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leukemia
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Leukaemia
Sunil Rao
Learning Objectives• Define leukemia• Identify the etiology of leukemia• Discuss the definition, Pathophysiology , signs
and symptoms, & management of: Acute Lymphoblastic leukaemia (ALL) Acute Myeloid Leukaemia (AML) Chronic Lymphocytic Leukaemia (CLL) Chronic Myeloid Leukaemia(CML)
LeukemiaDefinitionIt is a group of malignant disorders, affecting the blood and
blood –forming tissue of the bone marrow lymph system and spleen.
A etiology Combination of predisposing factors including genetic and
environmental influences. Chronic exposure to chemical such as benzene Radiation exposure. Cytotoxic therapy of breast, lung and testicular cancer.
Classification of leukemiasTwo major types (4 subtypes) of leukemias
Acute leukemias
Acute lymphoblastic leukemia (ALL)
Acute myelogenous leukemia (AML)
(also "myeloid" or "nonlymphocytic")
Chronic leukemias
Chronic lymphocytic leukemia (CLL)
Chronic myeloid leukemia (CML)
(Within these main categories, there are typically several subcategories)
Myeloid vs Lymphoid
• Any disease that arises from the myeloid
elements is a myeloid disease
….. AML, CML
• Any disease that arises from the lymphoid
elements is a lymphoid disease
….. ALL, CLL
Acute vs. chronic leukemia• Acute leukemias:• Young, immature, blast cells in the bone marrow (and often blood)• More fulminant presentation• More aggressive course
• Chronic leukemias:• Accumulation of mature, differentiated cells• Often subclinical or incidental presentation• In general, more indolent (slow) course• Frequently splenomegaly • Mature appearing cells in the B. marrow and blood
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
Acute leukemiasDefinition: Malignancies of immature hematopeotic cells.
(> 20% blast cells in the bone marrow)
Types: Acute Myeloid Leukaemia (AML)
Acute Lymphoblastic leukemia (ALL)
Groups: Childhood (< 15) > 80% ALL
Adult (> 15) > 80% AML
Elderly (> 60 years)
Acute leukemiasEtiology• Drugs & chemicals
• Alkylating agents (Chlorambucil, N mustard, Melphalan)
Topoisomerase inhibitors (Etoposide)
• Benzene• Ionizing radiation• Viruses
HTLV-1 (Adult T-cell leukemia Lymphoma)• Genetic disorders
Down’s syndrome• Myelodysplastic syndrome
Clinical presentationSymptoms• Usual 1-3 Month History : MDS – 1yr• (Features of BM failure)• Fatigue, malaise, dyspnea (anemia)• Bleeding eg after dental procedure
Easy bruisability
Severe epistaxis• Fever (infections)• Bone Pain
Clinical Presentation
Signs Pallor Hemorrhage from the gums, epistaxis, skin,
fundus, GI tract, urinary tract Hepato-splenomegaly Enlarged lymph nodes Gum (hypertrophy) or skin infiltration (M5) Fever (sepsis, pneumonia, peri-rectal abscess)
Differential Diagnosis
1. Aplastic anemia
2. Myelodysplastic syndromes
3. Multiple myeloma
4. Lymphomas
5. Severe megaloblastic anemia
6. Leukemoid reaction
Laboratory Tests
1. CBC a. Anemiab.
Trombocytopeniac. WBC
High Normal Low
2. Coagulation Studies (M3-DIC)
3. Biochemical Studies (U/E, LFT) Cont..
4. Peripheral Blood smear – blasts in almost all
cases
5. Bone Marrow Examination (>20% blasts)
6. Flow cyometry
(Surface immunophenotype of blast cells)
7. Cytogenetics (chromosomal analysis)
8. CSF analysis (all ALL patients, some AML)
9. HLA typing (for younger high risk patients)
Diagnostic methods of importance
• Bone marrow aspirate & Romanowsky stain (morphology) Enumeration of blasts, maturing cells, recognition of dysplasia
• Cytochemistry Myeloperoxidase, Sudan Black B, esterases to determine involved lineages
• Immunophenotyping
Defines blast cell lineage commitment as myeloid, lymphoid or biphenotypic
• Cytogenetics & molecular studies (FISH, PCR)Detects clonal chromosomal abnormalities, including those of prognostic importance
Blood Film-Normal
Blood Film-Normal
Normal BM cells
AML
AMLAuer rods
BMT/Stem CellCord BloodThrombosisHemostasisLaboratoryMalignanciesPediatricsRed Cell DisordersTransfusion MedicineVeterinary
Plasma Cells, Acute myelomonocytic (M-4) leukemiaClump of Plasma Cells most of which are small with a deep basophilic blue cytoplasm. Two cells in the center are partially smudged and show a paler cytoplasm and less dense and redder staining nuclear chromatin. Acute myelomonocytic (M-4) leukemia. Marrow - 100X
Image ID: 0147-094
Copyright 2001 - Carden Jennings Publishing Co., Ltd. All rights reserved. The material available at this site is for educational purposes only and is NOT intended for any diagnostic, clinically related, or other purpose. Carden Jennings Publishing Co., Ltd., assumes no responsibility for any use or misuse of this material and makes no warranty or representation of any kind with respect to the material available at this site.
• Age Above the age of 50 years the complete remission rate falls progressively
• Cytogenetics Three risk groups defined
– Good risk: patients with t(8;21), t(15;17) and inv/t(16)– Intermediate risk: Normal, +8, +21, +22, 7q-, 9q-, abnormal
11q23, all other– Poor risk: patients with -7, -5, 5q-, abnormal 3q and complex
karyotypes
Acute Myeloid Leukaemia (AML)
Prognostic factors in AML
1. Wheatley K, Burnett AK, Goldstone AH et al. Br J Haem 1999; 107: 69-792. Grimwade D, Walker H, Oliver F et al. Blood 1998; 92: 2322-33
• Treatment response – Patients with >20% blasts in the marrow after first course of treatment
have short remissions (if achieved) and poor overall survival
• Secondary AML – Patients with AML following chemotherapy or myelodysplasia respond
poorly
• Trilineage myelodysplasia – Patients with trilineage myelodysplasia have a lower remission rate
Acute Myeloid Leukaemia (AML)
Prognostic factors in AML
1. Wheatley K, Burnett AK, Goldstone AH et al. Br J Haem 1999; 107: 69-792. Grimwade D, Walker H, Oliver F et al. Blood 1998; 92: 2322-33
• Intensive chemotherapy – Patients < 55 years old: 80% remissions– Patients > 55 years old: progressive reduction in remission rate
• Bone marrow (stem cell) transplantation – Autologous and allogeneic transplants reduce the relapse rate
• Importance of cytogenetics for prognosis in children and adults < 55 years old
• Good risk cytogenetic group – 91% remissions, 65% five year survival
Acute Myeloid Leukaemia (AML)
Treatment and prognosis of AML
1. Wheatley K, Burnett AK, Goldstone AH et al. Br J Haem 1999;107: 69-792. Grimwade D, Walker H, Oliver F et al. Blood 1998; 92: 2322-33
Acute Lymphoblastic Leukaemia (ALL)
Poor Prognostic Factors• Age < 2 yrs and > 10 yrs • Male sex• High WBC count ( > 50 х109/L)• Presence of CNS disease• Cytogenetics Good risk Poor risk
Hyperdiploid (>50 ch) Hypodiploid,
t(9:22), t(4:11)• Bone Marrow: Blasts present on day 14• Day 28:No complete response
Prognostic factors in ALL
ALL
Bone Marrow-ALL
Treatment of acute leukemias
1. Specific therapy (chemotherapy)
2. Supportive treatment
Stages of Therapya. Induction
b. Consolidation
c. Maintenance
(Treatment of acute leukemias)
InductionObtained by using high doses of chemotherapy1. 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 leukemias)
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
1. Vascular access (Central line)
2. Prevention of vomiting
3. Blood products (Anemia, ↓Plat)
4. Prevention & treatment of infections
(antibiotics)5 Management of metabolic
complications
ALL vs AML
ALL
Induction
Consolidation
Maintenance
CNS prophylaxis all patients
AML
Induction
Consolidation
No maintenance
CNS – Selected group only
Definition: Neoplastic proliferations of mature haemopoeitic cells.
Types: Chronic lymphocytic leukemia (CLL)
Chronic myeloid leukemia (CML)
CHRONIC LEUKEMIAS
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.
CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)
SYMPTOMS of CLL
May be entirely absent in 40%
Weakness, easy fatigue, vague sense
of being ill
Night sweats
Feeling of lumps
Infections esp pneumonia
PHYSICAL EXAMINAITON-CLL
Pallor Lymphoadenopathy
a. Cervical, supraclavicular nodes more commonly involved than
axillary or inguino-femoral
b. Non-tender, not painful, discrete, firm, easily movable on palpation
Splenomegaly, mild to moderate Hepatomegaly
Stage
(0-1) - lymphocytosis LNS.
(II) - above + hepatosplenomagely.
(III-IV) - Anaemia. Hb< 10 g/l Thrombocytopenia.
Platelet count : <100x109/L.
CLINICAL STAGING-CLL
LABORATORY TESTS-CLL
CBC Lymphocyte count > 5 x 109/L (5 -500 x 109/L ). Platelets may be decreased Hb may be low Blood film PB immunophenotyping Bone marrow biopsy (needed before starting
treatment) Imaging
Observation Chemotherapy. Oral chlorambucil
Fludarabine, cyclo Immunotherapy Anti-CD 20 (rituximab), Anti-CD 52 (Alemtuzumab) FC-R is the current standardIndications for starting chemotherapy
a. Progressive Symptoms
b. Progressive Anemia or Thrombocytopenia
c. Bulky LN, large spleen
d. Recurrent Infections
TREATMENT OF CLL
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.
CHRONIC MYELOID LEUKEMIA
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)
Symptoms
Asymptomatic (50% of patients) Fatigue Weight loss Abdominal fullness and anorexia Abdominal pain, esp splenic area Increased sweating Easy bruising or bleeding
CLINICAL PRESENTAITON OF CML
Splenomegaly (95%)
(50% of patients have a palpable spleen ≥ 10 cm BCM,
Usually firm and non-tender)
Hepatomegaly (50%)
SIGNS OF CML
Chronic phase.
Peripheral blood – neutrophil leukocytes 20,000 - >500, 000/ L
basphilia LAP
scoreblasts < 5% Nucleated RBCsThrombocytosis
Anaemia
DIAGNOSIS OF CML
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)
CML-Treatment Response Criteria
• Hematological response Normalisation of blood count• Cytogenetic response
Major cytogenetic response 1-35% Ph +ve cells in metaphase Minor cytogenetic response 36-65% Ph +ve cells in metaphase• Molecular response Absence of BCR/ABL gene
CML-Principles of Treatment
• Control & prolong chronic phase (non-curative)
- Tyrosine kinase inhibitors-Imatinib (Glivec)
- Alpha-Interferon
- Oral chemotherapy (Hydroxyurea, ARA-C)• Eradicate malignant Clone (curative)
- Allogeneic BM/stem cell transplantation
- Alpha Interferon?
- Imatinib? 2nd line TKIs
• 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 phaseGlivec, 2nd line TKIs
Treat like AML or ALL followed by BMT
TREATMENT OF CML
1. LA P Score
2. Philadelphia Chromosome
3. Basophilia
4. Splenomegaly
CML VS LEUKEMOID REACTION
Bone marrow or PBSC transplantation in leukemias
Types of transplant1. 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
Bone marrow or PBSC transplantation in leukemias
Technique of transplantationMHC + HLA matchingChemotherapyTotal body irradiationGVHD prophylaxis
Complications of transplantation• Prolonged BM suppression (graft failure)• Serious infections• Mucositis• Graft versus host disease (GVHD)
Complications of BMT
Lung toxicity13%
Other Organ toxicity
4%
Hemorrhage5%
Other5%
Relapse12%GVHD
29%
Infection26%
VOD6%