PubMed Health⌕ Search

Biomedical subjects

A Saven

Publications and source records attributed to A Saven.

At least 37 records · Page 2Linked to original sources
PubMed1997

2-chlorodeoxyadenosine administration to patients with the myeloid blast phase of chronic myelogenous leukemia.

Three patients with chronic myelogenous leukemia (CML) in myeloid blast phase received 2-chlorodeoxyadenosine (2-CdA) at 0.7 mg/kg per course over 5 days every 2-4 weeks for 7, 2 and 5 courses. Each patient had a decrement in their white blood cell count, and in the absolute number and percentage of circulating immature cells following 2-CdA administration. Two patients achieved hematologic responses of 14 and 3 months and survived 19 and 6 months, respectively, while the non-responder died 2 months later. 2-CdA-induced anemia and thrombocytopenia, generally mild and reversible, were observed in all patients. Given the dismal results and considerable toxicities that follow multiagent induction chemotherapy for CML in myeloid blast phase, 2-CdA therapy may represent a reasonable therapeutic alternative, although confirmation is required in larger numbers of patients.

Aged↗
PubMed1996

Prolonged, complete remission after 2-chlorodeoxyadenosine therapy in a patient with refractory essential mixed cryoglobulinemia.

Essential mixed cryoglobulinemia is a systemic disorder in which cutaneous vasculitis and frequently glomerulonephritis are associated with cryoprecipitable serum immune complexes. Typically, the treatment regimen consists of plasmapheresis, high-dose corticosteroids, and cytotoxic chemotherapy, as well as interferon alfa for hepatitis C virus-related cryoglobulinemia. Herein we describe a man with progressive, symptomatic cryoglobulinemia and multisystem organ dysfunction in whom corticosteroid and alkylating therapy failed; however, he had a complete and long-lasting remission after administration of 2-chlorodeoxyadenosine (cladribine).

Aged↗
PubMed1996

Acute myelogenous leukemia presenting with bulky lymphadenopathy. Case report and literature review.

We report a patient with acute myeloid leukemia (AML) presenting with generalized lymphadenopathy, clinically stimulating aggressive non-Hodgkin's lymphoma. This patient presented with anemia and bulky lymphadenopathy in the oropharyngeal (Waldeyer's ring), submandibular, supraclavicular and inguinal nodal regions. Lymph node biopsy was initially suggestive of a T-cell lymphoblastic lymphoma, based on morphologic features together with positive immunohistochemical staining for CD7 and CD43 (Leu 22). Definitive diagnosis of AML was established when a more detailed immunophenotypic analysis showed expression of the myeloid markers CD13 and CD33, and by the demonstration of rare Auer rods and positive peroxidase staining in bone marrow blast cells. Although this is a rare presentation, AML must always be considered in the clinical and pathologic differential diagnosis of aggressive non-Hodgkin's lymphoma.

Aged↗
PubMed1996

Pharmacokinetic study of oral and bolus intravenous 2-chlorodeoxyadenosine in patients with malignancy.

PURPOSE: This study was designed to evaluate the absolute bioavailability (F value) of 2-chlorodeoxyadenosine (cladribine; 2-CdA) after multiple oral administrations, and the intersubject variability after oral and 2-hour intravenous (IV) administration schedules in patients with malignancy. PATIENTS AND METHODS: Patients with advanced malignancies were eligible. There were two treatment cycles; during cycle 1, patients received 2-CdA solution at 0.28 mg/kg/d orally under fasting conditions for 5 consecutive days concomitantly with omeprazole, and 4 weeks later during cycle 2 patients received 2-CdA as a 2-hour IV infusion of 0.14 mg/kg/d for 5 consecutive days. Serial blood samples for 2-CdA plasma levels were obtained after drug administrations on days 1 and 5 during each treatment cycle. RESULTS: Ten patients completed cycles 1 and 2. The F value of oral 2-CdA measured on days 1 and 5 was 37.2% and 36.7%, respectively. For both oral and IV multiple administrations, there was no significant accumulation in maximum concentration (Cmax), and the intersubject variabilities (coefficient of variation [CV], approximately 40%) in Cmax and area under the concentration-time curve from 0 to 24 hours [AUC(0-24)] values were comparable for both routes on days 1 and 5. A three-compartment open model was applied to the plasma concentration data after oral and IV administrations and resulted in good agreement between observed and simulated concentration-time profiles. Neutropenia was the principal adverse event observed when 2-CdA was administered orally and IV. CONCLUSION: The F value of 2-CdA after oral administration was approximately 37% and there were no cumulative differences in bioavailability observed on multiple dosing of the drug. The absorption and disposition characteristics of oral 2-CdA were linear and predictable with this dosing regimen.

Administration, Oral↗
PubMed1996

Cladribine and mitoxantrone dose escalation in indolent non-Hodgkin's lymphoma.

PURPOSE: Since cladribine (2-chlorodeoxyadenosine [2-CdA]) and mitoxantrone both exhibit major activity against indolent lymphoid malignancies and have different mechanisms of action, we performed a dose-escalation study of 2-CdA and mitoxantrone in patients with alkylator-failed indolent lymphoma to determine the maximum-tolerated dose (MTD) of this combination and to make preliminary observations about efficacy. PATIENTS AND METHODS: Twenty-three patients were treated every 28 to 35 days, in cohorts of at least three patients, with stepwise dose escalations until dose-limiting toxicities (DLTs) were encountered. The initial dose levels were 2-CdA 0.1 mg/kg/d by continuous infusion for 7 days, mitoxantrone 5 mg/m2 intravenously (i.v.) on day 1, and prednisone 100 mg/d on days 1 to 5. Mitoxantrone was dose-escalated in increments of 2.5 mg/m2 i.v. on day 1. RESULTS: The MTD of the combination was 2-CdA 0.1 mg/kg/d for 7 days, mitoxantrone 7.5 mg/m2 i.v. on day 1, and prednisone 100 mg/d on days 1 to 5. Myelosuppression and infection were the DLTs. The recommended phase II doses were 2-CdA 0.075 mg/kg/d for 7 days mitoxantrone 5 mg/m2 i.v. on day 1; prednisone was omitted to decrease the risk of opportunistic infections. The overall response rate was 70%, with 22% complete responses (CRs) and 48% partial responses (PRs). The median duration of CR was 15 months and PR 5 months. CONCLUSION: These results demonstrate the feasibility and safety of combining 2-CdA and mitoxantrone in the treatment of indolent lymphoma, and appear to confirm clinically the mechanistic synergism and rationale for this combination regimen. Prednisone exacerbated the risk of opportunistic infection and was omitted. The overall response rate was high, including durable CRs. Further studies of this combination regimen are warranted in untreated and alkylator-failed indolent lymphoma.

Adult↗
PubMed1996

New perspectives on the approach to chronic lymphocytic leukemia.

Investigation of the biological actions of loxoribine in chronic lymphocytic leukemia (CLL) was undertaken because of the pervasive immunostimulatory effects of the nucleoside on normal B cells. In vitro studies with cells from a spectrum of CLL patients demonstrate that loxoribine induces B-CLL cells to enter and traverse the cell cycle. This is reflected by marked increases in DNA synthesis, by standard morphological criteria, and by flow cytometric evaluation of cell cycle status and of cell surface activation markers. Cells from about 75% of patients studied evince this response. Analysis of a variety of biological parameters indicate that only the ratio of T cells (CD4+ or CD8+) to B-CLL cells correlates with induction and degree of proliferative response. Co-stimulation with loxoribine and IL-2 results in modest proliferative synergy, presumably due to upregulation of IL-2R alpha expression on B-CLL cells by loxoribine. Prolonged exposure of B-CLL cells to stimulatory concentrations of loxoribine frequently culminates in progression of the responsive cells to apoptosis. The capacity of loxoribine to transiently approximate the reversible transformation of a low grade B cell malignancy to one of a higher grade presents the opportunity for evaluation of cycle-active drugs under these conditions. Recent studies indicate that pre-treatment of B-CLL cells with loxoribine results in synergistic killing of leukemic cells with cycle-active drugs. The ability to induce B-CLL cells into cell cycle entry and/or into either activation-induced apoptosis or into phases of the cell cycle sensitive to cytotoxic therapy opens up new perspectives for the development of potentially curative strategies for this chronic leukemia.

Adjuvants, Immunologic↗
PubMed1996

2-Chlorodeoxyadenosine: a potent antimetabolite with major activity in the treatment of indolent lymphoproliferative disorders.

2-Chlorodeoxyadenosine (2-CdA) is unique compared with traditional antimetabolites in that it is equally active against dividing and resting lymphocytes, which may be especially important in the treatment of indolent lymphoproliferative disorders because most cells in these disorders are in the resting phase. Significant clinical activity has been demonstrated for 2-CdA in the treatment of hairy cell leukemia, chronic lymphocytic leukemia, low-grade non-Hodgkin's lymphoma, Waldenström macroglobulinemia, and more recently prolymphocytic leukemia. More modest activity has been shown for 2-CdA in acute and chronic leukemias and in a variety of miscellaneous conditions, including Langerhans'-cell histiocytosis and multiple sclerosis.

Antineoplastic Agents↗
PubMed1995

2-Chlorodeoxyadenosine activity in patients with untreated, indolent non-Hodgkin's lymphoma.

Based on the encouraging results of the use of 2-chlorodeoxyadenosine ([2-CdA], cladribine) in patients with advanced, low-grade lymphomas resistant to conventional therapy and the acceptable toxicity profile encountered, we conducted a phase II trial of 2-CdA in patients with untreated indolent lymphomas. Twenty-eight patients with untreated low-grade lymphomas were given 2-CdA at 0.1 mg/kg/d as a 7-day continuous infusion every 28 to 35 days. A total of 89 courses, median of three courses per patient, of 2-CdA were administered. Seventeen men and 11 women with a median age of 58 years were treated. Fifteen patients had diffuse small lymphocytic (8 with plasmacytoid features), 10 had follicular small cleaved-cell, and there were single patients with monocytoid B-cell, mantle cell and mucosa-associated lymphoid tissue (MALT) lymphoma histologies. All 28 patients were evaluable for toxicity and 26 were evaluable for response. Nine (35%) patients (4 with diffuse small lymphocytic, 3 with follicular small cleaved-cell, 1 with mantle cell, and 1 with MALT lymphoma) achieved a complete response, and 14 (54%) patients (8 with diffuse small lymphocytic, 5 with follicular small cleaved-cell, and 1 with monocytoid B-cell lymphoma) achieved a partial response, for an overall response rate of 88%. The median response duration was 10 months (range, 3 to 44+). Myelosuppression was the principal toxicity. Actuarial survival at 60 months from initial diagnosis was 60% (95% confidence interval, 35% to 82%) and at 48 months from treatment onset was 62% (95% confidence interval, 39% to 83%). These results establish the major activity of 2-CdA in patients with untreated indolent lymphoma, especially those with the diffuse small lymphocytic subtype.

Actuarial Analysis↗
PubMed1995

2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia.

PURPOSE: 2-chlorodeoxyadenosine (2-CdA; cladribine) is a purine analog with activity in patients with chronic lymphocytic leukemia (CLL) who fail to respond to alkylator therapy. We conducted a phase II trial of 2-CdA in previously untreated CLL patients. PATIENTS AND METHODS: 2-CdA was administered to 20 patients with previously untreated CLL as a 0.1-mg/kg/d 7-day continuous intravenous infusion every 28 to 35 days until maximum response or prohibitive toxicity. RESULTS: A median of four courses (range, one to nine) was administered to each patient. Five patients (25%) achieved a complete response and 12 (60%) achieved a partial response, for an overall response rate of 85%. The median response follow-up duration was 8+ months (range, 3 to 27). Myelosuppression was the principal toxicity. Four of 20 patients (20%) experienced grade III or IV thrombocytopenia. Three patients, all of whom received corticosteroid therapy, developed opportunistic infections at a median of 19 months following discontinuation of 2-CdA therapy. CONCLUSION: 2-CdA has major activity in patients with previously untreated CLL, and the lower response rates seen in previously treated patients may be due in part to poor marrow reserve from prior therapy. Determination of the relative effectiveness of 2-CdA, fludarabine, and chlorambucil in the treatment of CLL patients will require a randomized trial.

Adult↗
PubMed1995

The optimal management of hairy cell leukaemia.

Hairy cell leukaemia is an uncommon B cell chronic lymphoproliferative disorder characterised by circulating lymphocytes displaying prominent cytoplasmic projections. Therapy is initiated for severe cytopenias or recurrent infections. Splenectomy, the first standard treatment, is now less commonly used as primary treatment. Interferon-alpha (IFN alpha) induces partial responses in most patients but complete responses in only a few. Adverse effects from IFN alpha are common but not life-threatening. The ability of two newer purine analogues, pentostatin (2'-deoxycoformycin) and cladribine (2-chlorodeoxyadenosine), to induce long-lasting complete remissions in the majority of patients has revolutionised the treatment of this disease. Cladribine is emerging as the treatment of choice because of its favourable toxicity profile, brief duration of treatment, high percentage of unmaintained complete remissions and low incidence of relapse.

Antineoplastic Agents↗
PubMed1994

Immunomorphologic analysis of bone marrow biopsies after treatment with 2-chlorodeoxyadenosine for hairy cell leukemia.

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA) induces complete remissions in 85% of patients. Complete remission has been defined as the absence of hairy cells in the bone marrow after routine morphologic examination. To determine if hairy cells could be detected in complete remission bone marrows using immunohistochemical techniques with antibodies L26 (CD20) and DBA.44, 154 bone marrow biopsies performed between 3 months and 25 months after therapy were studied. Of the biopsies, 50% exhibited staining with L26 and/or DBA.44 in five or more cells with morphologic features of hairy cells. Minimal residual disease was usually less than 1% of the total cellular population. DBA.44-positive cells were demonstrated in 91% of the biopsies, although in 48% of these the morphologic features of the positive cells were not sufficiently distinctive for hairy cells. The proportion of biopsies with residual hairy cells was similar over the 25 months of follow up, indicating a relatively stable amount of residual disease. Immunomorphologic analysis is a more sensitive method for detecting residual hairy cells than morphology alone. Although further follow up is necessary to determine the clinical significance of the L26/DBA.44-positive staining in cells with and without distinctive morphologic features of hairy cells, we conclude that many patients in a stable clinical remission may have residual hairy cells.

Antibodies, Monoclonal↗
PubMed1994

Complete hematologic remissions in chronic-phase, Philadelphia-chromosome-positive, chronic myelogenous leukemia after 2-chlorodeoxyadenosine.

BACKGROUND: 2-Chlorodeoxyadenosine (Cladribine, Leustatin, Ortho Biotech, Raritan, NJ) (2-CdA) is a purine analog with activity in the treatment of lymphoid neoplasms. Interferon induces cytogenetic remissions in chronic myeloid leukemia (CML) and partial remissions in hairy cell leukemia, a disorder in which single courses of 2-CdA induce complete remissions. In vitro clonal growth of immature myeloid progenitors from normal marrow is markedly inhibited by 2-CdA. METHODS: 2-CdA was administered to 12 patients with Philadelphia-chromosome-positive CML, 11 chronic phase, and 1 accelerated phase, at 0.1 mg/kg/day by continuous intravenous infusion for 7 days every 28-35 days, until maximum peripheral hematologic response. RESULTS: Of 12 patients, 10 (83%) achieved complete hematologic responses and 2 (17%) partial hematologic responses after a median of two courses of 2-CdA. The median first hematologic response duration was 3 months. Of the seven patients who relapsed and were retreated with a median of two further courses of 2-CdA, five obtained responses (four complete and one partial) and two did not respond. The median second hematologic response duration was 4 months. No patient had significant Philadelphia-chromosome suppression. Reversible myelosuppression and severe cumulative T-cell immunosuppression associated with opportunistic infections in four patients were the principal toxicities. CONCLUSIONS: 2-CdA is active in CML, inducing complete hematologic responses, but the absence of cytogenetic responses and severe immunosuppression may limit its clinical use.

Adult↗
PubMed1994

2-Chlorodeoxyadenosine: a newer purine analog active in the treatment of indolent lymphoid malignancies.

OBJECTIVE: To review the structure, mechanism of action, pharmacologic features, and clinical trial results of the newer purine analog, 2-chlorodeoxyadenosine (2-CdA). DATA SOURCES AND STUDY SELECTION: English-language medical literature review of more than 70 articles. DATA SYNTHESIS: 2-Chlorodeoxyadenosine is unique compared with traditional antimetabolite drugs in that it is equally active against dividing and resting lymphocytes, which may be especially important in indolent lymphoid malignancies, such as chronic lymphocytic leukemia, because most cells in these disorders are in the resting phase. In patients with alkylator-refractory chronic lymphocytic leukemia who were treated with 2-CdA, 44% achieved a response (4% complete responses, 40% partial responses), and 54%, scored as nonresponders, had a sustained reduction in their peripheral lymphocytosis. Patients with untreated chronic lymphocytic leukemia had an 85% response rate (25% complete responses, 60% partial responses). Patients with previously treated low-grade lymphoma achieved an overall response rate of 43%. The most striking clinical effects of this drug have been seen in hairy cell leukemia, in which a single course of therapy induces complete remissions in 85% of partial remissions in 12%. Activity has also been shown in cutaneous T-cell lymphoma and the myeloid leukemias. CONCLUSIONS: 2-Chlorodeoxyadenosine is a newer purine analog with potent activity in the treatment of indolent lymphoproliferative diseases and illustrates the model for rational drug development.

Animals↗