Post on 17-Jan-2016
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Chronic Leukaemia
Dr. MO KehindeDepartment of MedicineCollege of Medicine University of Lagos
CHRONIC MYELOID LEUKAEMIA
A Disease characterised by insidious ill health increasing splenomegaly and leucocytosis (Particularly granlocyte
precursors ) which invariably leads to death within a few years(2-10yrs)
A myeloproliferative disease
CHRONIC MYELOID LEUKAEMIA
Other names Chronic granulocytic leukaemia (CGL)
Typical disease with Philadelphia positive chromosome. or
Chronic myelogenous leukaemia .
Epidemiology
Annual incidence 1 :100,000 common in the 5th and 6th decade. males > females (1.4:1.) In Nigeria peak age 20 – 40 years M: F 1.3:1 Any age could be affected
Predisposing factors
Largely Unknown Irradiation-Hiroshima and Nagasaki
Toxic chemical – Others leukaemias But not CGL
Pathogenesis
The main pathogenesis is the Philadelphia chromosome
Nowell amd Hungerford-1960 in Philadelphia Observe deletion of chromosomes in CGL Chromosomes in G group i.e. same as
Down’s syndrome (Trisomy21 ) : named Chromosome 22 now called
Philadelphia chromosomes PhI
Philadelphia Chromosomes
Reciprocal translocation between long arms of chromosome 9 and 22
Abelson gene (ABL-gene ) : found on Chromosome 9
BCR gene (Breakpoint Cluster Region ) on chromosome 22
BCR – ABL gene;
51 31XI
ABL □ ---------------------------------------------------------------- □ Chr 95’ M-ber 3 1
XIBCR □ ---------------□--□----□----□----□ --□----□----□----□--□----□---Chr.22
5’ 31 X1
BCR-ABL □--□--□---□---□----------------------------------------□ Philadelphia Chr.
Philadelphia Chromosome
Chimeric protein whose 51 is from BCR gene and 31 is from Abl gene.
Observed in 95% of cases of CML ie typical CML or CGL
Moves the Abl gene (? Function) from the nucleus to the cytoplasm.
Has increased tyrosine Kinase activity → ↑ phosphonylation and switching on of the cell cycle.
. seen in 95% of CML → CGL.
Philadelphia Chromosome
Found in all cells lines- Granulocyte, Erythroid , megakaryocytes, B or even T Lymphocytes t(9,22) seen under the light microscope is called Philadelphia Chromosome
BCL –ABL gene rearrangement
May not be demonstrable under light microscope but in PCR. Still of same significance as Philadelphia chromosome.
Also seen in A.L.L ( P210 -? Transformed CGL (P190 – De novo A.L.L.) Aim of treatment is elimination of Ph1
Classification of Chronic myeloid Leukaemia
CML Ph tve (CGL) –95% Chronic myeloid leukaemia Ph Negative Juvenile chronic myeloid leukaemia Chronic neutrophilic leukaemia Eosinophilic leukaemia Chronic myelomonocytic Leukaemia
(CMML)
Clinical features: Chronic Phase
Asymtomatic Abdominal mass (Dragging sensation) Hypermetabolism e.g weight loss, lassitude, night sweats
Clinical features: Chronic Phase
* Hyperviscosity : Headache , tinnitus , heaviness in the head , priapism.
Clinical features: Chronic Phase
*Bruising , epistaxis menorrhagia, muscle haematoma *Hyperuricaemia
Clinical features: Chronic Phase
Leucocytosis > 50 x 109/L with a complete spectrum of myeloid precursors, a myelocytes peak * Mild anaemia , Thrombocytosis * Bone marrow is hypercellular with granulocyte predominance
Accrelerated phase
Patient more ill Requires more medication for lower
counts than previously Increasing promylelocytes
Blast transformation phase
Increasing splenomegaly Lymphadenopathy Worsening anaemia Thrombocytopaenia Development of additional chromosomal
abnormalities
Other Lab features
* Neutrophil alkaline Phosphatase is low - but increased in infectious, before treatment ,in pregnancy or post splenectomy. * ↑Basophil * ↑Serum vitamin B12
Treatment
Conventional Therapy
Specific therapyBusulphan 2-8 mg daily 4 –7 days week ; not curative controls symptoms, of advantage: elderly patient Poor follow-up patients Myloablation pre-transplant
Busulphan: Side effects
Hyperpigmentation Pulmonary and Retroperitonieal fibrosis Infertility Pulmonary and Ovarian malignancy
Hydroxyurea
Haemaological remission Control of symptoms Short half life Reversible Cytopaenia ? prolonged survival Advantage over Busuphan treatment
Alfa Interferon
Complete Haematologic remission in 70 to 80% of patients – Normal WBC.
and platelet count, absent splenomegaly. Major Cytogenetic remission (MCR) in 50- 60%
( 20 – 30 % of which have complete - 0% Ph)+ Minor cytogenetic response 35-90% residual
Ph+ Response is done dependent
Alfa Interferon
Recommended dose is 5mu/m2 daily Major cytogenic response- 5year
survival 70-80% Addition of cytosine arabinoside → ↑rate of MRC 10 mg daily subeut → MCR in 50% of patients.
Side effects
early fever, Dulls post nasal drip unrelated to dose anorexia dose limiting ← fatigue weight loss , depression
insomnia diarrhea -late autoimmune response noted in 5% of patients associated with better response.
Side effects
depression Insomnia diarrhea -late autoimmune response noted in 5% of
patients associated with better response.
Allogeneic BMT
Established curative strategy. 2 mechs.i. Myeloablation with chemo ii. Radiotherapy Immune mediated Graft Versus Leukaemia
Allogeneic BMT
Best results in < 30years old , in early chronic phase age < 55years (70 – 80% Disease Free Survival). Leukaemia Relapse in 10 –20% Mortality rate of 20 – 30% esp. in older patient > 55yrs
Allogeneic BMT
Complications: * GVHD Interstitial pneumonitis Serious Viral and Funcal infection Organ damage from conditioning regime Bleeding.
Imatinib Mesylete (Gleevec.)
1. Signal transduction inhibition (STI 571) 300mg p.o daily 25%
partial (< 35% ph-) 10% complete (100% Ph-) Specific inhibitor of tyrosine of the tyrosine Kinase activity.
Side effects
Nausea, Vomitting, Skin rashes, muscle cramps, aches.
IFN
Polyethylene glycol (PE – IFN) – clinical trial.
Longer ½ life and weekly closing Fewer side effects allowing for dose
escalation PEG – IFN/Arac – being tried
Homoharringtonine
is– plant alkaloid with significant anti leukemia activity.
For failed IFN Rx Synergistic with Arac & IFN
blast transformation phase
ALL – C- VAD can induce
a chronic phase in 50 – 60% AML –
Chronic Lymphocytic Leukaemia
Clonal disease resulting form expansion of the mature lymphocyte compartment.
30% of leukaemias (most common) in western world Mean age 55 –65 years rarely < 40 years In Nigeria 27- 74 years (63% between 50 –69 years ) M:F 1.3: 1
Pathology:
Characterised by progressive accumulation of
mature lymphocyte - B cell (95%) . Morphologically mature, Immunologically immature Immune phenotype: CD19 (B cell marker) CD 5 (T cell marker)* CD 23 (Cf mantle lymphoma)
Immunologic Abnormalities
Autoimmune disease-75% of patients ↑ with disease stage Autoimmune Haemolytic –Anaemia ITP, Autoimmune neutropaenia
Treatment
Prednisolone 60 – 100mg daily Cyclosporine (anti leukaemia activity)
(Pure Red Cell Aplasia - < 1 % of patients Rx cyclosporine ,
SLE ,Rh. Arthritis ,Sjogrens syndrome)
Treatment
.HYPOGAMMA GLOBULINAEMIA 1gG, 1gA, 1gM Rx IV Immunoglobin 500 MG/ Kg 3- 4
weekly.
Clinical features:
. Asymptomatic .Fever, weight loss . Lymphdenopathy (cf prolymphocytic) . Recurrent infection . Splenomegaly . Anaemia
Clinical features
Thrombocytopaenia Natural Hx: increasing resistance to drugs then succumb to autoimmune disease or cytopaenia.
Diagnostic Criteria (National Cancer Institute Working Group)
Absolute Lymphocyte count > 5x109/L for at least weeks > 30% Lymphocytes in the Bm. Monoclonal B cell phenotype with co –expression of CD5 and low levels of surface 1g.
methods of staging.RAI Risk Median Survival:yrs.
0 - Lymphocytosis low 0 1- + Enlarged LN Intermediate 6 11- + Spleno /Hepatomegaly III - + Anaemia (Hb < 11 g/dl) High 2 IV- + Thrombocytopaenia
Binet
Median Survival:yrs A <3 LN areas >
10yrs B ≥ 3LN areas 6 C Anaemia, Thrombocytopaenia 2
Indications for Treatment
Disease related symptoms Progressive cytopaenias Advanced disease (RAI 3 or 4) Bulky 1ymphadenopthy
Indications for Treatment
Massive/Painful splenomegaly Short Lymphocyte doubling time ≤ months Absolute lymphocyte count > 150 x 109/L Recurrent infection
Conventional Chemotherapy
Alkylating agents Chlorambucil – of choice Cyclophosphamide Addition of steroid
Nucleoside Analogue
Fludarabine – treatment of choice effective single agent in CLL. Given 25 –300mg/mz daily x 5/7 every 4 weeks. No need for steroid Rx (Risk of opportunistic
infection).
Fludarabine + Cyclophosphamide better response rate 2 Chlorosdeoxyadenosine Deoxycorformycin Pentostatin Monoclonal antibodies - Anti CD 20 - Anti CD 52 Bone marrow Transplanatation – young < 55 with advanced disease
Transformation:
Richter’s syndrome ; Prolymphocytic Leukaemia; Acute Leulaemia, multiple myeloma
Many Thanks
For Your Attention