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Biomedical subjects

Alan Saven

Publications and source records attributed to Alan Saven.

18 recordsLinked to original sources
PubMed2006

Prolonged follow-up after initial therapy with 2-chlorodeoxyadenosine in patients with indolent non-Hodgkin lymphoma: results of Cancer and Leukemia Group B Study 9153.

BACKGROUND: The objective of this study was to determine the efficacy and toxicity of 2-chlorodeoxyadenosine (2-CdA) in patients with untreated, indolent non-Hodgkin lymphoma (NHL). METHODS: For this multicenter, single-arm, Phase II study, 44 patients with treatment-naive, stage III or IV, indolent NHL (International Working Formulation subtypes A, B, and C) were enrolled. Patients received 0.14 mg/kg per day of 2-CdA as a 2-hour bolus infusion for 5 consecutive days every 28 days until maximal response or a total of 6 cycles. RESULTS: Thirty-eight patients were eligible for response evaluation. The overall response rate was 100% (95% confidence interval [95% CI], 90.8-100%), and the complete response rate was 31.6% (95% CI, 17.5-48.7%). In the intent-to-treat population, the median failure-free survival was 2.0 years (95% CI, 1.3-3.4 years), and the overall survival rate was 7.0 years (95% CI, 4.3-9.4 years). Six patients had sustained remissions that lasted a median of 8.7 years (range, from 5.9 years to > or =11 years). Although 68% of patients experienced at least 1 grade 3 or 4 event, consisting primarily of myelosuppression, severe infections were rare, with only 8 grade 3 infections. Four late malignancies (prostate adenocarcinoma, ductal carcinoma in situ, and myelodysplasia) and 4 patients with large cell transformation were reported. CONCLUSIONS: 2-CdA is an active, well-tolerated therapy for patients with untreated, indolent NHL.

Adolescent↗
PubMed2006

Antibodies selected from combinatorial libraries block a tumor antigen that plays a key role in immunomodulation.

We searched for cell-surface-associated proteins overexpressed on B cell chronic lymphocytic leukemia (CLL) to use as therapeutic antibody targets. Antibodies binding the immunosuppressive molecule CD200 were identified by cell panning of an antibody phage display library derived from rabbits immunized with primary CLL cells. B cells from 87 CLL patients exhibited 1.6- to 5.4-fold cell-surface up-regulation of CD200 relative to normal B cells. An effect of increased CD200 expression by CLL cells on the immune system was evaluated in mixed lymphocyte reactions. Addition of primary CLL but not normal B cells to macrophages and T cells downregulated the Th1 response, as seen by a 50-95% reduction in secreted IL-2 and IFN-gamma. Antibodies to CD200 prevented downregulation of the Th1 response in most B cell CLL samples evaluated, indicating abrogation of the CD200/CD200R interaction can be sufficient to restore the Th1 response. A disease-progression-associated shift of the immune response from Th1 to Th2 has been observed in numerous cancers. Because this cytokine shift is also believed to promote the induction of regulatory T cells, reverting the immune response to Th1 through direct targeting of the cancer cells may provide therapeutic benefits in CLL by encouraging a cytotoxic T cell response.

Antibodies↗
PubMed2006

Cladribine in hairy cell leukemia.

Cladribine results in prolonged complete remissions in most patients wo have HCL. Several studies have indicated that patients who are in complete remission have survivals that are comparable to those of normal age-matched controls. HCL-related mortality is distinctly uncommon. Nevertheless, it is unlikely that cladribine treatment of HCL is curative because MRD is common in the bone marrows of complete responders. Response criteria for HCL include clinical, hematologic, and morphologic criteria, but do not include flow cytometry, immunohistochemical analysis, or molecular studies. More sensitive techniques have been used by Filleul and colleagues to detect MRD. The used clonoegenic probes from the hypervariable regions of the immunoglobulin heavy-chain gene and performed polymerase chain reactions (PCRs) on bone marrow biopsy specimens, All seven patients who were in morphologic complete remission after a single cladribine infusion were PCR positive. These data indicate that cladribine induces protracted remissions but is not necessarily curative. MRD can be detected in most patients when sensitive techniques are used. Persistence of immunohistochemical MRD may predict detected MRD remains to be studied in a large number of patients. Investigators from the University of Pisa in Italy have used a combination of cladribine and rituximab to eradicate MRD in patients who have HCL. Ten patients received treatment with a standard infusion of cladribine. Two patients achieved a complete remission, 6 patients achieved a partial remission, and 2 patients failed to respond. All were PCR positive for the immunoglobulin heavy-chain (IgH) gene product at the completion of cladribine treatment. All 10 patients had achieved a complete hematologic response 2 months after the completion of ritximab therapy. The curative nature of this treatment will require long-term follow-up. Cladribine represents a major therapeutic advance in the treatment of HCL. The prognosis of patients who have HCL has improved greatly with cladribine therapy. Future strategies should address combination therapy with purine analogs and monclonal antibodies. These strategies should address eradication of MRD in an attempt to develop a potentially curative combination treatment program.

Antibodies, Monoclonal↗
PubMed2006

Use of optophoresis as an in vitro predictor of cell response to chemotherapy for chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia [CLL] is characterized by active accumulation of clonal CD5+/CD19+/CD23+ B cells. Individualized characterization of patient cell resistance/sensitivity to specific agents can provide important information to guide therapy selection. We have utilized optophoresis, which is a technique for the analysis of the motion of cells within a moving optical gradient field. It detects the broad cellular changes associated with apoptosis based on physical characteristics of the cell, such as morphology, size, refractive index, density, and surface properties. We analyzed peripheral blood samples from 62 CLL patients in the presence of varying concentrations of chemotherapeutic agents. Optophoresis and a more conventional measurement of cell death were utilized. The outcome of ex vivo drug resistance using optophoresis was compared to clinical response in 30 patients for which there was clinical outcome data available. The overall accuracy of optophoresis in reflecting clinical response was 80%. It has advantages over alternative methods of determining chemoresistance including the ability to evaluate very small sample sizes and ability to work in mixed-cell populations. Changes in cell physical characteristics in response to chemotherapy, as measured by optophoresis is an accurate method for predicting chemosensitivity ex vivo in CLL.

Adenosine Triphosphate↗
PubMed2005

SHP1 expression in bone marrow biopsies of myelodysplastic syndrome patients: a new prognostic factor.

Myelodysplastic syndrome (MDS) progresses into acute leukaemia with a variable time course. We analysed 45 newly diagnosed patients and found that the expression of the Src homology 2 domain-containing tyrosine phosphatase 1 (SHP1) had a significant impact on disease severity, progression and overall prognosis. Global or lineage-specific loss of SHP1 was observed by immunohistochemistry in bone marrow biopsies of MDS patients who progressed rapidly (P = 0.0021) and had shorter survival (P < 0.001). Cox regression analysis demonstrated that SHP1 expression in megakaryocytes had prognostic relevance for time to progression (P = 0.009) and overall survival (P = 0.001).

Adult↗
PubMed2004

Combinatorial antibody libraries from cancer patients yield ligand-mimetic Arg-Gly-Asp-containing immunoglobulins that inhibit breast cancer metastasis.

Combinatorial antibody libraries have the potential to display the entire immunological record of an individual, allowing one to detect and recover any antibody ever made, irrespective of whether it is currently being produced. We have termed this the "fossil record" of an individual's antibody response. To determine whether cancer patients have ever made antibodies with disease-fighting potential, we screened combinatorial antibody libraries from cancer patients for immunoglobulins that can identify metastatic tumor cells. This strategy yielded human antibodies specific for the activated conformation of the adhesion receptor integrin alphavbeta3 that is associated with a metastatic phenotype. In a remarkable example of convergent evolution, two of these antibodies were shown to contain the Arg-Gly-Asp integrin recognition motif of the natural ligand within the third complementarity-determining region of the heavy chain. These antibodies interfered with lung colonization by human breast cancer cells in a mouse model and inhibited existing metastatic disease. Our data imply that, at least at some time, these antibodies were part of a patient's surveillance system against metastatic cells, targeting the activated conformer of integrin alphavbeta3 and disrupting its functions. The ligand-mimetic nature of these antibodies, combined with specificity for a single receptor, is unique in the integrin-ligand repertoire. The convergent evolution of critical sequences in antibodies and other ligands that bind to the same target means that the immune response has sufficient power to find a best chemical solution for the optimization of binding energy, even though antibodies evolve in real time, as compared with billions of years for the natural ligand.

Amino Acid Sequence↗
PubMed2004

Cladribine: from the bench to the bedside--focus on hairy cell leukemia.

Cladribine is an adenosine deaminase-resistant deoxyadenosine analog with a unique mechanism of action. It is directly toxic towards both resting and proliferating human lymphocytes and monocytes. The development of this compound into clinical practice best exemplifies rational drug development and the success of translational research. Cladribine is well established as first-line treatment for hairy cell leukemia, inducing an overall response rate of 75-100%, with the majority being complete responses following only a single 7-day treatment course. The 9-year overall survival for hairy cell leukemia is currently 97%. Cladribine has also proven useful in the treatment of a variety of other hematologic malignancies, and its current place in the oncologic therapeutic armamentarium, as well as in potential areas of development, are outlined.

Antineoplastic Agents↗
PubMed2003

Evidence for ozone formation in human atherosclerotic arteries.

Here, we report evidence for the production of ozone in human disease. Signature products unique to cholesterol ozonolysis are present within atherosclerotic tissue at the time of carotid endarterectomy, suggesting that ozone production occurred during lesion development. Furthermore, advanced atherosclerotic plaques generate ozone when the leukocytes within the diseased arteries are activated in vitro. The steroids produced by cholesterol ozonolysis cause effects that are thought to be critical to the pathogenesis of atherosclerosis, including cytotoxicity, lipid-loading in macrophages, and deformation of the apolipoprotein B-100 secondary structure. We propose the trivial designation "atheronals" for this previously unrecognized class of steroids.

Arteriosclerosis↗
PubMed2003

Activated integrin alphavbeta3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells.

Expression of adhesion receptor integrin alphavbeta3 in an activated functional form strongly promotes metastasis in human breast cancer cells. Here, we report that alphavbeta3 cooperates with matrix metalloproteinase type 9 (MMP-9) in breast cancer cell migration. This cooperation is regulated by the activation state of the integrin. Expression of activated alphavbeta3 in metastatic variants of MDA-MB 435 human breast cancer cells and primary metastatic cells from breast cancer patients strongly enhanced migration toward vitronectin and fibrinogen. This enhancement was mediated by a soluble factor produced by breast cancer cells expressing activated alphavbeta3. When transferred, this factor also up-regulated alphavbeta3-dependent migration of breast cancer cells that express the nonactivated integrin. The factor was identified as metalloproteinase MMP-9. Whereas all tested breast cancer cell variants produced latent MMP-9, only those with activated alphavbeta3 produced the mature form of this metalloproteinase. Recombinant mature MMP-9, but not latent MMP-9 or either form of MMP-2, enhanced alphavbeta3-dependent breast cancer cell migration. The migratory response was inhibited by tissue inhibitors of metalloproteinase or when MMP-9 was depleted from the inducing supernatants. The results indicate a causal relationship between the expression of activated integrin alphavbeta3 and production of enzymatically active MMP-9 in metastatic breast cancer cells. These molecules cooperate to enhance breast cancer cell migration toward specific matrix proteins, and this may contribute to the strongly enhanced metastatic capacity of breast cancer cells that express activated alphavbeta3.

Breast Neoplasms↗
PubMed2003

Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia.

Hairy cell leukemia (HCL) is an indolent B-cell neoplasm, strongly expressing CD20. Despite initial very high response rates following cladribine, many patients (pts) ultimately relapse. Having relapsed after prior treatment with cladribine, 24 HCL pts (21 male, 3 female) with a median age of 53.5 years were treated with rituximab at 375 mg/m2 intravenously weekly for 4 weeks. Of the pts, 3 (13%) achieved complete remissions and 3 (13%), partial responses. Thus, 6 (25%) of 24 pts achieved a response following rituximab. At a median follow-up of 14.6 months, 2 responders have relapsed; median time to relapse was not yet reached. The only grade III or IV toxicities demonstrated were culture-negative febrile neutropenia, transient and reversible disseminated intravascular coagulation related to rituximab administration, and a diverticular abscess, each in single patients. Of 18 nonresponders, 9 pts subsequently received other treatments; 5 pts were retreated with cladribine, 3 underwent splenectomy, and 1 received pentostatin. Follow-up data are available on 7 of these 9 patients; all 7 patients achieved improvements in hematologic parameters. Rituximab, administered at this dose and schedule, has only modest single-agent activity in cladribine-failed HCL patients when compared with other agents active in this disease.

Adult↗
PubMed2003

Extended follow-up of patients with hairy cell leukemia after treatment with cladribine.

PURPOSE: Hairy cell leukemia (HCL) is an uncommon, indolent, chronic B-cell lymphoproliferative disorder involving the marrow and spleen. Therapy for HCL includes splenectomy, interferon alfa-2a and alfa-2b, pentostatin, and cladribine. The purpose of this article was to report the extended follow-up of HCL patients treated with cladribine. PATIENTS AND METHODS: Two hundred nine patients with HCL who were treated with cladribine had at least 7 years of follow-up. A course of cladribine constituted a 7-day continuous intravenous infusion at a dose of 0.1 mg/kg/d. RESULTS: Of the 207 assessable patients who had at least 7 years of follow-up, 196 (95%) achieved a complete response (CR) and 11 (5%) achieved a partial response (PR) after a single course of cladribine (overall response rate, 100%). The median first-response duration for all responders was 98 months. Seventy-six patients (37%) experienced relapse after their first course of cladribine. The median time to first relapse for all responders was 42 months. Time to treatment failure of CRs compared with PRs was statistically significant (P <.0005). The overall survival rate was 97% recorded at 108 months. Forty-seven patients developed 58 second malignancies. The observed-to-expected ratio for second malignancies was 2.03 (95% confidence interval, 1.49 to 2.71). CONCLUSION: These results confirm previous observations that single courses of cladribine administered to patients with HCL induce high response rates, the majority of which are CRs. Most patients enjoy long-lasting complete remissions, and those patients who experience relapse can be successfully re-treated with cladribine.

Adult↗
PubMed2003

CD52 expression in hairy cell leukemia.

Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder characterized by splenomegaly, pancytopenia, and circulating atypical lymphocytes with circumferential cytoplasmic projections. Although uncommon, HCL cases refractory to standard therapy occur, and effective alternatives are limited. There is evolving literature supporting monoclonal antibody therapy in the treatment of B-cell lymphoid malignancies, including anti-CD52 (Campath-1H, alemtuzumab). We have examined nine cases of HCL and one case of HCL variant by flow cytometry for CD52 expression. All cases expressed CD52 antigen in 92-100% of the malignant cells. The demonstration of CD52 antigen expression on HCL cells provides the rationale for the use of alemtuzumab in refractory HCL.

Adult↗
PubMed2003

Cladribine in the treatment of hairy-cell leukaemia.

Cladribine, a purine nucleoside analogue, is a safe and effective treatment for patients with hairy-cell leukaemia. It is administered at a dose of 0.09 mg/kg daily as a continuous intravenous infusion over 7 days. This chapter discusses the history, rationale, chemical structure and mechanism of action of cladribine. The indications for therapy and guidelines for clinical usage are reviewed. The response of hairy-cell leukaemia to cladribine, the acute and chronic complications and the risk for second malignancies are summarized. The chapter concludes with a section on salvage therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Hairy cell leukemia: an update.

Hairy cell leukemia is an indolent, chronic B-cell lymphoproliferative disorder comprising approximately 2 to 3% of all adult leukemias in the United States. Hairy cells are clonal expansions of mature, activated B-cells. They co-express CD11c, CD19, CD20, CD22, CD25, and CD103. Hairy cells possess clonal immunoglobulin gene rearrangements and express monoclonal surface immunoglobulin of either IgG or multiple heavy-chain isotypes. Treatment of hairy cell leukemia should be considered for symptomatic patients. It is indicated in patients with significant neutropenia, anemia, thrombocytopenia, symptomatic splenomegaly, constitutional symptoms due to hairy cell leukemia, or recurrent serious infections. Many treatments exist, including cladribine, pentostatin, interferon-alpha, splenectomy, rituximab (mabthera), and BL-22 immunotoxin.

Antineoplastic Agents↗
PubMed2003

Fourteen-day CHOP supported with granulocyte colony-stimulating factor in patients with aggressive non-Hodgkin's lymphoma: results of a phase II study.

The safety and efficacy of compressed-cycle (14-day) standard-dose CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) supported with prophylactic recombinant granulocyte colony-stimulating factor (G-CSF; filgrastim) were evaluated in patients with aggressive non-Hodgkin's lymphoma (NHL). Patients with intermediate- or high-grade NHL (Working Formulation groups D-H and J; N = 120), accrued from 25 clinical practices, were given 6 cycles of standard-dose CHOP every 14 days. Granulocyte colony-stimulating factor 5 microg/kg was given daily subcutaneously in each cycle, starting on day 2 and continuing until the absolute neutrophil count was = 10000/microL. The overall response rate was 89%, with complete responses (CRs) in 52 of 120 patients (43%) and partial responses in 55 (46%). These results are consistent with previously reported outcomes from trials in this population. Of the 720 chemotherapy cycles planned for all patients, 615 (85%) were given on time at full dose. The median relative dose intensity (RDI) of cyclophosphamide and doxorubicin was 99%; the RDI of vincristine was 73%. In the 53 patients = 60 years of age, 80% of the chemotherapy cycles were given on time at full dose, with median RDIs similar to those in the entire population. Response rates in the older patients were also similar, with CRs in 24 patients (45%) and partial responses in 21 (40%). Hematologic toxicity was significant but tolerable, with no treatment-related deaths. At a median follow-up of 20.6 months, 77% of patients were still alive. Standard-dose CHOP administered every 14 days with prophylactic G-CSF support was delivered as planned in most patients and produced response rates comparable with those with CHOP given every 3 weeks, without exceptional toxicity.

Adolescent↗
PubMed2002

Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study.

Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.

Adult↗