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ACUTE &

CHRONIC
LEUKEMIA
Leukemia

Group of malignant disorders of the


hematopoietic tissues characteristically
associated with increased numbers of white cells
in the bone marrow and / or peripheral blood
Development of Leukemia in the
Bloodstream

Stage 1- Normal Stage 2- Symptoms Stage 3- Diagnosis

Legend
Stage 5a- Anemia
White Cell
Red Cell
Platelet Stage 4- Worsening
Blast
Stage 5b- Infection
Germ
ALL
nave

B-lymphocytes

Plasma
Lymphoid cells
progenitor T-lymphocytes

AML
Hematopoietic Myeloid Neutrophils
stem cell progenitor

Eosinophils

Basophils

Monocytes

Platelets

Red cells
Types of Leukemia
Acute Lymphoblastic Leukemia (ALL)

Acute Myeloblastic Leukemia (AML)

Chronic Lymphocytic Leukemia (CLL)

Chronic Myelocytic Leukemia (CML)


Myeloid vs Lymphoid

Anydisease that arises from the myeloid


elements (white cell, red cell, platelets) is a
myeloid disease
.. AML, CML

Anydisease that arises from the lymphoid


elements is a lymphoid disease
.. ALL, CLL
Acute vs. chronic leukemia
Leukemias are classified according to cell of origin:
Lymphoid cells
ALL - lymphoblasts
CLL mature appearing lymphocytes
Myeloid cells
AML myeloblasts
CML mature appearing neutrophils
On a CBC, if you see:
Predominance of blasts in blood
consider an acute leukemia
Leukocytosis with mature lymphocytosis
consider CLL
Leukocytosis with mature neutrophilia
consider CML
Chronic and Acute
Chronic Leukemia:
accumulation of mature granulocytes or lymphocytes

longer clinical course (several to many years)


Progress slowly (runs a slow course)
Not immediately fatal.
Acute Leukemia:
excess myeloblasts or lymphoblasts
short clinical course (weeks to months)
Progress rapidly (runs a fast course)
Life expectancy short without treatment.
Acute leukemias
Definition: Malignancies of immature
hematopoietic cells.
(> 20% blast cells in the bone marrow)

Types: Acute Myeloid Leukemia (AML)

Acute Lymphoblastic leukemia (ALL)

Groups: Childhood (< 15) > 80% ALL


Adult (> 15) > 80% AML
Chronic Myeloid Leukaemia
Themyeloproliferative diseases (MPDs)
are clonal stem cell disorders
characterised by leukocytosis,
thrombocytosis, erythrocytosis,
splenomegaly, and bone marrow
hypercelularity
Acute Lymphoblastic Leukemia
(ALL)
Clonal proliferation and accumulation
of blast cells in blood, bone marrow and
other organs
Disorder originates in single B or T
lymphocyte progenitor
Incidence in adults : 20% of acute
leukemias
Bone Marrow Pathology
Acute Leukemia

accumulation of blasts in the marrow


Acute leukemias - laboratory
findings
. Blood examination
- anemia,
- thrombocytopenia,
- variable leukocyte count, usually increased,
- blood morphology: presence of blast cells
2. Bone marrow morphology
- presence of blast cells,
- suppression of normal haematopoiesis
Acute leukemias - clinical
features
1. Bleeding
2. Fever/infection
3. Bone/joint pain
4. Hepatomegaly
5. Splenomegaly
6. Lymphadenopathy
7. CNS involvement
Acute leukemias - Laboratory
findings
1. Cytochemical stains
2. Immunophenotyping
3. Cytogenetics
4. Molecular studies
Differentiation between AML
and ALL
Age
AML - mainly in adults
ALL - common in children
Blood
AML - anemia, neutropenia, thrombocytopenia, myeloblasts and
promyelocytes
ALL - anemia, neutropenia, thrombocytopenia, lymphoblasts and
prolymphocytes
Morphology
AML - blasts are medium to large with more cytoplasm which may
contain granules, Auer rods, fine nuclear chromatin, distinct
nucleoli
ALL - blasts are small to medium with scarce cytoplasm, no
granules, fine nuclear chromatin and indistinct nucleoli
Cytochemistry
AML - positive peroxidase and Sudan black, negative TdT
ALL - negative peroxidase and Sudan black, positive TdT
Acute Leukemia:
Clinical Manifestations
Constitutional & Metabolic effects:

Weight loss
Fever
Hyperkalemia
Hyperuricemia
Acute Leukemia:
Clinical Manifestations
Marrow
replacement, organ infiltration
& metabolic effects

Marrow replacement
Neutropenia: infection
Anemia: pallor, fatigue, dyspnea
Thrombocytopenia: abnormal
bruising and bleeding
Acute Leukemia:
Clinical Manifestations
Organ infiltration

Bone pain
Hepatosplenomegaly
Lymphadenopathy
Gingival hypertrophy
Leukemic meningitis
AML:
FAB classification
French American British classification

M0-M7 based on morphology, and


special cytochemical studies

Historically,
distinguishing AML M0 from
ALL was a major clinical problem
AML
FAB classification
M0,M1, M2: Myeloblasts with no, little or
some granulocytic maturation
M3: Promyelocytic leukemia
M4: Myelomonocytic or eosinophilic
M5: Monocytic
M6: Erythroleukemia
M7: Megakaryoblastic

Not all that useful except for M3


AML M1
Note the myeloblasts and the auer rod:
AML M2
Note
myeloblasts and hypogranulated
PMNs:
AML M3
Note hypergranular promyelocytes:
AML M4
Note monoblasts and promonocytes:
AML M5A
Note monoblasts:
AML M6
Note M1 type monoblasts
Morphologic subtypes of
acute lymphoblastic
leukemias (FAB
classification
Subtype Morphology Occurrence (%)
L1 Small round blasts 75
clumped chromatin
L2 Pleomorphic larger blasts 20
clefted nuclei, fine chromatin
L3 Large blasts, nucleoli, 05
vacuolated cytoplasm
FAB Classification
L1
Small, uniform lymphoblasts
Scant cytoplasm, indistinct nucleoli,
occassional clefting of nucleus, chromatin is
clumped
Affects primarily children
FAB Classification: L2
L2
Large, pleomorphic lymphoblasts
Abundant cytoplasm, predominant nucleoli,
nuclear clefting and indentation
Affects adults
FAB Classification: L3
L3: Burkitts type
Uniform population of large lymphoblasts with
deeply basophilic cytoplasm, vacuoles,
round to oval nuclei without indentation
Affects adults and children
CHRONIC LEUKEMIAS
Definition: Neoplastic proliferations of
mature haemopoeitic cells.

Types: Chronic lymphocytic leukemia


(CLL) Chronic myeloid leukemia (CML)
CHRONIC LYMPHOCYTIC
LEUKAEMIA (CLL)
Neoplastic proliferations of mature
lymphocytes.
Distinguished from ALL by

A. Morphology of cells.
B. Degree of maturation of cells.
C. Immunologically immature blasts in
ALL.
D. CLL affects mainly elderly.
SYMPTOMS of CLL

Weakness, fatigue, vague sense of


being ill

Night sweat
Infections esp pneumonia
TREATMENT OF CLL
Observation
Chemotherapy. Oral chlorambucil
Fludarabine,
Immunotherapy Anti-CD 20 (rituximab),
Anti-CD 52 (Alemtuzumab)
Indications for starting chemotherapy
a. Progressive Symptoms
b. Progressive Anemia or Thrombocytopenia
c. Bulky LN, large spleen
d. Recurrent Infections
CHRONIC MYELOID
LEUKEMIA
CML is a clonal stem cell disorder
characterised by increased proliferation
of myeloid elements at all stages of
differentiation.

Incidence increases with age, M > F.


CML is characterised by 3
distinct phases
a) Chronic Phase:Proliferation of
myeloid cells, which show a full
range of maturation.

b) Accelerated Phase decrease in


myeloid differentiation occurs.

c) Blast crisis (acute leukemia)


CLINICAL PRESENTAITON OF
CML
Symptoms

Asymptomatic (50% of patients)


Fatigue
Weight loss
Abdominal fullness and anorexia
Abdominal pain, esp splenic area
Increased sweating
Easy bruising or bleeding
CYTOGENETICS OF CML
Philadelphia (Ph) chromosome is an
acquired cytogenetic abnormality in all
leukaemia cells in CML

Reciprocal translocation of
chromosomal material between
chromosome 22 and chromosome 9.

t(9;22)
Treatment
ACUTE LYMPHOBLASTIC LEUKEMIA ( ALL)
DOSE ROUTE REGIMEN
Induction ( 4 weeks)
Vincristin 1.5 mg/m2 I.V Weekly for 4 weeks
Prednisolone 40mg/m2 Oral Daily for 4 weeks
L- Asparaginase 6000u/m2 I.M 3xWeekly for 3
Daunorubicin 45mg/m2 I.V weeks
Daily for 2 days
Intensification(1 week)
Vincristin 1.5mg/m2 I.V 1 dose
Daunorubicin 45mg/m2 I.V Daily for 2 days
Prednisolone 40mg/m2 Oral Daily for 5 days
Etoposide 100mg/m2 I.V Daily for 5 days
Cytarabine 100mg/m2 I.V 2x daily for 5 days
Thioguanine 80mg/m2 Oral Daily for 5 days
CNS Prophylaxis( 3 weeks)
Cranial irradiation 24 Gy
Methotrexate I.T weekly for 3 weeks

Maintenance Therapy ( 2
years) 20mg/m2 Oral Weekly
Methotrexate 75mg/m2 Oral Daily
6-Mercaptopurine 40mg/m2 Oral 5days/ Month
Prednisolone 1.5mg/m2 I.V Monthly
vincristine
(Treatment of acute
leukemias)Induction
Obtained by using high doses of chemotherapy
1 Severe bone marrow hypoplasia
2 Allowing regrowth of normal residual stem cells to
regrow faster than leukemic cells.
Remission
Normal neutrophil count
Normal platelet count
Normal hemoglobin level
Remission defined as < 5% blast in the bone marrow
(Treatment of acute leukemia)
Consolidation
Different or same drugs to those used during
induction

Higher doses of chemotherapy

Advantage: Delays relapse and improved


survival
(Treatment of acute leukemias)
Maintenance
Smaller doses for longer period

Produce low neutrophil counts & platelet


counts

Objective is to eradicate progressively any


remaining leukemic cells.
(Treatment of acute leukemias)
Supportive Care
Vascular access (Central line)
Prevention of vomiting
Blood products (Anemia, Plat)
Prevention & treatment of infections
(antibiotics)
Management of metabolic
complications
ALL vs AML
ALL AML

Induction Induction

Consolidation Consolidation

Maintenance No maintenance

CNS prophylaxis all CNS Selected


patients group only
DRUGS USED TO TREAT ACUTE
MELOBLASTIC LEUKEMIA ( AML)
Anthracycline Antimetabolite

Daunorubicin Cladribine
Doxorubicin Cytarabine
Idarubicin Fludarabine
Hydroxyurea
Mitoxantrone
Methotrexate
6-Mercaptopurine
6-Thioguanine
DRUGS USED TO TREAT ACUTE
MYELOBLASTIC LEUKEMIA (
AML)
TOPOISOMERASE CELL MATURING AGENT
INHIBITORS
ALL-TRANS RETIONIC ACID
ETOPOSIDE (ATRA)
TOPOTECAN ARSENIC TRIOXIDE

o DNA DAMAGING o HYPOMETHYLATING


( ALKYLATING AGENT) AGENT

CYCLOPHOSPHAMIDE AZACITIDINE
CARBOPLATIN DECITABINE
TEMOZOLOMIDE
Treatment of Chronic
Lymphoblastic Leukemia (CLL)
Alkylatingagents :
Chlorambucil intermittently (10 mg/m2 x 7
days, monthly ) or continously ( 5 -10 mg /
day )
Combinations :
COP : Cyclophosphamide, Oncovin,
Prednisolone( 5 day monthly course )
Chlorambucil + Epirubicin
CHOP : COP + Doxorubicin
Treatment of Chronic
Lymphoblastic Leukemia (CLL)
Corticosteroids :
Prednisolone : 30 mg / m2 for 3 weeks + 1 week tailing
off for initial treatment of pts with Stage C disease.
High dose Methylprednisolone IV at 1 g/m2 ( 5-day
monthly course )
Nucleoside analogues :
Fludarabine ( 25 mg / m2 IV daily as 30 min infusion for
5 days every 28 days )
Fludarabine + Cyclophosphamide
Pentostatin ( 2 mg/m2/day IV for 5 days every 28
days)
Cladribine ( IV infusion over 2 hrs dose of 0.12
mg/kg/day for 5 consecutive days )
Nucleoside analogues
Studies have shown FLUDARABINE
superior to Chlorambucil in CLL with
higher clinical response rates, superior
time to treatment failure, better tolerance
in pts > 65 yrs.
FLUDARABINE Currently 1st line of
treatment in CLL
Monoclonal Antibodies
Alemtuzumab ( monoclonal antibody directed at
CD 52 ) :
1st line agent
For salvage in pts with fludarabine refractory
disease
Effective in CLL with p53 mutations
Very effective in clearing Bone Marrow disease
Limited activity in clearing bulky
lymphadenopathy
Has role in consolidation therapy for elimination of
minimal residual disease.
Monoclonal Antibodies
Anti-viral prophylaxis and prophylactic antibiotics for
Pneumocystis carnii are recommended for pts
receiving Alemtuzumab and for 2 4 months after
treatment
Rituximab (monoclonal antibody specific for CD 20)
used extensively in combination with chemotherapy.
Fludarabine combined with Rituximab shown higher
clinical remission rates than fludarabine alone .
FCR ( Fludarabine, Cyclophosphamide, Rituximab )
shown clinical response rates of 76% in trials.
CFAR ( Cyclophosphamide, Fludarabine,
Alemtuzumab, Rituximab ) still under trials
Monoclonal Antibodies
LENALIDOMIDE : An immunomodulatory
drug currently approved for use in
Multiple Myeloma and MDS with deletion
of Chr 5q .
Studies have shown response rates of 47
38 % with complete response rates of 9 %
and elimination MRD have been
reported.
Bone Marrow Transplantation
Allogenicbone marrow transplantation is
the only known curative therapy.

Addition of ALEMTUZUMAB to pts receiving


hematopoetic stem cell transplantation
aids in elimination of MRD ( Minimal
Residual Disease )
Radiotherapy
For many decades, irradiation of spleen was primary
treatment of CLL.
Useful in pts with bulky lymph nodes compressing nerves
/ other organs & massive / painful splenomegaly.
IRRADIATION of mediastinum, extracorporeal irradiation
of blood and total body irradiation may reduce the
peripheral blood lymphocyte counts and size of lymph
node, spleen and liver.
Total body irradiation plus cyclophosphamide &
prednisolone had higher response to those treated with
TBI alone.
Supportive therapy
Hypogammaglobulinemia : IV Immunoglobulins

Prednisolone - useful against autoimmune manifestations of


disease.

Rituximab alone / in combination : effective in eliminating the B


cell clone inducing autoimmune disorders, particularly
autoimmune thrombocytopenia

Leukapheresis : removal of leukemic cells reduces tumor load and


leukostasis.

Long term antibiotics


CML-Principles of Treatment
Control & prolong chronic phase (non-curative)
- Tyrosine kinase inhibitors-Imatinib
- Alpha-Interferon
- Oral chemotherapy (Hydroxyurea)
Eradicate malignant Clone (curative)
- Allogeneic BM/stem cell transplantation
- Alpha Interferon
- Imatinib? 2nd line TKIs
TREATMENT OF CML
Tyrosine kinase inhibitor (TKI) Imatinib (Glivec) is
the first line treatment
In resistent cases 2nd line TKIs (Nilotinib,
Dasatinib, Bosutinib) very useful
Allogenic bone marrow trasnsplantation can
be curative in pts resisrant to TKIs but has
significant complications & mortality
Accelerated and blast phase
Treat like AML or ALL followed by BMT
Bone marrow or PBSC
transplantation in leukemias
Types of transplant
1. Autologous transplant
2. Allogeneic Transplant
Purpose of transplant
Autologous
-To deliver a high dose of chemo to kill any
residual cancer
(lymphoma, multiple myeloma)
Allogeneic
-To eradicate residual leukemia cells
-Graft vs leukemia effect
THANK
YOU