CHRONIC LEUKAEMIA Mousa Q.Hussein Assistant Professor Consultant Physician 14th December 2015

Chronic myeloid leukaemia: A myeloprolifrative stem cell disorder resulting in Proliferation of all haematopoietic lineages but manifestation Predominantly in the granulocytic series. The disease occurs chiefly between 30 and 80 years, with A peak incidence at the 55 years. *accounts for 20% of all leukaemis. *found in all races. *the aetiology is unknown.

Cytogenetic and molecular aspects : The defining characteristic of CML is a chromosome abnormality Known as the philadelphia (Ph) chromosome. This is a shortened chromosome 22 and is the result of A reciprocal translocation of material with chromosome 9. The break on chromosome 22 occurs in the breakpoient Cluster region (BCR ).the fragment from chromosome 9 that Joins the BCR carries the abl oncogene, which form a fusion Gene with the remains of the BCR.

This BCR ABL chimeric gene codes for a 210 kDa Protein with tyrosine kinase activity, which plays A causative role in the disease, influencing cellular Proliferation, differentiation and survival. In some apparently Ph chromosome –negative patients The BCR ABL gene product is detectable by molecular Techniques.

Natural history : The disease has three phases: *a chronic phase, in which the disease is responsive to treatment And is easily controlled, lasting 3-5 years. *an accelerated phase (not always seen), in which disease control Becomes more difficult. *blast crisis, in which the disease transform into an acute leukaemia, Either myeloid (70%) or lymphoblastic (30%), which is refractory to Treatment. Blast crisis occurs at a rate of 10% per year and is the cause of death In the majority of patients. Patients survival is therefore dictated by the timing of blast crisis, Which can not be predicted.

Patients who are Ph chromosome- and also Prior to imatinib therapy approximately 10% of patients per year would transform. In those treated with imatinib for up to 5 years, only between 0.5-2.5% have transformed each year. Patients who are Ph chromosome- and also BCR ABL-negative tend to be older, with lower Platelet counts and higher absolute monocyte Counts, and respond poorly to treatment, with A median survival of less than one year.

Clinical features Symptoms at presentation may include lethargy, weight loss, abdominal discomfort and sweating, but about 25% of patients are asymptomatic at diagnosis. Splenomegaly is present in 90%; in about 10%, the enlargement is massive, extending to over 15 cm below the costal margin. A friction rub may be heard in cases of splenic infarction. Hepatomegaly occurs in about 50%. Lymphadenopathy is unusual.

Investigations: FBC results are variable between patients. There is usually a normocytic, normochromic anaemia. The leucocyte count can vary from 10 to 600 × 109/L. In about one-third of patients there is a very high platelet count, sometimes as high as 2000 × 109/L. Investigations: Investigations

In the blood film the full range of granulocyte precursors from myeloblasts to mature neutrophils is seen but the predominant cells are neutrophils and myelocytes . Myeloblasts usually constitute less than 10% of all white cells.

There is often an absolute increase in eosinophils and basophils, and nucleated red cells are common. If the disease progresses through an accelerated phase, the percentage of more primitive cells increases. Blast transformation is characterised by a dramatic increase in the number of circulating blasts.

In patients with thrombocytosis, very high platelet counts may persist during treatment, in both chronic and accelerated phases, but usually drop dramatically at blast transformation. Basophilia tends to increase as the disease progresses

Bone marrow should be obtained to: 1-confirm the diagnosis and phase of disease by morphology. 2- chromosome analysis to demonstrate the presence of the Ph chromosome. 3-and RNA analysis to demonstrate the presence of the BCR ABL gene product. Blood LDH levels are elevated and the uric acid level may be high due to increased cell breakdown

Management: Chronic phase: Imatinib specifically inhibits BCR ABL tyrosine kinase activity and reduces the uncontrolled proliferation of white cells. It is recommended as first-line therapy in chronic phase CML, producing complete cytogenetic response (disappearance of the Ph chromosome) in 76% at 18 months of therapy . Patients are monitored by repeated bone marrow examination until in a complete cytogenetic response, and then by 3-monthly real-time quantitative polymerase chain reaction (PCR) for BCR ABL mRNA transcripts in blood. .

For those failing to respond or progress on imatinib, options include second-generation tyrosine kinase inhibitors such as dasatinib or nilotinib, allogeneic bone marrow transplantation or classical cytotoxic drugs such as hydroxycarbamide (hydroxyurea) or interferon

Hydroxycarbamide was previously used widely for initial control of disease, and is still useful in this context or in palliative situations. It does not diminish the frequency of the Ph chromosome or affect the onset of blast cell transformation. Interferonalfa was considered first-line treatment before imatinib was developed

It is given alone or with the chemotherapy agent Ara-C, and can Induce and maintain control of this disease in chronic phase in 70%Of patients. It causes reduction in the percentage of Ph-positive cells in about 20% of patients, and prolongs survival in those who achieve this. Interferon therapy causes flu-like symptoms initially and although Some of those may be controlled with paracetamol , others such asSever bone pain and sever weight loss are reasons for Discontinuatio

Allogeneic or syngeneic stem cell transplantation From a matched sibling donor : Patients in the chronic phase of CML who are younger Than 65 years who have an identical twin or histocompa- Table sibling can be transplanted after intensive therapy . The best result are obtained in patients in early chronic phase when about 80% can expect probable cure. The result of transplantation in accelerated and blast transformation are Significantly worse. Studies are way to investigate the role of imatinib in transplantation for CML.

Accelerated phase and blast crisis Management is more difficult. For patients presenting in accelerated phase, imatinib is indicated if the patient has not already received it. Hydroxycarbamide can be an effective single agent and low-dose cytarabine can also be tried. When blast transformation occurs, the type of blast cell should be determined. Response to appropriate acute leukaemia treatment is better if disease is lymphoblastic than if myeloblastic. Given the very poor response in myeloblastic transformation, there is a strong case for supportive therapy only, particularly in older patients. Accelerated phase and blast crisis

Chronic lymphocytic leukaemia (CLL ) : The most common variety of leukaemia, accounting for 30% of cases. *male to female ratio is 2:1 *median age at presentation is between65 and 70. *in this disease B lymphocytes, which would normally respond to Antigens by transformation and antibody formation, fail to do so. *an ever-increasing mass of immuno-incompetentcells accumulate, To detriment of immune function and normal bone marrow Haematopoiesis.

Clinical features : The onset is very insidious. In around 70% of patients the diagnosis is made Incidentally on a routine full blood count. Presenting problems may be anaemia, infections, Painless Lymphadenopathy and systemic symptoms Such as night sweats or weight loss. However, those more often occur later in the progress of Disease.

Investigations the diagnosis is based on the peripheral blood finding of 9 A mature lymphocytosis(more than 5x10/l)with Characteristic morphology and cell surface markers. Immunophenotyping reveals the lymphocytes to be Monoclonal B –cells expressing the b-cell antigens CD19 And CD23 with either kappa or lambda immunoglobulin Light chains and, characteristically , T-cell antigen, CD5.

CLL blood film morphology

OTHER TEST : Reticulocytosis and positive direct coombs test as autoimmune Haemolytic anaemia may occur. Serum immunoglobulin level should be estimated to establish the Degree of immunosuppression. *bone marrow examination by aspirate and trephine is not essential For the diagnosis of CLL , but may be helpful in difficult cases, for Prognosis( diffuse marrow involvement tend to do worse ) and to The main prognostic factor is a stage Monitor response to therapy. 0f disease. Other poor prognostic factors include : *newer markers such as CD38 expression. *mutation of IgVH genes. *Cytogenetic abnormalities of chromosome 11or 17 .

Staging of CLL : Clinical stage A (60% of patients ) *no anaemia or thrombocytopenia and less than three areas of Lymphoid enlargement. Clinical stage B (30% of patients ) *no anemia or thrombocytopenia, with three or more involved areas of Clinical stage C (10% of patients ) *anaemia and /or thrombocytopenia, regardless of the number of areas of

Management : No specific treatment is required for most clinical stage A patients unless Progression occur. Life expectancy is usually normal in older patients. Treatment is only required if : *there is evidence of bone marrow failure *massive or progressive Lymphadenopathy or splenomegaly . *systemic symptoms such as weight loss or night sweats. *a rapidly increasing lymphocyte count. *autoimmune haemolytic anaemia or thrombocytopenia .

Initial therapy for those requiring treatment (stages B and C ) Consist of oral chemotherapy with alkylating agent chlorambucil. This will reduce the abnormal lymphocyte mass and produce Symptomatic improvement in most patientsGiven orally , Well tolerated started with 2-4 mg /day can be advance To 6-8 mg/dayif the patient not experience intoleratable hematologic side effects. .

More recently, the purine analogue fludarabine, in combination with the alkylating agent cyclophosphamide, has increased remission rates and disease-free survival, although there is an increased risk of infection. Bone marrow failure or autoimmune cytopenias may respond to corticosteroid treatment.

Supportive care is required in: *progressive disease, e.g. transfusion for symptomatic Anaemia or thrombocytopenia. *prompt treatment of infections and for some patients With hypogammaglobulinaemia, immunoglobulin Replacement. Radiotherapy may be used for lymph nodes causing Discomfort or local obstruction , and for symptomatic Splenomegaly. Splenectomy may be required to improve low blood Counts due to autoimmune destruction or to Hypersplenism, and can relieve massive splenomegaly.

Prognosis : The majority of clinical stage A patients have a normal life expectancy but patients with advanced CLL are more likely to die from their disease or infectious complications. Survival is influenced by prognostic features of the leukaemia and whether patients can tolerate intensive treatment. In those treated with chemotherapy and rituximab, 90% are alive 4 years later.

Prolymphocytic leukaemia This is a variant of CLL found mainly in males over the age of 60 years ;25% of the cases are of T –cell variety. There is a massive splenomegaly with little lymphadenopathy and a very high leucocyte count, often in excess of 400x 109, The characteristic cell is a large lymphocyte with prominent nucleolus.

PB morphology from a typical case of T-PLL showing medium-sized lymphoid cells with a regular nuclear outline, single nucleolus, and intense basophilic cytoplasm.

This is a malignancy of medium-sized (about twice the size of a normal small lymphocyte), round lymphocytes with a prominent nucleolus and light blue cytoplasm on Wright's stain.

Clinical presentation is generally from symptoms of splenomegaly or incidental detection of an elevated WBC count. The clinical course can be rapid.

Treatment : Nucleoside analogues like fludarabine and cladribine and combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, or CHOP) have produced responses. CHOP plus rituximab may be more effective than CHOP alone.

but the disease is sufficiently rare that large series have not been reported. Splenectomy can produce palliation of symptoms but appears to have little or no impact on the course of the disease.

Treatment is generally unsuccessful and the prognosis very poor Treatment is generally unsuccessful and the prognosis very poor. Leukapharesis, splenectomy and chemotherapy May be tried

Hairy cell leukaemia This is a rare chronic lymphoprolifrative B-cell disorder. The male to female ratio is 6:1 and the median age at diagnosis is 50 years.

Etiology Some studies suggest that prior exposure to radiation and organic solvents is more frequent among HCL patients. Some investigators have speculated on an etiologic role for the Epstein-Barr virus in the development of HCL, but the proposal has been disputed.

Patients usually present with pancytopenia Patients usually present with pancytopenia. Absolute neutropenia and Monocytopenia are nearly Constant features. The blood film and bone marrow biopsy contain hairy cell which are lymphocytes that have prominent cytoplasmic Projections and give the disease its name.

Clinical features: The diagnostic triad consist of pancytopenia, Splenomegaly and circulating hairy cells.

25%of patients present with fatigue and weakness. 25% present with easy bruising from thrombocytopenia or opportunistic infection from leucopenia, 25%present with early satiety or abdominal fullness from splenomegaly. 25%present with incidental finding of splenomegaly or abnormal blood count on routine examination for un unrelated condition.

Splenomegaly, which may be massive, is found in 90 percent of patients Splenomegaly, which may be massive, is found in 90 percent of patients. Hepatomegaly can occur. Palpable superficial lymphadenopathy is uncommon and is usually localized when found. However, as a result of the routine use of computerized axial tomography scans in the evaluation of patients with lymphoproliferative disorders, significant deep adenopathy has been found to be present in up to one-third of patients with HCL.

In 3 % of patients, the disease manifests as a painful bony lesion (osteolytic) in the axial skeleton or long bones, most commonly involving the proximal femur.

Investigations: Sever neutropenia Monocytopenia The characteristic hairy cells in the blood film morphology and bone marrow. These cells usually type as B-lymphocytes And also characteristically express CD25 And CD103.

Recently, all patients with hairy cell leukaemia have been found to have a mutation in the BRAF gene.

Laboratory Features Blood At the time of diagnosis, pancytopenia occurs in 50 percent of patients; the remaining half usually have bicytopenia. . Anemia is present in about three-quarters of patients and about one-third of patients have a hemoglobin of less than 9.0 g/dL.

Treatment : 90% of patients require treatment at presentation or during the course of the disease. Indications : 1- anaemia when Hb% less than 8-10 g/dl. 2-thrombocytopenia when platelet countless than 50-100x10 /l. 3-Neutropenia with absolute neutrophil count less than 0.5-1.0x10/l , especially when associated with recurrent serious infection.

treatment Over recent years a number of treatments Have been shown to produce long lasting Remissions. Cladribine and deoxycofromycin are Effective in producing long period of Disease control.