2-chloro-3--deoxyadenosine and Lymphoproliferative-Disorders

Myasthenia gravis (MG) is an autoimmune disease mediated by antibodies to acetylcholine receptors (AChRs) or muscle specific tyrosine kinase (MuSK). While the frequent association of MG with thymoma in patients aged 40-60 years is well recognized, its occurrence in patients with lymphoma has not been well studied. We review the literature on the association of MG and lymphoid malignancies and report two new patients. MG can occur in a synchronous or non-synchronous fashion with lymphoma. The pathogenesis of MG in lymphoid malignancies is probably heterogeneous and likely relates to perturbations in the immune mechanisms that normally prevent the emergence of autoimmunity. These perturbations could be the result of the lymphoid malignancy per se, or its treatment.

Topics: 2-Chloroadenosine; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cyclosporine; Deoxyadenosines; Fatal Outcome; Female; Humans; Lymphoma; Lymphoma, Follicular; Lymphoproliferative Disorders; Male; Middle Aged; Myasthenia Gravis; Paraneoplastic Syndromes, Nervous System; Prednisone; Pyridostigmine Bromide; Recurrence; Remission Induction; Rituximab; Waldenstrom Macroglobulinemia

Nucleoside analogues (NA) are essential components of AML induction therapy (cytosine arabinoside), effective treatments of lymphoproliferative disorders (fludarabine, cladribine) and are also used in the treatment of some solid tumors (gemcitabine). These important compounds share some general common characteristics, namely in terms of requiring transport by specific membrane transporters, metabolism and interaction with intracellular targets. However, these compounds differ in regard to the types of transporters that most efficiently transport a given compound, and their preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumors and others on neoplasia with a more protracted evolution. In this review, we analyze the available data concerning mechanisms of action of and resistance to NA, with particular emphasis on recent advances in the characterization of nucleoside transporters and on the potential role of activating or inactivating enzymes in the induction of clinical resistance to these compounds. We performed an extensive search of published in vitro and clinical data in which the levels of expression of nucleoside-activating or inactivating enzymes have been correlated with tumor response or patient outcome. Strategies aiming to increase the intracellular concentrations of active compounds are presented.

Topics: 2-Chloroadenosine; 5'-Nucleotidase; Acute Disease; Animals; Antimetabolites, Antineoplastic; Arabinonucleosides; Biological Transport; Carrier Proteins; Cytarabine; Cytidine Deaminase; Cytosine; Deoxyadenosines; Deoxycytidine; Deoxycytidine Kinase; Dioxolanes; DNA Repair; DNA Replication; DNA-Directed DNA Polymerase; Drug Resistance, Neoplasm; Gemcitabine; Hematopoietic Cell Growth Factors; Humans; Leukemia, Myeloid; Lymphoproliferative Disorders; Neoplastic Stem Cells; Nucleosides; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Remission Induction; Ribonucleotide Reductases; Vidarabine

We describe the occurrence of myelodysplastic changes (hypogranular myeloid series and Pelger cells, dyserythropoiesis with ring sideroblasts) in five of 31 patients with chronic lymphoproliferative disorders after treatment with purine analogues. The bone marrows of 31 patients with chronic lymphoproliferative disorders before and after treatment with purine analogues were reviewed. The majority of patients had received extensive prior treatment, but none had dysplastic changes prior to treatment with purine analogues. We suggest that a purine analogue may have been responsible for dysplastic change and that further follow-up of this phenomenon is warranted.

Topics: 2-Chloroadenosine; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Deoxyadenosines; Female; Humans; Lymphoproliferative Disorders; Male; Myelodysplastic Syndromes; Pentostatin; Vidarabine

Eosinophilia and allergic skin reactions are uncommon events after 2-chlorodoxyadenosine (2-CdA, cladribine) administration. A multicentre retrospective analysis of eosinophilia in 360 patients treated with 2-CdA for lymphoid malignancies has been made. B-cell chronic lymphocytic leukaemia (B-CLL) was diagnosed in 153, hairy cell leukaemia (HCL) in 68, low-grade non-Hodgkin's lymphoma (LGNHL) in 119, high-grade NHL in 2 and Waldenstrom's macroglobulinaemia (WM) in 18 patients. 2-CdA was administered at a dose 0.12 mg/kg/d in 2-h intravenous infusion for 5 consecutive d. The courses were repeated monthly. Patients with HCL received 1 cycle of 2-CdA, with NHL 2-6 (mean 3.5) cycles and with B-CLL 3-6 (mean 5) cycles. Twenty patients (5.5%), including 5 with HCL, 6 with LGNHL, 7 with B-CLL and 2 with WM, developed peripheral blood eosinophilia. The mean values of absolute eosinophil count were 0.78x10(9)/l (0.58-1.06x10(9)/l), 0.71x10(9)/l (0.52-1.3x10(9)/l), 85 (0.56-1.82x10(9)/l) and 0.75 (0.74-0.76x10(9)/l), respectively. Eosinophilia occurred in 13 patients after 1 course, in 4 after 2 courses, and in 5 after > or =3 courses of the therapy. In 17 cases it resolved spontaneously. Allergic skin lesions with pruritus were noticed in 3 patients simultaneously with an increase in eosinophil count. All of them required antihistaminic drugs and/or corticosteroids. One patient with B-CLL experienced repeated episodes of eosinophilia. The highest incidence of 2-CdA-induced eosinophilia was noticed in patients with MW (11.1%) and HCL (7.4%) who received only 1 cycle of this drug and entered a complete remission. This side effect was less frequently observed in LGNHL and B-CLL, i.e. in 5.0% and 4.6% of cases, respectively. The mechanism of 2-CdA-induced eosinophilia is not clear. It has been postulated that massive tumour cell lysis may trigger a release of IL-5 and probably other cytokines. The allergic mechanism of 2-CdA-induced eosinophilia is also possible, especially in patients with simultaneous skin reactions.

Topics: 2-Chloroadenosine; Aged; Antimetabolites, Antineoplastic; Deoxyadenosines; Eosinophilia; Female; Humans; Infusions, Intravenous; Leukocyte Count; Lymphoproliferative Disorders; Male; Middle Aged; Retrospective Studies