Malignant disease - Chronic leukaemias

CHRONIC MYELOID LEUKAEMIA (CML)
CML accounts for about 14% of all leukaemias and is almost exclusively a disease of adults with the peak of presentation being between 40 and 60 yrs. It is defined by the presence of the Philadelphia chromosome. If CML is not initially cured, will be followed by blast crisis transformation to acute leukemia (75% myeloid, 25% lymphoid) or myelofibrosis with death in a median of 3-4 years.

Clinical features
Symptoms

• Symptomatic anaemia
• Abdominal discomfort due to splenomegaly
• Weight loss
• Fever, sweats, in the absence of infection
• Headache or priapism due to hyperleucocytosis
• Bruising, bleeding

Signs

• Pallor
• Splenomegaly
• Lymphadenopathy
• Extramedullary soft tissue leukaemic deposit 'chloroma' (=blast crisis)
• Retinal haemorrhage due to leucostasis

Investigations

• Bloodcount. Hb low/normal, WBC raised
• Bloodfilm. Neutrophilia with spectrum of mature myeloid precursors. Elevated basophils and eosinophils.
• Bone marrow aspirate
• Fluoresence in situ hybridization (FISH)

Management
Treatment of CML has been transformed by the advent of imatinib, a tyrosine kinase inhibitor that specifically blocks the enzymatic action of the BCR-ABL fusion proteins. Side effects of imatinib include nausea, headache, rashes and cytopenia. The use of second generation tyrosine kinase inhibitors, dasatinib and nilotinib, may restore haematological or molecular remission in those patients in the chronic phase that have primary or acquired resistance to imatinib or who are intolerant to imatinib. In acute phase (blast transformation) most patients have only a short-lived response to imatinib and other chemotherapy, and stem cell transplantation is used in the hope of achieving a durable remission.

CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)
CLL results from the clinical expansion of small lymphocytes and is almost invariably (95%) B cell in origin. The majority of patients are asymptomatic, identified as a chance finding on a blood count performed for another indication. Other patients present with features of marrow failure or immunosuppression. This condition may present in leukaemic phase with significant marrow involvement (CLL) or may present as localized disease (small lymphocytic lymphoma, SLL)

Clinical features

• Recurrent infection because of leucopenia and immune failure
• Anaemia due to hemolysis or marrow infiltration
• Painless lymphadenopathy
• Left upper quadrant discomfort - hepatosplenomegaly

Investigation

• Blood count. Hb low/normal, WBC raised, platelets low/normal
• Bloodfilm
• Bone marrow
• Immunophenotyping shows CD19+, CD5+, CD23+ B cells with weak expression od CD20, CD79b and surface immunoglobulin
• Direct coombs' test. May be positive if there is haemolysis.
• Immunoglobulins. Low/normal.

Management
In CLL, the major consideration is when to treat, 30% of patients will never require intervention. Early stage disease is usually managed expectantly, advanced-stage disease is always treated immediately and the approach to the intermediate stage is variable. The absolute indications for treatments are:

• Marrow failure manifest by worsening anaemia and/or thrombocytopenia
• Recurrent infection
• Massive or progressive splenomegaly of lymphadenopathy
• Progressive disease manifest by doubling of the lymphocyte count in 6 months
• Systemic symptoms (fever, night sweats or weight loss)
• Presence of haemolysis or other immune-mediated cytopenias

General/supportive treatment
Anemia due to hemolysis is treated with steroids. Anemia and thrombocytopenia due to marrow infiltration is treated with chemotherapy and transfusion.
Infection is treated with prophylactic antibiotic, antiviral, anti-PCP therapy and antifungal therapy.

Lymphomatous transformation
CLL may undergo lymphomatous (Richter's) transformation in 5-15% of cases, most typically to diffuse large B-cell lymphoma, although Hodgkin's like transformation is recognized.