Chronic lymphatic leukemia. Peroral cladribine as primary treatment

Ten patients with newly diagnosed B-chronic lymphocytic leukaemia were treated with cladribin orally for five days every four weeks with a median of four series. This is the first reported clinical study where a purine analogue is administered orally. The tumour reducing effect was fast. Eight out of 10 patients responded with a partial or clinical complete remission. Two of these were in molecular biological complete remission. With an observation time of 22 months we have seen no serious side effects so far. A randomized study (including a long term follow up) between chlorambucil, fludarabin and cladribin is needed to clarify the future role of cladribin in B-CLL treatment.     

Autoantibody occurrence in hairy cell leukemia

The influence of galactoside-specific mistletoe lectin (ML-1) administration on defined acute phase reactants in the serum of cancer patients (mammary carcinoma, n = 4; larynx carcinoma, n = 11; TNM-stages II to IV; after appropriate surgery, chemotherapy, radiation) was studied. Regular subcutaneous injections of the optimal doses of ML-1 (1 mg/kg body weight, twice a week) yielded statistically significant increases of certain acute phase reactants (C-reactive protein, haptoglobin, coeruloplasmin, C3-complement, albumin, immunoglobulin IgM) after four weeks of treatment. However, serum concentrations of transferrin, C4-complement and the immunoglobulins IgG and IgA were found within the biological range (means +/- 2 s). The increase of acute phase reactants after administration of ML-1 correlates positively with the activity of lymphatic cells (e.g. expression of IL-2 and HLA-DR receptors) in FACS (fluorescence-activated cell sorter) staining experiments and indicates the immunoreactive potency of this substance which may be speculated to be cytokine-induced.     

Interferon alpha and intracytoplasmic free calcium in hairy cell leukemia cells

Hairy cell leukemia (HCL) is a B-cell tumor affecting the pre-plasma stage of B cell differentiation. One of the most striking characteristics of this disease is its remarkable responsiveness to alpha-interferon (IFN-alpha) therapy. Interferons constitute a heterologous family of multifunctional cytokines displaying anti-viral, anti-proliferative and immunoregulatory properties. These activities have been extensively studied in hairy cells, but the mechanism of action of IFN-alpha in hairy cell leukemia remains unknown. Our approach to investigate the mode action of IFN-alpha in HCL has been to identify abnormalities which occur in these tumor cells and then to ascertain whether these abnormalities can be rectified by IFN-alpha treatment. A high level of free Ca2+ in the cytoplasm of hairy cells was identified. Increases in cytosolic Ca2+ are believed to be a pivotal signal in regulating cell proliferation, cell differentiation and cell death. These high Ca2+ levels in hairy cells could be reduced upon treatment with IFN-alpha either in vitro or in vivo, probably acting by reducing Ca2+ influx into the leukemic cells. Moreover, the effect of IFN-alpha on [Ca2+]i seems to be correlated with down-regulation of CD20 phosphorylation, a B cell specific phosphoprotein involved in Ca2+ influx across the plasma membrane. The possible origins and implications of Ca2+ deregulation and the possible mechanisms or sites of action of IFN-alpha in tumor cells from HCL are explored in this review.     

Increased frequency of chromosome abnormalities in fibroblasts from hairy cell leukemia patients

A hereditary component is implicated in many different cancers, including hairy cell leukemia (HCL), and may involve an instability of the genome. We have previously documented recurrent clonal and non-clonal chromosomal abnormalities in hairy cells. To ascertain whether this instability of the genome is restricted to the malignant cells or if it might also include normal cells we performed cytogenetic investigations on skin fibroblasts and hairy cells from eight HCL patients and skin fibroblasts from eight referents. The frequency of chromosome abnormalities, regardless of clonality, was significantly increased in the fibroblasts from patients compared to referents. Also, five patients compared to one referent showed clonal abnormalities in their fibroblasts. Immunohistochemical investigations excluded the possibility that the fibroblast cultures were contaminated with hairy cells. Two patients had constitutional abnormalities, inv(5)(p13.1q13.3) and t(13;14), and one additional patient, possibly mosaic, showed the same abnormality, inv(9)(p21-22q22), in both fibroblasts (17/30) and blood (5/21) cells. Aberrations in patient fibroblasts also included sporadic inv(5), del(6)q, inv(19), and del(20)q, abnormalities previously shown to occur in hairy cells. A clonal expansion with trisomy 7 occurred in vitro as documented by fluorescence in situ hybridization (FISH). The only clonal abnormality occurring in a referent was -Y/-Y,+15 in an elderly male. In conclusion, a constitutional chromosomal instability may precede chromosome abnormalities and be of importance in the development of hairy cell leukemia.     

BCL-2 immunohistochemical evaluation in B-cell chronic lymphocytic leukemia and hairy cell leukemia before treatment with fludarabine and 2-chloro-deoxy-adenosine

Bcl-2 overexpression has been shown to be associated with several malignancies, including B-cell chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphomas (NHL), mainly low-grade and follicular in type. It has as yet not been described in hairy cell leukemia (HCL). In 30 patients with CLL and 14 with HCL who were consecutively selected for treatment with purine analogues (Fludarabine in CLL and 2-chloro-deoxy-adenosine in HCL), we evaluated bcl-2 oncoprotein expression in leukemic cells on marrow sections that were taken before treatment and stained immunohistochemically with a monoclonal antibody (Dakopatts 124 clone), by the avidin-biotin-peroxidase method. All samples were found to be bcl-2 positive, with a staining intensity that was moderate to strong in CLL and weak to moderate in HCL. 83% of CLL and 100% of HCL patients were responsive to purine analogues. These findings show that bcl-2 is overexpressed in almost all cases CLL and HCL and that bcl-2 overexpression does not predict a poor response to purine analogues, which are believed to induce apoptosis.     

Integrin receptors and hairy cell leukaemia

The ability of a cell to recognize and specifically localise within an appropriate tissue environment is essential to the proliferation and survival of that cell. The integrin family of cell-surface adhesion-receptors are essential to such tissue localisation, allowing a migrating cell to specifically recognise, localise within-, and respond to- the cellular or extracellular matrix ligands that characterise a given tissue. We have investigated how the expression and activity of integrin receptors underlies the consistent and unusual tissue distribution of the malignant B lymphocytes of hairy cell leukaemia (HCL). In this report we review our published work in this area. Our findings are then discussed within the context of current knowledge of integrin receptors and their ligands, and in relation to the clinical features of HCL.     

Development of essential thrombocythemia in a patient treated with interferon alfa and pentostatin for hairy cell leukemia

A patient is reported who developed essential thrombocythemia after successful treatment for hairy cell leukemia. He was initially treated with interferon alfa and subsequently relapsed within one year of treatment. His diagnosis was reconfirmed and then treated with Pentostatin. Six years after treatment he had a progressive increase in the platelet count and was diagnosed as essential thrombocythemia. Second cancers including various types of hematological malignancy have been reported in patients with hairy cell leukemia treated with chemotherapy or interferon alfa. These malignancies may represent either a new clonal disorder or a complication of drug treatment. This is the first report of a chronic myeloproliferative disorder following successful treatment of hairy cell leukemia.     

Chronic myelogenous leukemia

Chronic myelogenous leukemia is a clonal hematopoietic malignancy characterized by a balanced translocation between chromosomes 9 and 22 that results in the generation of an abnormal bcr/abl fusion protein with increased tyrosine kinase activity. This abnormal fusion protein has transforming activity for hematopoietic cells in vitro and causes chronic myelogenous leukemia-like myelopoiesis in mice. Chronic myelogenous leukemia progenitor cells display abnormalities in their interactions with bone marrow stroma, perhaps due to defective adhesion molecule function. Conventional therapies for chronic myelogenous leukemia include hydroxyurea, busulfan, or interferon. Treatment with interferon may prolong overall survival, especially in patients who achieve a cytogenetic response. Related donor marrow transplantation can result in long-term survival in more than 65% of patients treated early in the course of disease. For patients without an available matched sibling donor, unrelated donor marrow transplantation or autologous marrow transplantation are alternative therapeutic options.     

The development of congestive cardiac failure in a patient with hairy cell leukemia treated with 2-chlorodeoxyadenosine

Deoxyadenosines are closely related to adenosine and as such, may interfere with the cardiac adenylate cyclase pathway resulting in cardiac dysfunction. We report a rare case of a 42 year old man who developed transient cardiac failure following treatment with 2-CDA for hairy cell leukemia.     

Splenic irradiation for hairy cell leukaemia

In vitro studies show that the adhesive amalgam technique is superior to the nonadhesive technique. Also, early clinical results indicate that the adhesive technique can eliminate the microspace between amalgam and tooth. And, it can retain amalgam on unprepared occlusal surfaces of molars and premolars, sealing the fissures. Moreover, amalgam can be retained in preparations without undercuts. Early results indicate in traditional preparations, the adhesive technique appears to be at least equivalent to nonadhesive technique.     

Pancreatic pleural effusion. Diagnosis and therapy

Pancreaticopleural fistula is an uncommon complication of chronic pancreatitis or pancreatic trauma. Clinical features include pleural effusion and resulting pulmonary symptoms. Abdominal pain and other clinical manifestations of pancreatitis may be minimal or absent. As in this case, computed tomography and endoscopic retrograde cholangiopancreatography may provide complementary diagnostic information in the evaluation of this condition. A discussion of the pathophysiology, diagnosis and management of pancreaticopleural fistula is presented.     

2-CDA in treatment of hairy cell leukemia: a comparison between intravenous and subcutaneous administration. Swiss Study Group of Applied Cancer Research

2-chlorodeoxyadenosine (2-CDA) is very effective in the treatment of patients with hairy-cell leukaemia, with an overall response rate of 80-95%. The standard treatment is a continuous intravenous infusion for 7 days. The bioavailability of 2-CDA after subcutaneous injection is 100%, but the concentration-time profile is completely different compared to continuous intravenous administration. In the present study we compared the intravenous standard treatment (group 1, n = 22; 0.1 mg/kg/d for 7 days, civ.) with subcutaneous administration of 2-CDA (group 2, n = 62; 0.14 mg/kg/d for 5 days, s.c.) in patients with hairy-cell leukaemia. In group 1, 96% (21/22) of patients responded to 2-CDA (complete remission 73%, partial remission 23%) and in the second group 97% were responsive (complete response 76%, 47/62; partial remission 21%, 13/62). The percentage for moderate and severe infections in the trial with intravenous and subcutaneous treatment was 14% and 26% respectively (p = 0.37). We conclude that subcutaneous administration of 2-CDA in patients with hairy-cell leukaemia is feasible and economical and results in comparable responses and toxicity compared to the intravenous standard treatment.