treatment
▪ Additional advantage of graft-vs-leukemia
effect in allogeneic transplants
▪ Trade-off for allogeneic transplantation:
greater anti-leukemic effect but more toxic
 Prognosis

▪ Children w/AML have poorer prognosis than

w/ALL
▪ WBC < 20,000, mm is more favorable the
20-49,000 mm, > 50 worst prognosis
▪ Age, tumor burden at time of diagnosis,
drug sensitivity of cells are more important
prognostic indicators than cell morphology
Chronic Myelogenous Leukemia
I. Chronic Myelogenous Leukemia ( CML )

▪ Chronic Myelogenous Leukemia ( CML )

- Belongs to Myeloproliferative Disorders
- Adult & elderly
- Relatively slow clinical progression
- Relatively better live expectancy than
acute leukemia.
 II. Pathogenesis of CML :

▪ Majority : Philadelphia chromosome (+)

▪ t (9:22) : resiprocal transversion of genetic
material from chrom 9 to 22 (vv)
➔ new abnormal protein
➔ initiating abnormal proliferation of myeloid cells
in bone-marrow ➔ CML.
II. Pathogenesis of CML :
 III. Clinical picture of CML :

▪ Adult & elderly

▪ Male > female
▪ Splenomegaly ( Schuffner VII / VIII )
▪ Sometimes hepatomegaly
▪ Complaints : abd. fullness/dyspneu
abdominal mass
early satiety
 Physic
Hemato

Anamnesis CML

Cytogen

BCR-ABL
 Trias CML

Splenomegali

ADT : Pasar Malam Diagnosis CML

Pemeriksan BCR-ABL
Targeting terapi (TKI) :
- Imatinip mesylate (Glivec)
- Nilotinib (Tasigna)
- Dasatinib
 Bone marrow aspiration :

▪ Increased of BM cellularity ( hypercellularity )

▪ Common BM appearance :
- erythropoiesis normal / increased
- megakaryopoiesis normal / increased
- granulopoiesis : hyperactive
( increased of granulocytes in all of stage
of maturation )
 Chronic Myelogenous Leukemia (CML)
2. Accelerated phase :
1.Chronic stable - Blasts 10-19% of wBC
phase (CP): in peripheral & BM
- blast < 10% in - Persistent
the blood & BM
CML
thrombocytopenia (<
100 × 109/L)
- 85% pts dx/ in CP
(WHO) - persistent
- Progres to AP & BP thrombocytosis (>
after 3-5years 1000 × 109/L)
-Increasing white blood
cells & spleen size

3. Blast crisis :
- Blasts ≥ 20% of peripheral blood WBC or BM
- Extramedullary blast proliferation
- Large foci or clusters of blasts on bone marrow
biopsy
 IV. Management of CML

The goals of treatment of CML

1 2 3
1.Hemato 2.Cytogen 3. Molecular
remission remission remission
(normal (normal (negative of
complete chromosome) polymerase
bloodcell , chain reaction
count (CBC), (PCR) &
negative of the
mutational
BCR/ABL
mRNA)
IV. Management of CML

1. Cytoreduksi Agents

2. Tyrosine kinase inhibitors

3. Leucopharesis

4. Transplantation
 IV. Management of CML
Historis Terapi CML
1. Cytoreduksi Agents :
▪ Th 1959 : Busulfan (Myleran)
▪ Th 1969 : Hydroxyurea ➔ fase lekositosis atau
trombositosis.
▪ Th 1990 an : Interferon-α (IFNα) ➔ gold standard sampai
diperkenalkannya Tyrosine Kinase Inhibitors (TKI)
2. Tyrosine kinase Inhibitors (TKI)
▪ Imatinib (first TKI & gold standard /terapi lini pertama)
▪ TKI generasi ke 2 : Nilotinib & Dasatinib
( approved sbg lini kedua, kemudian juga utk lini pertama )
 IV. Management of CML

▪ Leucopharesis:

1. Severe leukositosis

2. Complication (leukostasis)
 V. Prognosis

▪ Prognosis depend on clinical & lab. Factor

▪ Prognosis depend on therapy associated

factors:
1. Time to hematology remission
2. Duration of remission
3. Total dose of chemotherapy
4. Suppression of Ph-cell
Clinical progression in CML :

I. ChronicPhase
relatively stabil, lasting months / years

II. Accelerated Phase

decreased clin condition, weeks /months
blood smear : increased of blast cells

III. Blast Crisis Phase

worsened condition & laboratory findings
as an acute leukemia