Chronic Leukemia Dr. Noha Noufal

Objectives: To understand the general features of Myeloproliferative neoplasms To understand the clinicopathological differences between acute myeloid leukemia and chronic myeloid leukemia (CML) To understand the diagnostic approach for chronic leukemia and the major differential diagnosis of CML. To recognize the importance of genetic study in diagnosis and treatment of CML. To understand the general aspect of myelodysplastic syndrome (MDS) including definition, pathogenesis, clinical features and prognosis. To understand the general aspect of chronic myelomonocytic leukemia CMML including definition, pathogenesis, clinical features and prognosis.

Myeloproliferative Neoplasms (MPN): MPN: These disorders are marked by the hyperproliferation of neoplastic myeloid progenitors that retain the capacity for terminal differentiation; as a result, 1- There is an increase in one or more formed elements of the peripheral blood 2- The neoplastic progenitors tend to seed secondary hematopoietic organs (the spleen, liver, and lymph nodes), resulting in hepatosplenomegaly and mild lymphadenopathy due to (extramedullay hematopoiesis).

Myeloproliferative Neoplasms (MPN): A common theme is the association of these disorders with mutated tyrosine kinases. The bone marrow is hypercellular and showing malignant proliferation of myeloid cells (maturing cells) which are mainly granulocytes, in blood and B.M. Splenomegaly is a constant finding. Occur mainly in adults. Slow onset and long course.  Phosphorylation of proteins by kinases is an important mechanism in communicating signals within a cell (signal transduction) and regulating cellular activity, such as cell division.

Myeloproliferative Neoplasms (MPN): Four diagnostic entities of MPN: 1- Chronic myelogenous leukemia (CML). 2- Primary myelofibrosis. 3- Polycythemia vera (PCV). 4- Essential thrombocythemia.

Chronic Leukemia Heterogeneous group of hematopoietic neoplasms . Uncontrolled proliferation and decreased apoptotic activity with variable degrees of differentiation (Chronic leukemia unregulated growth of mature cells) . Composed of relatively mature cells. Indolent - (If untreated, the course is in months or years) - (patient could be asymptomatic for years). Occurs mainly in adult

Chronic Myeloid Leukemia CML: Pathogenesis: CML is distinguished from other myeloproliferative neoplasms characterized by the presence of a chimeric BCR-ABL gene derived from portions of the BCR gene on chromosome 22 and the ABL gene on chromosome 9 (9;22) producing Philadelphia (Ph) chromosome . The resulting chimeric BCR‐ABL gene codes for a fusion protein with increased tyrosine kinase activity lead to cellular proliferation and differentiation. Predominant proliferation of granulocytic cells.

Philadelphia (Ph)chromosome: The Philadelphia chromosome. (a) There is translocation of part of the long arm of chromosome 22 to the long arm of chromosome 9 and reciprocal translocation of part of the long arm of chromosome 9 to chromosome 22 (the Ph. chromosome).

Incidence This disease occurs in either sex (male : female ratio of 1.4 : 1). Common between the ages of 40 and 60 years. It may occur in children and neonates, and in the very old.

Morphology of CML The  peripheral  blood: leukocyte count with predominant neutrophils, metamyelocytes, and myelocytes, also basophils, eosinophils and platelets are  also  prominent. The  bone marrow  is  hypercellular  owing  to increased numbers of  maturing granulocytic and megakaryocytic precursors.   Spleen: enlarged red pulp because of the presence of extensive extramedullary hematopoiesis. Splenic infarcts may occur.

Hypercellular Marrow in CML

Laboratory Work Up: 1- CBC: Leucocytosis is the main feature and may reach levels > 200 × 109/L . 2- Bone Marrow Biopsy: Bone marrow is hypercellular with granulopoietic predominance. 3- Molecular and Cytogenetic: Presence of the BCR‐ABL1 gene fusion by RT‐PCR analysis and in 98% of cases Ph chromosome on cytogenetic analysis.

Clinical presentation of CML 1- SILENT: Asymptomatic presentation (In up to 50% of cases). 2- Symptoms related to hypermetabolism (e.g. weight loss, lassitude, anorexia or night sweats). 3- Splenomegaly (Massive), Abdominal discomfort due to splenomegaly

Clinical Presentation of CML 4- Features of anaemia may include pallor, dyspnoea and tachycardia. 5- Abnormal platelet function: Bruising, epistaxis, menorrhagia or haemorrhage from other sites.

CML phases: Phases of CML Chronic phase Accelerated phase Leukocytosis (12-1000×10⁹/L) Mainly neutrophils & myelocytes Blasts ≤ 10% Stable course (years) Accelerated phase • anaemia, thrombocytopenia (platelets less than 100 × 10⁹/L), blasts 10-19% • Unstable course (months) Blastic phase • ≥20% blasts = Acute Leukemia • 80% AML & 20% ALL • (course: Weeks)

CML Prognosis: CML Treatment: FIRST LINE TREATMENT: Targeted therapy (tyrosine kinase inhibitors like Imatinib. Has excellent response (5 years overall survival =90%)→→ stops BCR-ABL. SECOND LINE THERAPY: If no response→ stem cell transplantation CML Prognosis: Even without treatment, the median survival is 3 years.

Main differential diagnosis of CML: 1- Lekemoid reaction: dramatic elevation of the granulocyte count in response to infection, stress, chronic inflammation, and certain neoplasms. Parameter CML Leukemoid Age Adult Any age WBC count High High but < 100,000 Differential Mainly myelocytes and segmented Mainly Bands Splenomegaly + (massive) +/- BCR/ABL +ve -ve Onset Chronic Acute

DD: of CML 2- Chronic myelomonocytic leukemia (CMML) Clonal hematopoietic malignancy is defined by proliferation of both monocytes & neutrophils. MDS/MPN disease (Combination of both). Features of MDS (dysplasia & enhanced apoptosis). Features of MPN (marked proliferation). DD With CML: Negative for the BCR‐ABL1 translocation

Primary Myelofibrosis The hallmark of primary myelofibrosis is the development of alliterative marrow fibrosis, which reduces bone marrow hematopoiesis and leads to cytopenias and extensive extramedullary hematopoiesis presented with hepatomegaly, splenomegaly and lymphadenopathy.

Myelodysplastic Syndromes (MDS): Group of clonal stem cell disorder characterized by maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to AML. Character of MDS: Peripheral cytopenia (low Hb ±low WBC & low PLT). Dysplasia (abnormal morphology). Ineffective hematopoiesis (hypercellular B.M). Progression to AML (preleukaemic disease). Enhanced apoptosis.

Prognosis of MDS The response to conventional chemotherapy usually is poor, perhaps because MDS arises in a background of stem cell damage. Transformation to AML occurs in 10% to 40% of patients. The prognosis is variable; The median survival time ranges from 9 to 29 months and is worse in cases associated with increased marrow blasts, Cytogenetic abnormalities, or TP53 mutations.

Illustrated diagram