Chronic Leukemias: An Overview

Chronic Leukemias Overview

• Clonal disorders arise from myeloid or lymphoid cell lines
• Results in neoplastic proliferation that causes mature cells to accumulate in blood, bone marrow, and tissues

Types of Chronic Leukemias

• Chronic myeloid leukemia (CML): mature myeloid cells present in blood and bone marrow
• Chronic lymphocytic leukemia (CLL): mature lymphoid cells present in blood and bone marrow
• Progression is slower compared to acute forms of leukemia
• Generally more difficult to cure with chemotherapy than acute leukemias

Chronic Myeloid Leukemia (CML)

• Synonyms include Chronic Myelocytic Leukaemia, Chronic Myelogenous Leukaemia, and Chronic Granulocytic Leukaemia
• Acquired clonal disorder affecting pluripotent stem cells in bone marrow
• Classified among chronic myeloproliferative disorders (MPDs), including Polycythaemia Rubra Vera, Myelofibrosis, and Essential Thrombocythaemia

Epidemiology of CML

• Myeloproliferative disorder linked to a specific genetic defect and a characteristic blood picture
• Annual worldwide incidence is 1 per 100,000 population
• More common in males, with a male-to-female ratio of 1.4:1
• Represents approximately 20% of all leukemia cases
• Most frequently occurs in adults aged 30-60 years, but can affect any age group
• Median age incidence is 38 years in Nigeria, compared to 50 years in the Western world
• About 50% of patients are diagnosed through routine lab tests, and 85% during the chronic phase

Natural History of CML

• The disease progresses through three recognized phases: chronic, accelerated, and blast crisis (blastic transformation)
• Approximately 50% of patients transition directly from the chronic phase to blast crisis
• Over 85% of patients are diagnosed during the chronic (stable or indolent) phase
• The chronic phase typically lasts 3-6 years, with a median duration of 4.2 years
• The accelerated phase is marked by increasing blood counts, organomegaly, refractoriness to therapy, and sometimes constitutional symptoms; this phase is brief
• Blast crisis resembles acute leukemia, with >20% blasts and promyelocytes in blood or marrow

Etiology of CML

• The exact cause is unknown (idiopathic)
• Exposure to ionizing radiation can damage the genetic apparatus and may lead to the development of CML
• Chronic exposure to benzene or other hydrocarbons is associated with development of CML
• Certain chemicals and drugs, such as etoposide (a topoisomerase II inhibitor), have been linked to the development of the Philadelphia chromosome (t 9,22)

Clinical Presentation of Chronic Phase CML

• About 50% of cases are asymptomatic
• Common symptoms include fatigue, weight loss/anorexia, and night sweats
• Common signs include palpable splenomegaly (usually massive), possible hepatomegaly, mild to moderate anemia (pallor, dyspnea, tachycardia)
• Further signs might include bleeding disorders (epistaxis, easy bruising, petechiae, menorrhagia) related to thrombocytopenia or abnormal platelet function, gout, and renal impairment from excessive breakdown of abnormal WBCs

Diagnosis and Investigations for CML

• FBC and peripheral blood film show increased WBC (generally >25 x 109/L, often 100-300 x 109/L)
• A complete range of myeloid series cells is found, which also includes blasts, promyelocytes, myelocytes, metamyelocytes, neutrophils, basophils, and eosinophils
• Anemia is common, and the platelet count tends to be normal or elevated
• Basophilia and/or eosinophilia are frequently present
• Neutrophil alkaline phosphatase (NAP) score is low
• LDH and uric acid levels are elevated in serum
• Bone marrow aspiration reveals markedly hypercellular marrow due to myeloid hyperplasia
• Cytogenetic examination of blood or marrow confirms the Philadelphia chromosome t(9;22)
• Plasma levels of Vitamin B12 and Vitamin B12-binding proteins are increased, primarily from gross neutrophilia

Pathogenesis of CML

• More than 95% of those affected have a characteristic genetic abnormality called the Philadelphia chromosome
• Peter C. Nowell and David Hungerford first discovered the abnormal chromosome in blood and bone marrow samples in 1960
• The Philadelphia chromosome involves reciprocal translocation of genetic materials between the long arms of chromosomes 9 and 22
• This leads to rearrangement of the bcr and abl oncogenes (abl on chr. 9 to bcr on chr. 22)
• The bcr-abl fusion gene encodes for a special mRNA that produces a protein, p210
• P210 enhances Tyrosine Kinase activity, leading to excessive cell proliferation and accumulation of immature and intermediate forms in peripheral blood and bone marrow
• Activated Tyrosine Kinase results in loss of cellular growth control and inhibits apoptosis
• Less than 5% of patients do not have the Philadelphia chromosome, which is associated with a worse prognosis

Differential Diagnosis of CML

• Chronic phase CML needs to be differentiated from leukemoid reaction
• Rule out leukemoid reaction caused by infection, inflammation, or carcinoma
• Differentiate from Chronic Myelomonocytic Leukaemia (CMML)

Prognosis of CML

• The chronic phase typically lasts 2-7 years, but in rare cases, it can extend to more than 15 or even 20 years
• Spontaneous remissions are rare but occur
• The Sokal score can predict prognosis

Prognostic Factors in CML

• The Sokal score uses age, spleen size, platelet count, and % blasts in blood to determine good, moderate, and poor prognostic groups
• The presence or absence of the Philadelphia chromosome influences prognosis
• Response to Interferon alpha (IFN-a) therapy is an important prognostic factor

Clinical Course of CML

• Basically biphasic or triphasic involving a chronic phase, accelerated phase, and blastic transformation phase
• The accelerated phase can be very brief and overlap with the blastic phase
• Patients in the chronic phase respond well to chemotherapy
• Patients in the chronic phase eventually tend to progress to the other phases, and may eventually die in the blastic transformation phase

Features of Accelerated Phase of CML

• Rapid leucocyte doubling time (less than 5 days)
• Unresponsiveness to standard chemotherapy
• 20% or more blasts plus promyelocytes in blood or marrow
• Basophilia and eosinophilia in blood and marrow
• Increasing anemia and/or thrombocytopaenia
• Persistent thrombocytosis (platelet count > 1000x109/L)
• Increasing splenomegaly
• Development of granulocytic sarcomas (chloromas)
• Acquisition of additional chromosomal abnormalities

Blastic Transformation Phase of CML

• Development can occur quickly over days or weeks
• Patients become chemotherapy-refractory with severe anaemia, thrombocytopaenia, and increased blasts (≥ 20%) in peripheral blood (PB) and bone marrow (BM)
• Blastic transformation can be AML (70%), ALL (25%), or mixed (<5%)

Treatment of CML

• Both supportive and specific treatments are necessary
• Supportive care includes red cell transfusions for anaemia and treatment of infections
• Counseling about the disease and prognosis is important

Specific Treatment of Chronic Phase CML

• Treatment reduces the total WBC count to keep patients symptom-free for extended periods
• Allopurinol prevents tumor lysis syndrome, gout, and renal impairment
• Busulphan (an alkylating agent) was previously the drug of choice
• Alpha interferon is another option
• Hydroxyurea reduces cytoreduction immediately
• Tyrosine Kinase inhibitors are now the mainstay of therapy
• Splenectomy or splenic irradiation is used in patients with massive splenomegaly not responsive to chemotherapy
• Autologous or allogeneic HSCT may be curative in patients under 50 years of age

Treatment of Accelerated and Blastic Phases

• Accelerated phase treatment includes switching to another drug
• Blastic transformation is managed as either AML or ALL, depending on the predominant blasts in blood and marrow

Other Variants of CML

• Juvenile CML (Ph negative)
• Chronic neutrophilic leukaemia (CNL)
• Chronic Eosinophilic Leukaemia (CEoL)
• Chronic monocytic leukaemia (CMoL)
• Chronic myelomonocytic leukemia (CMML)

Comparison of CML and Leukemoid Reaction

• CML is a clonal disorder, while Leukemoid Reaction follows infections or haemorrhage
• WBC count is usually > 50x109/L in CML, but WBC count rarely exceeds 50x109/L in a Leukemoid Reaction
• The NAP score is low in CML but elevated or within normal range for infections
• The Philadelphia (Ph) chromosome marker is an abnormality for CML but is negative for infections
• CML requires chemotherapy and the high WBC count will keep increasing unlike infections that are treated with antibiotics
• CML is chronic, while Leukemoid Reaction from infections is an acute condition

Chronic Lymphoproliferative Disorders

• Several B cell chronic lymphoproliferative diseases and T cell chronic lymphoproliferative diseases exist
• B cell disorders: B chronic lymphocytic leukaemia (B-CLL), B prolymphocytic leukaemia (B-PLL), Hairy cell leukaemia (HCL), and Plasma cell leukaemia (PCL)
• T cell disorders: Large granular lymphocytic Leukaemia (LGLL), T prolymphocytic leukaemia, and Sezary syndrome

Chronic Lymphocytic Leukemia (CLL)

• Typically presents as an acquired malignant condition of B lymphocytes
• B-CLL occurs more often than other forms of chronic lymphoproliferative disease
• Peak incidence for B-CLL appears between ages 60-80 years, and is rarely seen before age 40
• Males are twice as likely to be affected than females
• Chronic persistent lymphocytosis can infiltrate organ systems and cause enlargement of the spleen, liver, lymph nodes, and bone marrow

Aetiology of CLL

• The cause is unknown, but the factors that may be implicated include chronic stimulation of the immune system, and familial predisposition

Clinical Features of CLL

• Detected during routine exams or in individuals with no symptoms
• Systemic symptoms such as fever, night sweats and weight loss
• Symmetrical enlargement of superficial lymph nodes are discrete and non-tender
• Normocytic normochronic anaemia has been noted
• Bacterial and fungal infections due to immune suppression and neutropaenia have been noted
• Auto immune haemolytic anaemia (AIHA) resulting from production of abnormal antibodies against patients' red cells
• Bleeding disorders arise from thrombocytopaenia resulting from marrow suppression

Laboratory Diagnosis for CLL

• Full Blood count and lymphocytosis typically exceeds 15.0 x 109/L; anaemia, thrombocytopenia and neutropenia are not present in early stage CLL
• Peripheral Blood Film (PBF) shows small, mature lymphocytes with smudge or basket cells
• Autoimmune haemolysis identified via Coombs test (DCT) may occur
• Bone marrow aspiration that shows hypercellular marrow with diffuse or nodular lymphoid infilteration; reduced serum immunoglobulin concentrations, plus certain immunophenotying and cytogenetic changes

Classification and Staging in CLL

• Staging the classification helps determine the stage of CLL
• Rai stages CLL based on the number of lymphocytes, lymphnode involvement, plus other symptoms
• The Binet system stages based on a few clinical features like spleen size
• Rai Modified Staging identifies risk levels - low, intermediate, and high- and defines how lymphocytes may be increased
• Binet Staging also uses clinical features, like the number of lymphoid regions and anaemia to prognose survival outcomes