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A Saven

Publications and source records attributed to A Saven.

At least 55 records · Page 3Linked to original sources
PubMed1994

Identification of monoclonal immunoglobulins and quantitative immunoglobulin abnormalities in hairy cell leukemia and chronic lymphocytic leukemia.

Serum and urine samples from 161 cases of hairy cell leukemia (HCL) and 50 cases of chronic lymphocytic leukemia (CLL) were analyzed for monoclonal immunoglobulin (MIg) by using a combination of high-resolution protein electrophoresis, immunoelectrophoresis, and immunofixation. Quantitative immunoglobulin analysis also was performed on all serum samples. Monoclonal immunoglobulin, usually of low intensity, was identified in serum or urine in 26 (16.1%) cases of HCL compared with 27 (54%) cases of CLL. Forty-eight (29.8%) cases of HCL had an increase in one or more immunoglobulins; increases in IgG were the most frequent. In CLL, 48 (96.0%) cases had a decrease in one or more immunoglobulins, with decreases in IgG, IgA, and IgM in 76%, 68%, and 56% of the cases, respectively. The correlation between serum or urine monoclonal immunoglobulin light chain and the surface membrane light chain was 88% in CLL compared with 47.4% in HCL. These findings confirm previous observations of frequent polyclonal hyper-gamma-globulinemia in HCL, hypo-gamma-globulinemia in CLL, and weak monoclonal immunoglobulins in both disorders. The contrasting immunoglobulin abnormalities in HCL and CLL indicate distinctive biologic differences in these chronic B-cell leukemias.

Adult↗
PubMed1994

The Scripps Clinic experience with 2-chlorodeoxyadenosine in the treatment of hairy cell leukemia.

Follow-up data is now available on 144 patients with hairy cell leukemia treated with 2-chlorodeoxyadenosine (2-CdA) at the Scripps Clinic. Of 144 patients followed for a median of 14.2 months, 123 (85%) obtained complete responses, 17 (12%) partial responses, 3 (2%) did not respond and 1 patients was unevaluable. So far, only 4 patients have relapsed at a median of 36 months. Fever was the major toxicity occurring in 43% of patients. Five patients resistant (3 patients) or intolerant (2 patients) to 2'-deoxycoformycin were also treated. Of these 5 patients, 4 obtained complete responses, including 2 patients resistant to 2'-deoxycoformycin, and 1 patient a partial response, suggesting a possible lack of cross-resistance between 2'-deoxycoformycin and 2-CdA in hairy-cell leukemia. More than 200 patients have been treated with 2-CdA worldwide with 82% obtaining complete remission and 12% partial remissions. Serial peripheral blood immunophenotypic analyses have documented the absence of circulating hairy cells. When bone marrow biopsies were examined using sensitive immunohistochemical staining techniques, residual hairy cells were detected in 25-50% of morphologic complete responders. Patients will need to be observed longitudinally to determine if this staining is predictive of relapse. A double-blind, placebo-controlled study of pentoxifylline, a modulator of tumor necrosis factor-alpha and other cytokines, was performed in 2-CdA-treated hairy cell leukemia patients to determine whether the incidence of neutropenic fever would be reduced. Although pentoxifylline resulted in less febrile, hospital and antibiotic therapy days than placebo, only the number of days in the hospitalized patients achieved statistical significance. 2-CdA is emerging as the treatment of choice for hairy cell leukemia given the high percentage of long-lasting, complete responses that follow a single course of therapy.

Cladribine↗
PubMed1994

Purine metabolism of lymphocytes. Targets for chemotherapy drug development.

The unique metabolic profile that renders lymphoid cells sensitive to purine deoxynucleosides also accounts for the response of chronic lymphoid malignancies to purine analogues. Consistent with earlier observations in children with adenosine deaminase deficiency, a profound and relatively selective lymphocyte depletion results from treatment with drugs that elevate or mimic deoxyadenosine. Three such agents available for clinical use are 2-chlorodeoxyadenosine, 2'-deoxycoformycin, and fludarabine phosphate. In addition to a review of the relevant biochemistry and cellular pharmacology of these agents in target lymphoid cells, this article reviews the current clinical response data in leukemias and lymphoma.

Animals↗
PubMed1993

The newer purine analogs. Significant therapeutic advance in the management of lymphoid malignancies.

There are three new purine analogs, fludarabine, 2'-deoxycoformycin, and 2-chlorodeoxyadenosine, all of which have major activity in the treatment of indolent lymphoid malignancies. These three agents, with cytotoxicity against dividing and resting lymphocytes, have revolutionized the treatment of these diseases and, accordingly, represent a significant therapeutic advance. The development of these drugs emanated from an enhanced understanding of purine metabolism in lymphocytes and the mechanism of lymphocytotoxicity in severe combined immunodeficiency disease. Preclinical studies and phase I clinical trials are reviewed, as are phase II studies of these three purine analogs in chronic lymphocytic leukemia, hairy cell leukemia, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and the myeloid leukemias. Potential future strategies exploring possible synergy between these purine analogs and the concurrent administration of both alkylators and biologic response modifiers are explored. The development of the purine analogs and their appropriate clinical applications exemplifies the model for rational drug design and development.

Antineoplastic Agents↗
PubMed1993

Complete remissions in hairy cell leukemia with 2-chlorodeoxyadenosine after failure with 2'-deoxycoformycin.

OBJECTIVE: To determine whether clinical cross-resistance and intolerance exists between the nucleosides 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2-CdA) in the treatment of patients with hairy cell leukemia despite similar structures and mechanisms of action. DESIGN: Phase II clinical study. SETTING: Referral cancer center. PARTICIPANTS: Five patients with hairy cell leukemia who had been previously treated with DCF. INTERVENTION: Single course of 2-CdA at 0.1 mg/kg body weight per day for 7 days by continuous intravenous infusion. RESULTS: Of five patients, three were resistant to and two were intolerant of (having had life-threatening toxic reactions) DCF therapy. Four patients obtained a complete response with a median follow-up period of more than 11 months. The other patient in whom splenectomy, interferon, and DCF treatments were unsuccessful had a partial response lasting 2 months and subsequently died of Streptococcus pneumoniae bacteremia. Three of the four patients with complete responses remain in unmaintained remission, whereas the fourth has progressive splenic enlargement with stable hematologic parameters. The median leukocyte count increased from 2.0 x 10(9)/L to 3.8 x 10(9)/L, the median absolute neutrophil count increased from 0.56 x 10(9)/L to 2.73 x 10(9)/L, the median hemoglobin level increased from 112 g/L to 140 g/L, and the median platelet count increased from 55 x 10(9)/L to 123 x 10(9)/L. Two patients had culture-negative neutropenic fever associated with treatment. CONCLUSIONS: 2-Chlorodeoxyadenosine induced complete responses in patients with hairy cell leukemia resistant to DCF, suggesting a lack of cross-resistance. Also, 2-CdA is not prohibitively toxic in patients intolerant of DCF.

Adult↗
PubMed1993

Diagnostic application of two-color flow cytometry in 161 cases of hairy cell leukemia.

Recent immunophenotypic studies of hairy cell leukemia (HCL) have suggested specific patterns of immunoreactivity that may aid in diagnosis. We studied peripheral blood (PB) from 161 cases of HCL using two-color direct immunofluorescence flow cytometry and an extended panel of antibody combinations. Circulating hairy cells were identified by immunophenotypic features in 92% of the cases and could be detected even when representing < or = 1% of circulating lymphocytes. The 133 cases with > or = 2% detectable hairy cells were analyzed in detail. HCL showed a uniform and unique B-cell phenotype, with each of the following features identified in 99% to 100% of cases: (1) positive staining for B-ly7, coexpressed with CD19; (2) very intense, uniform expression of CD11c, with CD19; (3) moderately intense staining for CD25, with CD19; (4) very intense staining for CD22; (5) moderate to very intense staining for CD20; and (6) moderately intense monoclonal surface Ig. Phenotypic variability existed in expression of CD10 (26%) and CD5 (4%). Based on these features, HCL was easily distinguished from 50 cases of chronic lymphocytic leukemia (CLL). Although CLL exhibited frequent expression of CD11c (74%) and CD25 (68%), the intensity of staining was significantly less than HCL. Furthermore, CLL was uniformly positive for CD5 and showed weak staining for CD20, CD22, and surface Ig. B-ly7 proved to be the most specific marker, reacting with 100% of HCL cases, but absent in all cases of CLL. We conclude that two-color flow cytometry with specific antibody combinations is an efficacious method for characterization and sensitive detection of hairy cells in PB. Application of the phenotypic criteria described should help to increase accuracy in diagnosis of HCL.

Antigens, CD↗
PubMed1993

Genetic relatedness of lymphoid malignancies. Transformation of chronic lymphocytic leukemia as a model.

OBJECTIVE: Studies concerning the genetic relatedness between chronic lymphocytic leukemia and the more aggressive B-cell cancers that develop in about 10% of affected persons were reviewed. These B-cell cancers include large B-cell lymphoma (the Richter syndrome), prolymphocytic transformation, acute lymphoblastic leukemia, and multiple myeloma. Two possible relations were evaluated: development from the chronic lymphocytic leukemia clone (clonal evolution) and development of a genetically unrelated, independent second cancer. DATA SOURCES: An English-language medical literature search was done using MEDLINE (1982 to 1992) and CANCERLIT (1982 to 1992). An extensive manual search of the literature that included meeting abstracts and reports was also done. Approximately 500 articles, abstracts, and book chapters were identified; 102 were selected for detailed analysis. DATA ANALYSIS: Analysis of genetic relatedness between the two cancers considered concordance for immunoglobulin gene rearrangements, for immunoglobulin isotypes and idiotypes, and for cytogenetic abnormalities. CONCLUSIONS: In the case of large B-cell lymphoma, generally thought to arise from the chronic lymphocytic leukemia clone, approximately one half of the patients had genetically unrelated cancers. In prolymphocytic transformation, all cases studied appeared to evolve from the chronic lymphocytic leukemia clone. The few studies of acute lymphoblastic leukemia and multiple myeloma showed genetic relatedness in some cases and unrelatedness in others. These data indicate that progression to more aggressive B-cell cancers in persons with chronic lymphocytic leukemia can result from either clonal evolution or from an independent transforming event.

Burkitt Lymphoma↗
PubMed1993

Relationship of deoxycytidine kinase and cytoplasmic 5'-nucleotidase to the chemotherapeutic efficacy of 2-chlorodeoxyadenosine.

The agent 2-chlorodeoxyadenosine (2-CdA) has chemotherapeutic activity in hairy cell leukemia (HCL) and in refractory chronic lymphocytic leukemia (CLL). The cytotoxic activity of 2-CdA requires the intracellular accumulation of 2-CdA nucleotides. Deoxycytidine kinase (dCK) and cytoplasmic 5'-nucleotidase (5'-NT) are the principal enzymes that phosphorylate 2-CdA and dephosphorylate 2-CdA 5'-monophosphate, respectively. The net accumulation of 2-CdA nucleotides may therefore depend on both dCK and 5'-NT. The purpose of the present experiments was to determine if there is a relationship between pretreatment levels of dCK and 5'-NT in HCL and in CLL cells, and the clinical outcome of 2-CdA treatment. As measured by a direct immunoassay for dCK in 25 CLL patients, and by a 5'-NT activity assay in 23 patients, mean dCK levels were significantly higher in 2-CdA responders than in nonresponders (P < .01), whereas mean 5'-NT levels were significantly lower in 2-CdA responders than in nonresponders (P < .05). Mean dCK levels were higher in six HCL 2-CdA responders than in one nonresponder, whereas mean 5'-NT levels were lower in the 2-CdA responders than in the nonresponder. These results suggest that both dCK and 5'-NT are determinants of 2-CdA responsiveness.

5'-Nucleotidase↗
PubMed1993

2-Chlorodeoxyadenosine dose escalation in nonhematologic malignancies.

PURPOSE: We performed a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) in solid tumors to determine the maximum-tolerated dose (MTD) and define its toxicity profile at higher doses. PATIENTS AND METHODS: Twenty-one patients, seven with malignant astrocytoma, twelve with metastatic melanoma, and two with metastatic hypernephroma, were enrolled onto the study. Patients were entered onto cohorts that received 0.10, 0.15, or 0.20 mg/kg/d of 2-CdA by continuous intravenous infusion for 7 days every 28 days. 2-CdA levels were determined by radioimmunoassay. In tumor tissue samples, deoxycytidine kinase (dCK) levels were measured by both enzyme activity and immunoreactive protein analysis. RESULTS: Of seven patients treated with 2-CdA at 0.1 mg/kg/d, one experienced grade 3 or 4 myelotoxicity. Of 11 patients treated at 0.15 mg/kg/d, four experienced myelotoxicity, two after a single course of 2-CdA. All three patients who received 2-CdA at 0.2 mg/kg/d experienced myelosuppression. Neurologic events occurred in two patients, both with malignant melanoma. Two of seven patients (28.6%) with astrocytomas obtained partial responses with a median duration of 8 months. 2-CdA penetrated the blood-brain barrier. An association was found between dCK levels as measured by enzymatic activity and immunoreactive proteins, but this did not correlate with 2-CdA tumor responsiveness. CONCLUSION: The MTD for 2-CdA delivered as a 7-day intravenous infusion in patients with nonhematologic malignancies was determined to be 0.1 mg/kg/d, the same as the MTD for patients with hematologic malignancies. There was no clinical correlation with dCK expression and response to 2-CdA. The responses noted in patients with malignant astrocytoma warrant further phase II study.

Adult↗
PubMed1993

2-Chlorodeoxyadenosine in the treatment of hairy cell leukemia and chronic lymphocytic leukemia.

More than 450 patients with hairy cell leukemia have been treated at the Scripps Clinic. Of 144 patients followed for a median of 14.2 months (range, 8.1-70 months), 123 (85%) obtained complete responses, 17 (12%) partial responses, 3 (2%) did not respond, and 1 patient was unevaluable. So far, 4 patients have relapsed at a median of 36 months (range, 12-48 months). Fever was the principal toxicity occurring in 43% of patients. Five patients resistant (3 patients) or intolerant (2 patients) to deoxycoformycin were also treated. Of these 5 patients, 4 obtained complete responses, including 2 patients resistant to deoxycoformycin, and 1 patient a partial response, suggesting a possible lack of cross-resistance between deoxycoformycin and 2-CdA in hairy cell leukemia. Other single-institution studies have documented similar response rates and toxicities. Ninety patients with advanced chronic lymphocytic leukemia were treated with 2-CdA administered either as a 0.1 mg/kg/day 7-day continuous intravenous infusion or as a 0.028-0.14 mg/kg/day 2-hour bolus for 5 consecutive days. Four patients (4%) obtained complete responses and 36 patients (40%) partial responses, using NCI-sponsored Working Group guidelines. Of the 50 patients who were non-responders, 27 (54%) had a > or = 50% sustained reduction in the absolute lymphocyte count. The ratio of deoxycytidine kinase to cytoplasmic 5'-nucleotidase was predictive of 2-CdA responsiveness. Fourteen patients with fludarabine-failed chronic lymphocytic leukemia were also treated. No responses were achieved and 2 patients had progressive disease. Six patients had a > or = 50% reduction in the absolute lymphocyte count.(ABSTRACT TRUNCATED AT 250 WORDS)

Cladribine↗
PubMed1992

Hodgkin's disease.

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Antineoplastic Combined Chemotherapy Protocols↗