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