CHRONIC MYELOCYTIC LEUKAEMIA

DR JATAU ED

OUTLINE

• DEFINITION
• AETIOLOGY
• PATHOGENESIS
• CLINICAL FEATURES
• LABORATORY FEATURES
• PHASES/STAGING
• TREATMENT
• DIFFERENTIAL DIAGNOSIS

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Definition

• Clonal neoplastic disorders of pluripotent haematopoietic stem cell characterised by excessive proliferation of one or more of the myeloid cell lines, spillage into peripheral circulation, and tissue infilteration

AETIOLOGY

• Unknown
• Ionizing radiation

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PATHOGENESIS

• The ABL1 gene is translocated from chromosome 9 into the breakpoint cluster region (BCR) on chromosome 22 to form the BCR-ABL1 fusion gene
• This fusion gene encodes a 210-kDa protein with greatly increased tyrosine kinase activity compared to the normal ABL1 product.

Philadelphia chromosome and BCR/ABL fusion gene product.

CLINICAL FEATURES

• The disease occurs at all ages (peak age of 25–45 years, male : female ratio equal,
• Incidence of 5–10 cases per million population).
• Patients usually present in the chronic phase.
• Presenting symptoms include weight loss, night sweats, itching, left hypochondrial pain, gout. Priapism, visual disturbance and headaches caused by hyperviscosity
• (WBC >250 × 10⁹/L) are less frequent.
• Splenomegaly, often massive, occurs in over 90% of cases.
• Some cases are discovered on a routine blood test.

LABORATORY FEATURES

• Raised white cell count (often 50 × 10⁹/L or more), mainly neutrophils and myelocytes, Basophils may be prominent.
• Platelet count may be raised, normal or low and anaemia may be present.
• Raised serum uric acid.
• Bone marrow is hypercellular with a raised myeloid : erythroid ratio. Myeloid hyperplasia> 30% of all marrow nucleated cells
• Cytogenetic analysis of bone marrow cells shows the Ph chromosome in >95% of metaphases.
• The BCR-ABL1 fusion gene is detectable in 100% of cases by fluororescence in situ hydridization (FISH) and its RNA product by polymerase chain reaction

Peripheral blood film

CML

Phases of CML

• Chronic Phase;

Splenomegaly, moderate to marked granulocytosis

(TLC usually>50x10⁹/L) with presence of all stages of maturation, basophilia, decreased NAP score, and Ph’ chromosome or BCR/ABL gene rearrangement on chromosome 22., <10% blast

• Accelerated Phase;

Anaemia, thrombocytopenia/thrombocytosis, splenic enlargement, blast 10-19% and marrow fibrosis,

• Blastic Phase;

Additional morphological and chromosome abnormalities, Blast ≥ 20%

• Extramedullary tissue infilteration

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TREATMENT

• Supportive;

Counselling

Allopurinol, Rasburicase

Blood transfusion

Antibiotics

• Specific treatment

Chemotherapy

Stem cell transplant

TREATMENT

• First Line;

Imatinib mesylate (Gleevec)

Dasatinib

Nilotinib

• Second Line;

Hydroxyurea

α-Interferon

• Allogeneic stem cell transplant

DIFFERENTIAL DX

CHRONIC LYMPHOCYTIC LEUKAEMIA

• Chronic lymphocytic leukaemia (CLL) is a neoplastic disorder characterised by monoclonal proliferation of immunologically incompetent, slowly dividing, mature B-lymphocytes.
• A disease of older patients > 50 (peak age 70 years),
• It is the most common leukaemia in Western countries
• Male : Female ratio 2 : 1

AETIOPATHOGENESIS

• Aetiology is unknown
• Associated with certain chromosomal anomalies
• Trisomy 12, a 13q deletion and deletions of 11q including the ataxia telangiectasia (ATM) gene. Oncogene mutations e.g. of NOTCH1 or deletions occur, preventing cells from undergoing apoptosis.
• The 13q deletion is thought to eliminate expression of several micro-RNAs .
• Mutations or deletions of the P53 gene (chromosome 17) concerned in DNA repair may be present.

CLINICAL FEATURES

• Most patients present at an early stage and subsequently remain stationary or progress very slowly.
• Some patients never need treatment, while in others the disease follows an aggressive course.
• Local lymphoblastic transformation (Richter’s syndrome) may occur, with a poor prognosis.

CLINICAL FEATURES

• Lymphocytic leucocytosis, Lymphadenopathy, Splenomegaly
• Mostly asymptomatic.
• Typically symmetrical, painless and discrete Lymphadenopathy
• Night sweats, loss of weight,
• Symptoms due of bone marrow failure.
• Spleen is often moderately enlarged in Stages B or C.
• Hypogammaglobulinaemia and reduced cell-mediated immunity

predispose to bacterial and viral infection e.g. shingles.

• Autoimmune haemolytic anaemia occurs in 15–25% of cases.

LABORATORY FEATURES

• Lymphocytic leucocytosis > 5–30 × 10⁹/L
• Usually B cells (CD19, CD22 but also CD5 positive).
• Bone marrow aspiration/trephine biopsy with >30% mature looking lymphocytic infilteration in nodular, interstitial, diffuse or mixed pattern.
• Weak expression of surface immunoglobulin M (IgM) which is monoclonal (expressing only κ or only λ light chains).
• Serum immunoglobulins are depressed; a paraprotein may be present in plasma.
• Anaemia and thrombocytopenia may occur due to marrow infiltration, as a result of autoantibodies, or red cell aplasia.
• Expression of a protein kinase ZAP-70 and of CD38 are increased in some (poorer prognostic) cases.
• Cytogenetic and molecular changes

PERIPHERAL BLOOD FILM-CLL

PROGNOSTIC FEATURES

RAI STAGING

BINET STAGING

TREATMENT

• Observation for asymptomatic Stage A patients.
• Counselling and supportive care
• Prophylaxis against bacterial and viral infections
• Immunoglobulin infusions.
• Splenectomy or splenic irradiation

TREATMENT

• Fludarabine-(Purine analogue)with cyclophosphamide and rituximab (anti-CD20) (FCR) as initial or subsequent therapy.
• Bendamustine ( purine and alkylating agent) alone or with rituximab.
• Oral chlorambucil valuable in patients older than 70–75 years.
• Prednisolone
• Ibrutinib (Bruton kinase inhibitor )
• Allogeneic stem cell transplantation for younger patients

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VARIANTS OF CLL

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