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

            

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• 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%