Chronic lymphoid leukaemias

Heterogeneous group of conditions associated with accumulation of lymphoid cells in the peripheral blood. Classified by morphology, surface immunophenotype, cytogenetics, and molecular biology. Some lymphomas may present with lymphoid cells in the blood and bone marrow infiltration.

B-cell chronic lymphocytic leukaemia

Common leukaemia of late middle-age and old age with accumulation of small, mature-looking B lymphocytes in the peripheral blood, bone marrow, and lymphatic tissues.

Accounts for 30-40% of all leukaemias diagnosed in adults in Europe and North America. Annual incidence, 2.5 per 100 000; male to female ratio 2:1; median age at diagnosis 65-70 years; 79% of patients over 60 years of age at diagnosis; only 6% under 50 years. Environmental associations:

♦ Farming (especially soya bean, cattle, diary, herbicide use)

♦ Rubber manufacture

♦ Carbon tetrachloride exposure

Table 27.1 Chronic lymphoid leukaemias (CLL) B-cell

B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma

B-cell prolymphocytic leukaemia

Hairy-cell leukaemia and variants

Splenic lymphoma with villous lympocytes

Leukaemic phase of mantle cell lymphoma

Leukaemic phase of follicle centre cell lymphoma

Leukaemic phase of lymphoplasmacytoid lymphoma

T-cell

T-cell chronic lymphocytic leukaemia (large granular lymphocytic leukaemia)

T-cell prolymphocytic leukaemia

Adult T-cell leukaemia/lymphoma

Leukaemic phase of mycosis fungoides/Sezary syndrome

Genetic factors may predominate—compare, for example, the low incidence of CLL in Japanese people both in Japan and after emigration.

Clone expansion is due to prolonged survival of CLL cells through failure to respond to apoptotic signals rather than through prolifera-tive advantage; CLL cells constitutively express high levels of Bcl-2 protein, inhibiting apoptosis.

Pathology

Gradual accumulation of small lymphocytes in the lymph nodes, spleen, bone marrow, and blood causing slowly progressive enlargement of the lymph nodes and spleen and bone marrow infiltration with anaemia, thrombocytopenia, and neutropenia (important prognostic factors at diagnosis). Other features:

♦ Sometimes autoimmune haemolytic anaemia

♦ Hypogammaglobulinaemia

♦ Disorders of T-lymphocyte function are common

Clinical presentation

Variable but generally indolent clinical course. Now usually diagnosed early, often after routine blood count or presentation with painless lymphadenopathy, anaemia, or infection. Constitutional symptoms restricted to patients with advanced disease.

Lymphadenopathy is symmetrical, often generalized. Splenomegaly at presentation in 66%; hepatomegaly much less frequent at presentation but common in advanced disease; involvement of other organs infrequent at diagnosis.

Diagnosis

Clear criteria for the diagnosis of CLL. Surface antigen immuno-phenotyping is essential to exclude reactive causes (usually T-lympho-cytosis) and lymphocytosis due to other lymphoid neoplasms.

Management

No evidence that treatment prolongs survival of patients with lymphocytosis or uncomplicated lymphadenopathy. Systemic therapy is indicated for advanced disease and those with diffuse infiltration on the trephine biopsy or a low lymphocyte doubling time (<12 months), irrespective of stage. NCI Working Party guidelines are to initiate treatment if:

♦ Constitutional symptoms referable to CLL (weight loss >10% in 6 months, fatigue or performance score 2 or worse, fever without overt infection, night sweats)

♦ Symptomatic lymphadenopathy; symptomatic hepatosplenomegaly

♦ Progressive anaemia with haemoglobin <10 g/dl

Table 27.2 NCI Working Group revised criteria for diagnosis of CLL Peripheral blood lymphocytosis: (1) absolute lymphocyte count >5 x 109/l

(2) morphologically mature appearing cells Characteristic phenotype: (1) predominance of CD19+, CD20+,

(2) light chain restriction i.e. monoclonal — or k expression

(3) low-density surface immunoglobulin (sIg) expression

Bone marrow examination: >30% lymphocytes in bone marrow if peripheral blood lymphocytosis is relatively low i.e. close to 5 x 109/l

♦ Progressive thrombocytopenia with platelets <100 x 109/1

♦ Progressive lymphocytosis >300 x 109/1 or rapid rate of increase

♦ Autoimmune disease refractory to prednisolone

♦ Repeated infections with or without hypogammaglobulinaemia

Chlorambucil

Remains first-line therapy. Generally produces a partial response: reduction in peripheral blood lymphocytosis and improvement in haemoglobin and platelet count, shrinking of lymphadenopathy and splenomegaly, and improvement in constitutional symptoms in >50% of patients. Complete responses rare.

Discontinue when normal lymphocyte count is achieved or continue as long as patient responds, usually some 6-12 months. Restart on progression. Median survival in responding patients, four years.

Corticosteroids

Single-agent prednisolone (1 mg/kg/day) produces reduction in lymphocytic infiltration of bone marrow and can result in significant improvement in cytopenia and symptoms. Useful initial treatment (1-2 weeks) for patients with advanced disease and pancytopenia at diagnosis.

Combination chemotherapy

No survival advantage of COP^ or CHOP^ over chlorambucil. Higher response rate in advanced disease. Response rate low when resistant to chlorambucil. Purine analogues better second-line therapy.

COP: Cyclophosphamide, Oncovin (vincristine); Prednisolone; CHOP: Cyclophosphamide, Adriamycin, Oncovin, Prednisolone.

Purine analogues

Effective treatment of CLL. Cause profound depletion of normal lymphocytes especially CD4+ T-cells and predispose to opportunistic infection, in particular P. carinii, Listeria monocytogenes, M. tuberculosis, Norcardia and herpes viruses.

Single-agent fludarabine produces higher response rate than chlorambucil—previously untreated patients (70 vs. 40%), CR rate (27 vs. 3%), and disease-free survival (33 vs. 17 months). Also effective in previously treated patients (31-57% response rate, 13% CRs). No evidence of improved overall survival. Generally administered at a dose of 25 mg/m2 Intravenously for 5 days on a 4-6 week cycle until maximum response or 6 cycles. Complications include:

♦ Myelosuppression

♦ Prolonged CD4+ T-lymphocytopenia

♦ Autoimmune haemolysis

Routine prophylaxis of P. carinii pneumonia with either co-trimoxa-zole or pentamidine advisable for one year after treatment, with or without acyclovir prophylaxis of Herpes zoster reactivation. Caution is needed in patients with previous history of autoimmune haemolysis.

Fludarabine is an option for first-line therapy and also an effective second-line therapy for alkylator-resistant CLL.

Radiotherapy

Effective local treatment for lymph nodes compromising vital organ function. Splenic irradiation is effective for painful splenomegaly, though splenectomy better for massive splenomegaly if patient is fit for surgery.

Splenectomy

Effective for massive splenomegaly, anaemia, or thrombocytopenia due to hypersplenism and for autoimmune haemolytic anaemia refractory to prednisolone and cytotoxic therapy

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