The Leukaemias FAR TOO MANY CELLS FAR TOO

The Leukaemias - FAR TOO MANY CELLS; FAR TOO MANY VOWELS - toby m robins

Leukaemia may be Acute or Chronic

and it may be Lymphoblastic Myeloid or

Put that all together and you get Acute lymphoblastic leukaemia Acute myeloid leukaemia Chronic lymphoblastic leukaemia Chronic myeloid leukaemia

For each, we will briefly cover • • Definition Epidemiology Aetiology Pathogenesis Clinical features Investigations Management Prognosis

but first What exactly IS leukaemia?

Leukaemia is Production

of abnormal WBCs

at an excessive rate

+/- reduced destruction

i. e. it is malignancy of the leukocytes

and it is clonal - ie all the malignant cells have a recent common ancestor

it is classified according to 1. the dominant cell type and 2. the duration from onset to death

Chronic leukaemia Untreated, exceeds one year (with gradual onset of symptoms)

Acute leukaemia Untreated, death ensues within a few months

The acute ones ALL (acute lymphoblastic leukaemia) AML (acute myeloid leukaemia)

firstly Acute Myeloid Leukaemia

Definition of AML Neoplastic proliferation of myeloid blast cells

Myeloid blast cells explained Mature blood cells are derived originally from pluripotent stem cells

Meyloid blast cells explained Pluripotent stem cells then divide and M differentiate either into L myeloid stem cells or lymphoid stem cells

Myeloid blast cells explained Lymphoid stem cells make lymphocytes Myeloid stem cells make all the other blood cells

SEW

There’s more than ONE kind of AML • Morphologically, there are seven and a half: – M 1 = undifferentiated blast cells – M 2 = myeloblastic – M 3 = promyelocytic – M 4 = myelomonocytic – M 4 eo = myelomonocytic with dysplastic eosinophils – M 5 = monocytic – M 6 = erythroleukaemia

Epidemiology 70 -year-old, male, Eastern European Jews

Aetiology ?

Aetiology • All implicated have been – Heredity – Radiation – Mutagenic drugs – Chemical & other occupational exposures – secondary to previous chronic leukaemia or myelodysplasia

Clinical features • Symptoms and signs are a result of 3 things: – 1. Marrow failure – 2. Leukaemic infiltration of tissues – 3. Consitutional upset

Symptoms relating to marrow failure • Infection • Bleeding or easy bruising • symptoms of anaemia - shortness of breath, etc

Symptoms relating to leukaemic infiltration • Symptoms of a mass lesion (rarer, since leukaemias by definition tend not to form masses) – bone – breast, uterus, ovary – cranial or spinal dura – GI tract – lung or mediastinum – prostate

Symptoms relating to constitutional upset • • • Malaise Fatigue Weakness Fever or sweats Anorexia or weight loss Non-specific cough

Signs relating to marrow failure • Evidence of infection • Signs of anaemia • Purpura or signs of bruising/bleeding – including retinal haemorrhages

Signs relating to leukaemic infiltration • • • Hepatosplenomegaly Lymphadenopathy Sternal tenderness Thymic mass Gingival hypertrophy

Signs relating to constitutional upset • Fever

Investigations • • • FBC Blood film U&Es LFTs coagulation (especially for the DIC of M 3) • Bone marrow examination • cell markers and molecular studies (eg

FBC • Anaemia • Neutropenia • Thrombocytopenia

Blood film • Blast cells that contain – granules – Auer rods

U&Es, LFTs • The following are occasionally increased – calcium – urea – LFTs

Bone marrow examination • Blast cells constituting > 20% of the bone marrow cells is diagnostic

Cell markers, molecular studies • Flow cytometry (immunophenotyping) may aid in morphological (ie appearance-based) diagnosis and may add further prognostic information • Karyotyping, FISH, and PCR may confirm diagnosis (eg acute promyelocytic leukamia; =M 3), + may add information not otherwise

Management includes • Intensive chemotherapy • Bone marrow transplant • Supportive care

Chemotherapy • Divided into 3 phases – 1. Remission induction – 2. Remission consolidation – 3. Remission maintenance

1. Chemotherapy for remission induction • Complete remission (CR) – full recovery of haematopoiesis, with – blasts accounting for < 5% of bone marrow cells • Involves mainly – anthracyclines – cytosine arabinoside

Why have they chosen these drugs? • Anthracyclines – because AML is like cycling a “myel” and a half with anthrax • Cytosine arabinoside – think “sight-o-seen arabocide” – because some (ignorant, misinformed, prejudiced) people because think an Arab that comes within a “myel” radius should be shot on sight

2. Chemotherapy for remission consolidation • Involves similar chemotherapy to that of remission induction

3. Chemotherapy for remission maintenance • Treatment is continued for 2 years in ALL, but for a much shorter time in AML

Bone marrow transplant (BMT) • Suitable marrow may be – allogeneic (from histocompatible siblings or unrelated donors) – syngeneic (from an identical twin) – autologous

BMT continued • Used increasingly as a form of consolidation • Use depends on the pt’s age – the elderly develop more complications

BMT continued • Marrow is infused intravenously to “rescue” the pt from otherwise supralethal chemoradiotherapy • Enables destruction of (almost) all leukaemic cells and the entire immune system with eg cyclophosphamide plus total body irradiation

Why use cyclophosphamide? • ‘cause you midas well make phossels out of all those nasty leukaemia cells in one foul swoop (cycle) A FOUL SWOOP

BMT continued • To reduce graft vs host effect – cyclosporin +/– methotrexate • Complications – graft vs host disease – infections (commonly CMV) – veno-occlusive disease – relapse of leukaemia

Supportive treatment • Blood transfusion for anaemia • Platelet transfusion for thrombocytopenic bleeding • Prompt antibiotic treatment, and prevention, of infections • Hygeine

Prognosis • 70% achieve complete remission lasting (on average) 12 months • Long-term survival (~ 50%)

Secondly Acute Lymphoblastic Leukaemia

Definition Neoplastic proliferation of lymphoblasts

Types of ALL • Common – phenotypically pre-B lymphocytes – 75% of cases • T-cell • B-cell • Null-cell

Aetiology as for AML

Epidemiology (Common ALL) • 4 -year-olds

Epidemiology (T-cell ALL) • Adolesce nt males

Clinical features as for AML

Investigations • As for AML • Blood film shows – small blasts with – a high nuclear-cytoplasmic ratio