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Acute Leukaemias (Clinical Features (reflecting inadequate haematopoiesis…
Acute Leukaemias
Clinical Features
reflecting inadequate haematopoiesis secondary leukaemic cells infiltration of bone
- anaemia - short of breath on effort, excessive tiredness, weakness
- leucopenia - recurrent infections
- thrombocytopenia - bleeding and bruising (particularly acute promyelocytic leukaemia)
- marrow infiltration - bone pain
Examination may be unremarkable
- pallow
- fever (due to infection)
- petechiae, purpura, bruises, fundal haemorrhage (acute promyelocytic leukaemia)
- lymphadenopathy, hepatosplenomegaly (lymphoblastic leukaemia)
- violaceous skin lesions (acute myelomonocytic leukaemia)
- testiculae enlargement (acute lymphoblatic leukaemia)
- cranial nerve palsies occassionally found (acute lymphoblastic leukaemia)
Diagnosis: FBC - anemia, thrombocytopenia, WBC - high, normal, low but usually neutropenia
- abnormal blood count, blood film essential to decide whether leukocytosis is likely to be caused by malignancy or inflammation
- Blood film - likely to show blast cells - can be normal if blast cells are confined to bone marrow
- Clotting - DIC - elevated prothrombin time, reducing fibrinogen level and presence of fibrin degradation products
- lactic dehydrogenase - raised and rapid turnover --> raise uric acid
- liver and renal funciton tests- must be done before starting CTX
- fever --> treat infection
Radiology:
- CXR- pneumonia, mediastinal mass or lytic bone lesions
- testicular US- if testes are enlarged on examination
- ECG , echo- prior to anthracyclines (cardiotoxicity)
Haematology, Immunology, Genetic tests:
- bone marrow aspiration and biopsy - WHO >20% blasts in bone marrow and/or peripheral blood --> to diagnose ALL (aspiration - standard procedure with core biopsy only necessary if aspiration does not yield sufficient cells)
- immunophenotyping - helps to reveal subtype - positive confirmation of lymphoid vs myeloid origin - flow cytometric demonstration of lymphoid antigens
- bone marrow samples - undergo cytogenetics - hyperdiploidy - common
- t (12, 21) - most common translocation in childhood ALL (30%) - results in TEL-AML fusion gene and primarly associated with common phenotype
- T9/22 - Philadelphia chromosome - 15-30% of patients (most adults) - associated with very poor prognosis
- t(4,11) - MLL-AF4 fusion gene - poor prognosis
- t(1,19) - pre-B ALL - results in formation of E2A-PBX fusion gene
- -ve MPO stain - helps diagnose ALL (but acute monocytic leukaemia - negative stain with MPO)
- testting for bcr-abl (oncoprotein) by PCR or cytogenetics - identify patients in ALL arose as lymphoblastic phase of CML
Signs/Symptoms:
- physical anemia (pallor, cardiac flow murmur)
- infection - pneumonia
- thrombocytopenia - petechaie
- ecchymoses - DIC
- lymphadenopathy
- splenomegaly 10-20%
- fatigue, dizziness, palpitations, dyspnea
CLL:
-insidious
- enlarged lymph nodes, generalised lymphadenopathy
- repeated infections - pneumonia, herpes simplex, herpes zoster
- early satiety- enlarged spleen
- tiredness, fatigue
- RIchter syndrome --> B cell lymphoma (3-10%)
- splenomegaly - 30-54%
- hepatomegaly - 10-20%
- petechaie
- pallor
Definition
lymphoid progenitor cell proliferation
Precurosr B cell - ALL
- t9/22 (BCR-APL)
- t4/11 (MLL-AF4)
- t1/19 (E2A/PBalpha1)
- t12/21 (TEL-AML1)
Precursor T-ALL (CD2-CD8)
Burkit Cell Leukaemia
Epidemiology: 3 in 100, 000
75% children <6
peak - 2-5y
Morphology
Distinguish ALL from AML: ALL - compose >25% marrow cellularity, lymphoblasts have coarse, clumped chromatin, 1 or 2 nucleoli, scant agranular cytoplasm
Myeloblasts - nuclei with finer chromatin and more cytoplasm - often contains granules
B-ALL:
- CD 10, 19, 20 - good response to CTX
- prophylaxis to scrotum/CSF
- t12, 21 - good prognosis (common in kids)
- t9, 22 - poor prognosis (adults) - Philadelphia + ALL
T-ALL
- CD2-8
- do not express CD10
- thymic mass --> teenagers -
- poor prognosis, very aggressive
- blasts infiltrate --> lymphadenopathy, hepatosplenomegaly, CNS changes --> headache, vomitting, CN palsy
The French-American-British (FAB) classification has been modified by the WHO as follows:B-cell ALL:
- Early pre-B ALL (also called pro-B ALL) - about 10% of cases.
- Common ALL - about 50% of cases.
- Pre-B ALL - about 10% of cases.
- Mature B-cell ALL (Burkitt's leukemia) - about 4% of cases.
T-cell ALL:
- Pre-T ALL - about 5-10% of cases.
- Mature T-cell ALL - about 15-20% of cases.
Complications/Prognosis
- haemorrhage, hairloss, rashes, nausea/vomitting, nephrotoxic, peripheral neurpathy, pancytopenia, febrile neutropenia
- tumour lysis syndrome
- infertility --> prophylaxis post puberty
Prognosis Age- children, sex- girls, tumour burden - better if WBC < 20x10^3
- immunophenotype - proB, T-ALL- worse
- genetic
- time to clear blasts < 1 week
- remission <4
- CNS - absent
Treatment
ALL except mature B-cell ALL- Burkitt:
- short-term intensive chemotherapy
- remission induction
- consolidation (intensification)
- maintenance (continuation) therapies
- CNS prophylaxis
- Management of relapse
General supportive:
- replacement therapy of blood cells - pre-existing deficiency due to ALL can be profoundly aggravated by chemotherapy
- GF - alleviate profound myelosuppression - granulocyte colony stimulating factor
- antibiotics + antifungal agent - treat opportunistic infection
- allopurinol - often required during induction - control uric acid levels
- central venous catheter
Remission induction:
- vincristine, asparaginase, dexamethasone (anthracycline (daunorubicin, doxorubicin, rubidazone, idarubicin), with or without cyclophosphamide or cytarabine)
Consolidation
- daunorubicin, Ara-C, vincristine, Etoposide thioguanine, mercaptop-cyclophosphamide
CNS prophylaxis
- patients with ALL freq have meningeal leukaemia -at time of relapse (50-75% in 1 y)
- cranial irradiation - acute, late complications (secondary cancers, neurocognitive deficits, endocrinopathy)
- effective prophylaxis to prevent CNS replapse - essential part of ALL therapy
- CNS irradiation, intrathecal methotrexate, intrathecal triple therapy (methotrexate, steroids, cytarabine) and systemic high dose therapy with methotrexate/cytarabine
- combination of these - CNS prophylatic measures - CNS relapse rate in recent adult ALL trials - reduced from 10% to <5%
Maintanence:
- mercaptopurine, methotrexate, vincristine, dexamethasone
Late Consolidation Maintanence
Aetiology
Genetic - DS/Klinefelters/Fanconi
Environmental - radiation, smoking, hair dyes, benzene
Viral infection
Folate metabolism polymorphs
Alkylating agents - therapy related leukaemia
Pathophysiology
B/T cell differentiation regulated by lineage - specific transcription factors
- mutated transcription factors
eg allow tumour cells to proliferate
BCR-ABL gene --> created by 9/22 translocation
- lymphoblasts infiltrate BM/other organs
BCR-ABL --> encodes tyrosine kinase --> allows cells to proliferate without regulation from cytokines