PubMed Health⌕ Search

Biomedical subjects

M Talpaz

Publications and source records attributed to M Talpaz.

At least 163 records · Page 9Linked to original sources
PubMed1995

Pattern of neurobehavioral deficits associated with interferon alfa therapy for leukemia.

We evaluated the neuropsychological and personality profiles of 25 patients with chronic myelogenous leukemia treated with interferon alfa (IFN-alpha). This group of persons performed well below expectation on tests of cognitive speed, verbal memory, and executive functions. Personality changes included depression, increased somatic concern, and stress reactions. A control group of leukemia patients not treated with IFN-alpha had significantly better cognitive speed and mood. The pattern of cognitive and personality changes in patients receiving IFN-alpha is highly suggestive of frontal-subcortical brain dysfunction.

Adult↗
PubMed1995

Treatment of neurotoxic side effects of interferon-alpha with naltrexone.

Interferon-alpha (IFN-alpha) has potential dose-limiting neurotoxic side effects when used in cancer therapy. The nature of this neurotoxicity is speculative, and there is no definitive treatment. Because animal studies suggest that IFN-alpha acts at opioid receptor sites, we gave naltrexone, a long-acting opioid antagonist, to 9 patients who had hematological malignancies and who suffered from IFN-alpha side effects. Seven of these patients experienced complete or moderate relief of side effects. Five of the patients tested before and during naltrexone treatment showed improvement of cognitive functioning. Two patients could not tolerate naltrexone side effects. This study suggests an intervention against IFN-alpha side effects and provides support for the role of opioid receptor interaction in IFN-alpha neurotoxicity.

Adult↗
PubMed1995

Role of suramin as an IL-1 inhibitor in suppression of acute myelogenous leukemia progenitor proliferation.

Interleukin-1 (IL-1) modulates both autocrine and paracrine growth-stimulatory mechanisms of acute myelogenous leukemia (AML) cell proliferation. Recent studies show that blocking the interaction between IL-1 and its receptor may suppress this proliferation. Because suramin, a polysulfonated naphthylurea originally described as an antitrypanosomal agent, was found to inhibit the binding of several growth factors to their receptor, we tested its effect on AML progenitor proliferation. We first examined the effect of suramin on murine EL-4.6.1 cells that express type I IL-1 receptors and found that suramin inhibited the binding of IL-1 to its receptor. We then tested the effect of suramin on AML progenitors using bone marrow samples from 17 patients with AML. In all experiments, suramin inhibited AML blast proliferation in a dose-dependent fashion at concentrations ranging from 30 to 240 microM. IL-1 beta (100 U/mL) partially reversed this inhibitory effect. Suramin also inhibited normal early and mature hematopoietic progenitors, as assessed by both the delta assay and the mixed colony culture assay; however, at the same concentration, suramin suppressed the colony growth of colony-forming units granulocyte-macrophage (CFU-GM) by only 45% compared with an 89% suppression of AML progenitors. IL-1 beta did not negate this inhibitory effect, which suggests that another growth inhibitory mechanism might be operative. Our data suggest that suramin may inhibit AML progenitor proliferation by blocking the interaction of IL-1 and its receptor; therefore, further studies are warranted to evaluate suramin's therapeutic potential in patients with AML.

Adult↗
PubMed1995

Treatment of chronic myelogenous leukemia.

Allogeneic BMT and IFN-A-based therapy have undoubtedly changed the natural history of CML. Despite these advances, many patients still die from their disease. Most patients do not qualify for an allogeneic BMT either because of age or lack of an appropriate donor, and only a fraction of patients achieve a complete cytogenetic remission with IFN-A-based therapy. The timing of BMT and treatment sequences of IFN-A and BMT have been discussed. Prior treatment with IFN-A does not seem to affect transplant outcome; however, delaying transplantation has been reported to impact adversely on transplant results. Until controlled trials are performed, the issue of optimal timing of allogeneic BMT will remain controversial. The use of alternative donors may extend the option of allogeneic BMT to younger patients; however, for older patients this therapeutic modality still has an unacceptably high incidence of morbidity and mortality with current BMT regimens and other alternative treatments are needed. Investigational strategies searching for ways of improving the proportion of patients achieving complete cytogenetic remissions with IFN-A therapy need to be actively explored. These include new agents (eg, HHT) or new modalities such as intensive chemotherapy with autologous stem cell transplantation with in vitro purging. Investigators in the field must decide whether to continue randomized trials of IFN-A versus conventional chemotherapy, or to explore strategies that may enhance the effect of IFN-A-based therapy. Only when the durable cytogenetic response rates with IFN-A combinations increase to 40% or 50% will it be of value to proceed to phase III trials. Further understanding in the basic biology of CML and the effect of IFN-A in this disease will also provide clues to improving therapy with the goal of obtaining long-term disease control and cures in the majority of patients with the least burden of therapy.

Antineoplastic Agents↗
PubMed1995

The natural history of chronic myelogenous leukemia in the interferon era.

INF-alpha therapy has been a major development in the treatment of CML. Maturing experience has confirmed its ability to induce durable major cytogenetic remissions, which translate into durable long-term disease control, and change in the natural history of the disease. Future studies aimed at improving the percentage and quality of cytogenetic remissions by combining INF-alpha therapy with other chemotherapeutic agents and/or biologicals are needed. The goal would be to identify strategies that can consistently achieve a major cytogenetic response rate of 40% to 50% in the general community setting with acceptable morbidity. Continued studies of the interactions between INF -alpha therapy and transplant strategies will permit the optimization of treatment for each individual patient with CML.

Humans↗
PubMed1995

Interferon-alpha and interleukin-2 as treatment for leukemia relapse after allogeneic bone marrow transplantation.

We treated 12 patients with leukemia relapse after allogenic bone marrow transplantation with a combination of interferon-alpha (IFN-alpha) ((2.5-5.0) x 10(6) u/m2 subcutaneously three times a week) and interleukin-2 (IL-2) ((1.8-3.6) x 10(6) IU/m2 subcutaneously five times a week) to determine the toxicity and efficacy of combination cytokine therapy in this setting. The median age of the patients was 39 years (range: 16-50). There were nine females and three males. The median time to relapse from BMT was 98 days (range: 0-963). At the time of relapse, six patients had AML, four patients had CML (two in blast crisis and two in chronic phase with clonal evolution), and one patient had lymphoblastic lymphoma. Combination cytokine therapy was started a median of 108 days post BMT (range: 37-2404). Nine patients treated at the higher dose level required a 50% dose reduction because of toxicity or GVHD (three CNS, two GVHD, one high fever, one diarrhoea with hypotension, and one pericarditis). At a lower dose level, 2 of 10 patients had their treatment discontinued because of toxicity or GVHD. Six patients developed clinical findings consistent with acute GVHD while on combination cytokine therapy. Two patients responded to combination cytokine therapy: one with CML and one with AML. Combination cytokine therapy is feasible in the setting of relapse post allogeneic BMT. The combination of IL-2 1.8 x 10(6) IU/m2 five times a week with IFN-2 2.5 x 10(6) U/m2 three times a week seems to be tolerable, and merits further study in this setting.

Acute Disease↗
PubMed1995

Interleukin-1 and its inhibitors: a biologic and therapeutic model for the role of growth regulatory factors in leukemias.

Production of growth factors may provide a mechanism for disease evolution in some leukemias. Interleukin-1 is a plelotropic cytokine with the ability to synergize with other growth factors as well as to stimulate their production and release. Autocrine and/or paracrine secretion of interleukin-1 has been implicated in the pathogenesis of both chronic and acute myelogenous leukemia. Recently, a series of both specific and nonspecific IL-1 inhibitory molecules have been identified. These include IL-1 receptor antagonist, soluble IL-1 receptors, IL-1-converting enzyme inhibitor, IL-4, IL-10 and IL-1-antisense. Early experiments demonstrating the ability of some of these molecules to inhibit acute and chronic myelogenous leukemia growth suggest that clinical trials of these compounds may provide a novel management approach in these malignancies. Here we review the potential biologic and therapeutic role of IL-1 and its inhibitors in the myeloid leukemias.

Animals↗
PubMed1994

Altered levels of interleukin-1 beta and interleukin-1 receptor antagonist in chronic myelogenous leukemia: clinical and prognostic correlates.

We have recently demonstrated that interleukin (IL)-1 beta levels are elevated in advanced chronic myelogenous leukemia (CML) and that IL-1 inhibitors can suppress CML clonogenic growth. To further assess the clinical implications of increased IL-1 beta expression in CML, we analyzed IL-1 beta and IL-1 receptor antagonist (IL-1RA) levels in leukocyte lysates from a series of CML patients and from normal volunteers. Both IL-1 beta and IL-1RA were measured by enzyme-linked immunosorbent assays (ELISAs), with the lower limits of sensitivity of the assays being 20 pg/mL and 6.5 pg/mL, respectively. The median IL-1 beta level in the 81 CML patients tested was higher (115.8 pg/2.4 x 10(7) cells; range, 0 to 2,000 pg/2.4 x 10(7) cells) than the median level in 25 control samples (10.8 pg/2.4 x 10(7) cells; range, 0 to 95.5 pg/2.4 x 10(7) cells) (P < .01). IL-1 beta was bioactive, as demonstrated with a bioassay based on cytotoxicity to a melanoma cell line (A375). For survival analysis, elevated IL-1 beta levels were defined as those exceeding the mean + 2 SD of normal levels (83 pg/2.4 x 10(7) cells). The survival of the 44 patients with elevated IL-1 beta levels was significantly shorter than that of those who had low IL-1 beta levels (median, 44 v 58 months; P = .049 by Wilcoxon-Gehan method). An association between IL-1 beta and CML prognostic criteria shows that IL-1 beta levels were significantly higher in patients in accelerated/blastic crisis phases of the disease (364.0 pg/2.4 x 10(7) cells) compared with patients in chronic phase (102.0 pg/2.4 x 10(7) cells) (P < .01), and that high IL-1 beta levels correlated with increased blasts in the marrow and peripheral blood (P < .01). In contrast, while IL-1RA levels did not differ between chronic-phase CML patients (median, 471.7 pg/2.4 x 10(5)) and healthy volunteers (median, 454.4 pg/2.4 x 10(5)), patients with accelerated/blast crisis disease had significantly lower levels of IL-1RA (median, 218.7 pg/2.4 x 10(5); P = .03). Finally, although IL-1 beta has been previously shown to increase IL-1RA levels, there was no correlation between IL-1 beta and IL-1RA levels in our CML patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone Marrow↗
PubMed1994

BCR-ABL protein expression in peripheral blood cells of chronic myelogenous leukemia patients undergoing therapy.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome (Ph1) in more than 95% of these patients. The Ph1 and the resulting BCR-ABL fused genes are markers for this type of leukemia. In CML, the product of the fused BCR-ABL gene is typically a protein of approximately 2,000 amino acids termed P210 BCR-ABL. We have developed an assay for the BCR-ABL protein involving Western blotting of circulating white blood cells (WBC) with an anti-ABL monoclonal antibody that can detect P210 BCR-ABL and P145 ABL in peripheral blood cells from chronic phase Ph1-positive leukemia patients. This assay was used to analyze the BCR-ABL protein content of circulating WBC from CML patients before and after various treatments. In parallel to changes in percentages of Ph1-positive blood cells as determined by cytogenetic analyses of bone marrow samples, BCR-ABL protein expression in blood cells decreased or increased as patients entered remission or underwent relapse. Of interest, six Ph1-negative CML patients were BCR-ABL protein-positive. All except one had a rearrangement in the major breakpoint cluster region and that patient expressed P185 BCR-ABL and not P210. Our results indicate that the BCR-ABL Western blotting assay has clinical applications for both diagnosis and prospective evaluation of Ph1-positive and Ph1-negative CML patients.

Fusion Proteins, bcr-abl↗
PubMed1994

Leukemia inhibitory factor in long-term adherent layer cultures: increased levels of bioactive protein in leukemia and modulation by IL-4, IL-1 beta, and TNF-alpha.

In the current study, we used a monoclonal antibody-based enzyme-linked immunosorbent assay and bioassay to assess leukemia inhibitory factor (LIF) protein levels, activity, and function in supernatants of 59 adherent layers derived from acute and chronic myelogenous leukemia, myelodysplastic syndrome, and hairy cell leukemia patients and from normal controls. We demonstrate that biologically active LIF protein is constitutively produced and secreted by cultured bone marrow stromal cells from all of the studied subjects. Furthermore, various cytokines can alter endogenous LIF protein levels. Twenty-four h of exposure to recombinant human (rh) interleukin (IL) 4 (100 units/ml) significantly decreased LIF protein levels in adherent layer conditioned media [median base line level, 2.6 ng/ml; range, 1.6-8.0 ng/ml; median post rhIL-4 exposure levels, 1.9 ng/ml; range, 0.9-5.8 ng/ml (n = 7; P = 0.022)]. In contrast, rhIL-1 beta and rh tumor necrosis factor alpha consistently increased LIF protein levels. In the samples exposed to 50 units/ml rhIL-1 beta, median base line LIF level was 2.6 ng/ml; median post-LIF level was 9.0 ng/ml (n = 8; P = 0.014). In the two samples exposed to rh tumor necrosis factor alpha (200 units/ml), LIF levels increased from baseline levels of 2.6 and 2.7 ng/ml to postexposure levels of 7.7 and 12.2 ng/ml, respectively. Finally, the presence of LIF may be relevant to both normal and malignant hematopoietic processes as evidenced by: (a) LIF protein levels in adherent layer conditioned media were significantly elevated in samples from patients with a spectrum of hematological neoplasms [acute myelogenous leukemia: median level, 3.0 ng/ml (range, 1.6-11.0 ng/ml); myelodysplastic syndrome: median level, 4.5 ng/ml (range 1.4-15.5 ng/ml); hairy cell leukemia; median level, 3.5 ng/ml (range 2.2-10.3 ng/ml); chronic myelogenous leukemia-chronic phase: median level, 4.35 ng/ml (range 0.3-19.0 ng/ml); and chronic myelogenous leukemia-blast crisis: median level, 6.25 ng/ml (range 0.7-20.3 ng/ml)] as compared to samples from normal individuals (median level, 2.0 ng/ml; range, 0.7-4.6 ng/ml; P < 0.05); and (b) in normal controls, in vitro abrogation of endogenous LIF bioactivity by neutralizing antibody decreased the number of committed granulocyte-macrophage hemopoietic progenitors.

Blast Crisis↗
PubMed1994

Interleukin 4 alters human bone marrow stroma and modulates its interaction with hematopoietic progenitors.

To investigate the functional activity of interleukin 4 (IL-4) on human marrow stroma formation, normal bone marrow (BM) samples were cultured in "Dexter-type" long-term cultures in the presence and absence of IL-4. IL-4 (0.001 to 1.0 micrograms/ml) added at the initiation of culture and once weekly when the cultures were fed effaced the culture architecture. In four-week old confluent cultures smooth muscle-like and endothelial-like cells were rare, the fibronectin network and cobblestone areas were absent, and a preponderance of monocyte-macrophages characterized the adherent layer. Exposure to IL-4 reduced the numbers of CD34+ cells, colony-forming unit granulocyte-macrophage (GFU-GM) cells and burst-forming unit-erythroid (BFU-E) cells in the adherent layer, and increased their numbers in the nonadherent layer. In five of eight IL-4-containing cultures the concentrations of macrophage colony-stimulating factor (M-CSF) were increased and in two of eight IL-4-treated cultures the concentrations of tumor necrosis factor-alpha (TNF-alpha) were significantly elevated as compared to those in control cultures, whereas there were no consistent differences in the levels of either IL-6 or transforming growth factor-beta (TGF-beta). IL-1 beta and granulocyte-macrophage CSF (GM-CSF) were not detected in any culture. These data suggest that IL-4 suppresses stroma formation and alters its structure and cellular composition.

Antigens, CD↗
PubMed1994

What is the contribution of molecular studies to the diagnosis of BCR-ABL-positive disease in adult acute leukemia?

The detection of BCR-ABL transcripts by polymerase chain reaction and hybridization protection assay was investigated in 59 adults with acute leukemia in whom the Philadelphia chromosome (Ph) abnormality was not documented by cytogenetic analysis. These included 35 patients with acute lymphocytic leukemia (ALL) and 24 with acute myelogenous leukemia (AML). Overall, three patients were found to have Ph-related molecular abnormalities; one had p190 and two had p210 disease. All three patients had ALL and were among 16 patients with insufficient metaphases by cytogenetic analysis, yielding an incidence of 19% in the latter category. Based on a 32% incidence of insufficient metaphases in our adult ALL population, we project an additional detection rate of 6% Ph-positive ALL by molecular studies and an overall incidence of 20% (14% + 6%) Ph-positive or BCR-ABL-positive ALL. None of the remaining patients with ALL and none of the 24 patients with AML investigated had BCR-ABL-positive disease. We conclude that molecular studies are useful in detecting BCR-ABL-positive disease in a subset of patients with Ph-positive ALL who are not identified by cytogenetic analysis because of insufficient metaphases.

Acute Disease↗
PubMed1994

Persistence of dormant leukemic progenitors during interferon-induced remission in chronic myelogenous leukemia. Analysis by polymerase chain reaction of individual colonies.

Interferon-alpha induces durable cytogenetic remissions in about one-quarter of newly diagnosed patients with chronic myelogenous leukemia (CML). Even so, after short-term follow-up, previous studies have shown that residual leukemic cells can be detected by the polymerase chain reaction (PCR) in all of these individuals. The objectives of our study were therefore to obtain long-term follow-up data on residual disease in a cohort of complete responders and to determine if leukemic cells with clonogenic potential are present in patients despite the absence of relapse. We performed (a) serial analysis of blood and/or bone marrow for a reverse transcriptase PCR amplified BCR-ABL transcript at times well beyond the point that cytogenetic remission was first attained and (b) reverse transcriptase PCR of individually plucked myeloid and erythroid colonies for the presence of the same transcript. Seven CML patients who had previously attained complete cytogenetic remission while on interferon-alpha were investigated. Six of the seven patients were in complete cytogenetic remission at the time of analysis, whereas one patient had early evidence of cytogenetic relapse. With ongoing therapy, five patients with the longest follow-up eventually achieved PCR negativity at time periods of 27, 32, 36, 49, and 67 mo after a complete cytogenetic remission was first noted. Even so, residual disease was detected in progenitor cells derived from two patients, each of whom had been in continuous cytogenetic remission for approximately 2.5 and 3.5 yr, respectively. Progenitors expressing BCR-ABL transcripts were also detected in the patient with early cytogenetic relapse. These observations demonstrate that residual disease resides in colony-forming cells that should have the potential to repopulate the bone marrow. However, the presence of a minority of Ph-positive CML progenitor cells for a very long period of time is still compatible with durable remission, confirming that a situation of tumor dormancy may be induced in CML by interferon therapy.

Adult↗
PubMed1994

High doses of cyclophosphamide, etoposide and total body irradiation followed by autologous stem cell transplantation in the management of patients with chronic myelogenous leukemia.

Eighteen patients with chronic myelogenous leukemia (CML) in chronic (9 patients) or advanced phases (9 patients) underwent autologous bone marrow transplantation (BMT) with a preparative regimen using high doses of cyclophosphamide, etoposide and total body irradiation (CY-VP16-TBI): cyclophosphamide 60 mg/kg daily on days 1 and 2; VP16 250 mg/m2 twice daily on days 1-3 and TBI 1020 cGy in six fractionated doses on days 5-7. Autologous marrow cells were reinfused on day 8. Three of the 8 patients in late chronic phase Philadelphia (Ph) chromosome-positive CML (37%) achieved a cytogenetic response, with Ph suppression to 25%, 29% and 44% Ph-positive metaphases, respectively, and lasting for 11, 1 and 3 months, respectively. The median duration of chronic phase following BMT was 26+ months (range 2-33+ months). One patient with Ph-negative, BCR-rearranged, chronic phase CML had a decrease of the BCR-rearranged band to 10% of pretreatment levels, which persisted for 6 months. None of the 9 patients with advanced CML phases (5 in second chronic, 1 in blastic, 3 in accelerated) achieved meaningful cytogenetic responses. Their median survival was 7 months from the time of BMT. Toxicities were mostly related to myelosuppression, particularly thrombocytopenia. Febrile episodes developed in 16 patients (89%). Treatment-related deaths occurred in 2 patients (11%). In summary, autologous BMT using a TBI-containing regimen had acceptable toxicity. Future investigations will evaluate the additional benefit of purged autologous stem cell transplantation in patients with chronic phase CML.

Adolescent↗
PubMed1994

Use of interferon in the treatment of chronic myelogenous leukemia.

In a series of studies spanning 14 years, investigators from M.D. Anderson Cancer Center (Houston, TX) documented the activity of interferon-alfa (IFN-alpha) in chronic myelogenous leukemia (CML). Beginning with partially purified IFN-alpha, we demonstrated that this biologic compound has clinical activity against CML, that some malignancies are resistant to IFN-alpha, and that the effect is selective whereby the malignant clone can be restored to normalcy. These observations were confirmed by us and others when larger quantities of IFN-alpha became available through recombinant DNA technology (rIFN-alpha). In contrast with our experience with chemotherapy, myelosuppression was not required for cytogenetic remission; this dissociation may be the basis for the selectivity of IFN-alpha against CML. Recently, another group demonstrated that patients randomized to receive rIFN-alpha 2a survived longer than those treated with standard hydroxyurea chemotherapy. New tests are needed to identify the subset of patients most likely to benefit from IFN-alpha therapy and to distinguish cytogenetic responders who are truly cured from those with minimal residual disease.

Clinical Trials as Topic↗
PubMed1994

Chemotherapy and bone marrow transplantation in the treatment of chronic myelogenous leukemia.

Many therapeutic modalities have been or are being investigated for the management of chronic myelogenous leukemia (CML). Conventional chemotherapy with hydroxyurea or busulfan continues to be the most widely prescribed modality. Recent data suggest that hydroxyurea is preferred over busulfan on the basis of survival rates, particularly among patients who undergo bone marrow transplantation. To improve on responses associated with interferon-alfa (IFN-alpha) alone, IFN-alpha has been added to drugs with selective activity against CML. Combining low-dose cytosine arabinoside and IFN-alpha improves outcome in patients with late chronic-phase CML. Preliminary results with homoharringtonine as induction therapy followed by the addition of IFN-alpha as maintenance therapy are also promising in patients with early chronic-phase CML. Enthusiasm regarding allogeneic bone marrow transplantation remains high, but there are problems related to paucity of ideal candidates, controversies regarding optimal timing, and some mortality. Interferon-alfa has been used in the immediate posttransplant period to reverse early cytogenetic relapse in a limited number of patients, which suggests that IFN-alpha also may be useful in preventing relapse in high-risk patients. In autologous bone marrow transplantation, there is interest among investigators in reducing the leukemic burden and altering the marrow microenvironment to favor normal hematopoiesis, but the effect of this alternative on survival is not yet known. Results suggest that young patients are candidates for allogeneic bone marrow transplantation, whereas older patients should be offered IFN-based therapy initially.

Antineoplastic Agents↗