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Biomedical subjects

T M Kuzel

Publications and source records attributed to T M Kuzel.

At least 37 records · Page 2Linked to original sources
PubMed1998

Antitumor activity of DAB389IL-2 fusion toxin in mycosis fungoides.

BACKGROUND: DAB389IL-2 is a novel fusion toxin that retargets the cytotoxic A-chain of diphtheria toxin to interleukin-2 (IL-2) receptor-expressing tumors. OBJECTIVE: The purpose of this phase I trial was to study the toxicity, maximum tolerated dose, and clinical efficacy of DAB389IL-2 in IL-2 receptor expressing lymphoproliferative malignancies, including cutaneous T-cell lymphoma. METHODS: DAB389IL-2 was administered intravenously daily for 5 days every 3 weeks. Dose escalation occurred between patient groups. Patients were monitored for laboratory and clinical toxicity, kinetics, immune response, and clinical efficacy. RESULTS: Thirty-five patients with cutaneous T-cell lymphoma (including 30 patients with mycosis fungoides) were treated. Previously, conventional therapy had not worked for 34 of the patients. Thirteen patients (37%) achieved an objective response, including a complete response in five patients (14%). Complete response was achieved in patients with extensive erythroderma and tumor stage mycosis fungoides. Adverse events consisted of reversible fever/chills, hypotension, nausea/vomiting, and elevation of hepatic transaminase. Doses of less than 31 microg/kg per day were well tolerated. Clinical responses were observed at all dose levels. CONCLUSION: DAB389IL-2 is well tolerated at doses of less than 31 microg/kg per day, and it induced clinical responses in previously treated mycosis fungoides, providing evidence for the antitumor activity of this molecule.

Adult↗
PubMed1998

Interleukin-1 alpha increases the preferential cytotoxicity of an interleukin-2-diphtheria toxin fusion protein against neoplastic lymphocytes from patients with the Sezary syndrome compared to normal lymphocytes.

DAB389IL-2 is a recombinant fusion toxin composed of the diphtheria A chain and a protion of the translocating region of the diphtheria B chain, replacing the receptor binding domain with human IL-2. DAB389IL-2 can be safely administered to humans with mycosis fungoides (MF) or Sezary syndrome (SS), and antineoplastic effects occur. This agent binds optimally to the high-affinity IL-2R. The decreased efficiency of uptake by neoplastic cells which do not express the high-affinity IL-2R represents a potential limitation. Treatment of the HUT-78 cutaneous T-cell lymphoma with IL-1 alpha preceding exposure to DAB389IL-2 overcame their resistance to the toxin, IL-1 alpha inducing high-affinity IL-2R expression. Similarly, pretreatment with IL-1 alpha of SS patient lymphocytes demonstrated increased cytotoxicity compared to treatment with the fusion toxin alone. Normal lymphocytes and monocytes were not sensitive to DAB389IL-2 when pretreated with IL-1 alpha, suggesting a differential sensitivity which may be exploited clinically in the treatment of lymphomas.

Cell Line↗
PubMed1997

Recurring structural chromosome abnormalities in peripheral blood lymphocytes of patients with mycosis fungoides/Sézary syndrome.

Cytogenetic analysis was performed on peripheral blood lymphocyte cultures from 19 patients with mycosis fungoides (MF)/Sézary syndrome (SS) stimulated with either phytohemagglutinin, a conventional mitogen, or a combination of interleukin-2 (IL-2) plus IL-7. The use of both PHA-stimulated and IL-2 plus IL-7-stimulated cultures enhanced the ability to identify clonal abnormalities. Clonal abnormalities were observed in 11 patients (53%) including one with monosomy for the sex chromosome as the sole abnormality. Five of the 11 patients with clonal abnormalities had normal peripheral white blood cell counts, indicating detectability of clones in the absence of frankly leukemic disease. The presence of clonal abnormalities correlated with advanced stage disease and a significantly reduced survival duration from the time of cytogenetic studies. Clonal abnormalities involving chromosomes 1 and 8 were observed in six cases. In five cases with aberrations of chromosome 1, loss of material involved the region between 1p22 and 1p36. In an additional case, a reciprocal translocation involving 1p33 was observed. Clonal abnormalities involving chromosomes 10 and 17 were observed in 5 cases, clonal abnormalities involving chromosome 2 in 4 cases, and clonal abnormalities involving chromosomes 4, 5, 6, 9, 13, 15, 19, and 20 in 3 cases. In 2 cases a der(8)t(8;17)(p11;q11) was observed. Regions of the genome that encode T-cell receptors were not involved in abnormalities. The region between 1p22 and 1p36 is identified as a region of the genome that requires detailed analysis toward the identification of potential gene(s) involved in the process of malignant transformation and/or progression in MF/SS.

Adult↗
PubMed1997

Interleukin-2 fusion protein: an investigational therapy for interleukin-2 receptor expressing malignancies.

DAB389IL-2 is an interleukin-2 receptor (IL-2R) specific fusion protein with a molecular weight of 58 kD containing the enzymatic and translocation domains of diphtheria toxin (DT) and human IL-2. This fusion protein is able to direct the cytocidal action of the DT enzymatic region only to cells which bear the IL-2R. The human IL-2R exists in three forms: low, intermediate and high affinity. The high-affinity form is believed to be the biologically relevant form on mature, activated T-lymphocytes, B-lymphocytes and monocytes. DAB389IL-2 is able to bind selectively to the high-affinity IL-2R in a concentration-dependent manner, and once bound is internalised via receptor-mediated endocytosis. Upon acidification of the formed vesicle, the enzymatic portion of the fusion protein is believed to pass into the cytosol where it ultimately inhibits protein synthesis by inactivation of elongation factor-2, resulting in cell death. The constitutive expression of the IL-2R on certain leukaemic and lymphomatous cells of T and B cell origin has been reported to occur in patients with chronic lymphocytic leukaemia, cutaneous T cell lymphoma (CTCL), Hodgkin's disease and non-Hodgkin's lymphomas (NHLs). A multicentre DAB389IL-2 dose-escalation study of patients with IL-2R expressing lymphomas has been conducted. A 10-fold range of doses were evaluated on a five-daily dose schedule. Patients received up to six courses, with an additional two courses permitted for patients with partial responses that appeared to be still improving after six courses. Most adverse experiences were transient and mild. Preliminary assessment of response indicated five complete responses (CR, duration ongoing at 20, 11, 7, 5 and 4 months) and seven partial responses (PR, duration 3-20 months) in the 35 patients with CTCL. One CR (duration > 20 months) in a patient with NHL (Lennett's lymphoma) and two PR (duration 9 and 2 months) in 17 patients with B-cell NHL have been observed. Based on the mode of action of DAB389IL-2, its safety profile, and the patient responses associated with the phase I/II clinical trials, a phase III programme in CTCL patients has been initiated and plans for additional trials in NHL patients are targeted for 1996.

Antineoplastic Agents↗
PubMed1997

Metastatic bladder cancer: advances in treatment.

At present, a combination of cisplatin, methotrexate, vinblastine and doxorubicin is the most widely used chemotherapy for metastatic bladder cancer. However, long-term follow-up shows that this combination may have little effect on survival. In addition, this regimen is toxic. New agents are needed which combine efficacy with good safety profiles. Agents which have been investigated include gallium nitrate, interferon-alpha and paclitaxel both as single agents and in combination with established cytotoxic drugs. A number of studies have been conducted in bladder cancer with the novel nucleoside analogue, gemcitabine. Response rates of up to 33% have been recorded in two phase II studies. Gemcitabine was well tolerated in both studies with few of the side-effects normally associated with cytotoxic drugs. A third study is ongoing.

Adult↗
PubMed1997

2-Chlorodeoxyadenosine in cutaneous T-cell lymphoproliferative disorders.

The efficacy and toxicity of 2-chlorodeoxyadenosine (2-CdA) in cutaneous T-cell lymphoproliferative disorders was examined. Between February 1991 and April 1996, 25 patients with relapsed or refractory cutaneous T-cell lymphoproliferative disorders (24 mycosis fungoides or Sezary syndrome, one Ki-1+ anaplastic large cell lymphoma) were treated with 2-CdA initially administered by continuous intravenous infusion at a dose of 0.1 mg/kg/d for 7 days (13 patients). The infusion duration was subsequently reduced to 5 days (9 patients) because of prohibitive hematologic toxicity. Three patients were treated at the same daily dose by bolus injection over two hours for 5 days. Cycles were administered at 28 day intervals. Seventeen patients received more than one cycle. An overall response rate of 24% was achieved. Three patients (12%) had a complete response with a median duration of 4.5 months (range, 2.5 to 16). Three (12%) had a partial response with a median duration of 2 months (range, 2 to 4). Nineteen patients (76%) had no response. The most significant toxicities encountered were myelosuppression (64%) and infectious complications (64%). 2-CdA has activity as a single agent in patients with previously treated relapsed T-cell lymphoproliferative disorders.

Adult↗
PubMed1996

Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma.

We investigated the efficacy of 2-chlorodeoxyadenosine (2-CdA) therapy in patients with mycosis fungoides (MF) and the Sezary syndrome (SS). Between February 1991 and November 1993, 21 patients with relapsed or refractory MF/SS were treated with 2-CdA. 2-CdA was administered by continuous intravenous infusion at a dose of 0.1 mg/kg/d for 7 days initially (13 patients), but was subsequently reduced to 5 days (nine patients) due to hematologic toxicity. All patients had failed to respond to at least one prior treatment for MF/SS (median number of total prior therapies, five; median number of systemic prior therapies, three) and had an Eastern Cooperative Oncology Group performance status of two or better. Cycles were administered at 28-day intervals. Assessable patients received at least 5 days of 2-CdA. Fourteen patients received more than one cycle of 2-CdA. An overall response rate of 28% was achieved. Three patients (14%) had a complete response with a median duration of 4.5 months (range, 2.5 to 16). Three (14%) had a partial response with a median duration of 2 months (range, 2 to 4). Fifteen patients (72%) had no response. The most significant toxicities encountered were bone marrow suppression (62% of patients) and infectious complications (62% of patients). Thirty-eight percent of patients experienced no toxicity from 2-CdA. 2-CdA has activity as a single agent in patients with previously treated relapsed MF/SS. Studies in less heavily pretreated individuals with 2-CdA alone or in combination will be undertaken.

Adult↗
PubMed1995

Hand-foot syndrome associated with liposome-encapsulated doxorubicin therapy.

BACKGROUND: Acquired immune deficiency syndrome (AIDS)-related Kaposi's sarcoma (KS) is a common complication of patients infected with human immunodeficiency virus and can cause significant morbidity. Long term therapy with standard chemotherapeutic regimens has been limited by relatively short durations of response and potential toxicity. Once therapy is discontinued, the disease typically progresses. Liposome-encapsulated doxorubicin (DOX-SL) currently is being evaluated for treating patients with AIDS-related KS. Early reports suggest a high response rate and good patient tolerance permitting continued therapy for extended periods. METHODS: Patients with AIDS-related KS are treated with a DOX-SL regimen every 2-3 weeks and are followed carefully for evidence of adverse treatment effects. RESULTS: Two cases of hand-foot syndrome (HFS) in patients receiving DOX-SL for AIDS-related KS are reported. Tissue studies demonstrated changes consistent with a toxic effect of the drug on keratinocytes. Hand-foot syndrome was reversible once treatment stopped; however, treatment cessation resulted in primary disease recurrence. CONCLUSIONS: Hand-foot syndrome can be debilitating and may be a limiting factor in the prolonged use of DOX-SL for AIDS-related KS for some patients. It is critical for clinicians using this drug to identify this side effect to limit HFS-associated morbidity.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up.

BACKGROUND: Mycosis fungoides (MF) is a non-Hodgkin's T-cell lymphoma of the skin that often begins as limited patches and plaques with slow progression to systemic involvement. No studies have been published comparing photochemotherapy (PUVA) with other topical therapies in the treatment of early-stage disease. OBJECTIVE: The purpose of the study was to examine our long-term experience using PUVA to treat early-stage MF and to compare its effectiveness and side-effect profile with other previously reported topical therapies. METHODS: Eighty-two patients with MF (83% stage IA or IB) were treated with PUVA. Clinical and histologic features were observed for a period from 2 months to 15 years (median, 43 months). RESULTS: A response was noted in 78 patients (95%) with complete clinical and histologic clearing in 53 patients (65%) for all stages. The mean duration of total complete response to PUVA for all stages was 43 months (3.6 years). The mean survival of our study group for all stages was 8.5 years. Signs of chronic actinic skin damage were found in 10% of patients, including three patients with basal cell carcinomas and three patients with squamous cell carcinomas. In a nonrandomized comparison with previously reported data for other topical therapies, the efficacy and side-effect profile of PUVA compared favorably. CONCLUSION: PUVA is an effective and safe therapy for MF with prolonged disease-free remissions being achieved. Patients with stage I and II MF respond best to PUVA. Palliative therapy with PUVA is useful in more advanced cases of MF.

Biopsy↗
PubMed1995

Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sézary syndrome.

PURPOSE: To investigate the efficacy of combined topical therapy and systemic interferon alfa-2a in patients with mycosis fungoides (MF) and the Sézary syndrome (SS). PATIENTS AND METHODS: Between December 1987 and April 1993, 39 patients with all stages of MF and SS were treated with combined phototherapy and systemic interferon alfa-2a as part of two institutional studies. The initial phase I study of 15 patients established the maximum-tolerated dose of interferon and has been previously reported. Subsequently, 24 patients have been entered onto a phase II trial. Long-term follow-up data are provided for both studies. RESULTS: The median follow-up duration for the entire cohort is 28 months. Patients with all stages of disease were enrolled (stage IB, n = 14; IIA, n = 5; IIB, n = 6; III, n = 8; IVA, n = 5; IVB, n = 1). Thirty-four patients had received previous therapy. Overall, 36 of 39 patients achieved a complete response (CR; 62%) or partial response (28%) to therapy. The median response duration is 28 months (range, 1 to 64). Twenty-nine of 39 patients are alive, with a median survival duration of 62 months (range, 1 to 66). CONCLUSION: Interferon alfa-2a combined with phototherapy is an effective, safe, durable therapy for MF and SS.

Combined Modality Therapy↗
PubMed1995

Experimental therapies in the treatment of cutaneous T-cell lymphoma.

Although meaningful clinical responses have been demonstrated in cutaneous T-cell lymphoma using a number of therapeutic modalities, survival benefits have not been demonstrated for the majority of patients. Several novel therapies, including retinoids, purine analogs, biologic response modifiers, monoclonal antibodies, and fusion toxins have demonstrated activity and clinical promise in early studies.

Antibodies, Monoclonal↗
PubMed1994

Neurologic complications of patients with small cell prostate carcinoma. Report of two cases.

BACKGROUND: Primary small cell carcinoma arising in organs other than the lung were thought to be relatively rare. However, with the increasing technical sophistication of pathology departments, tumors with foci of small cell neuroendocrine components are being identified more frequently. The pattern of disease involvement and optimal treatment have yet to be defined. METHODS: Two cases of primary small cell carcinoma of the prostate are described in which patients previously had unreported degrees of central nervous system disease. RESULTS: Approximately 75 cases of small cell carcinoma of the prostate have been reported. Neurologic complications have been reported infrequently, although a variety of neurologic paraneoplastic sequelae have been noted. However, carcinomatous meningitis or development of intraductal tumors without concomitant vertebral bone disease has never been reported. These tumors respond poorly to hormonal therapy alone, and recent reports suggest optimal therapeutic strategies may involve combination hormone and chemotherapy. CONCLUSION: Small cell carcinoma of the prostate must be recognized when it arises de novo or with components of adenocarcinoma because the prognoses and response to treatment differs from the more common adenocarcinomas of the prostate.

Adult↗
PubMed1994

Antibodies in the treatment of human cancer.

Monoclonal antibody-based therapy has the theoretic appeal of selective targeting of tumor cells. Most promising is the use of toxins and radioisotope immunoconjugates in the treatment of hematologic malignancies. Obstacles to effective treatment have been defined and solutions are being pursued. The future use of this therapeutic strategy will be determined by creative approaches to enhance delivery, decrease immunogenicity, and maximize potency of antibody reagents.

Antibodies, Monoclonal↗
PubMed1993

A phase II study of continuous infusion 5-fluorouracil in advanced hormone refractory prostate cancer. An Illinois Cancer Center Study.

BACKGROUND: 5-Fluorouracil (5-FU) has been previously associated with therapeutic benefit in hormone refractory prostate cancer. However, no previous study has administered 5-FU as a prolonged continuous infusion, which may be the optimal schedule for this cell-cycle specific agent. METHODS: Therefore, 25 patients were treated with 5-FU administered as a continuous intravenous infusion at a dose of 1000 mg/m2/day for 5 days every 28 days. Eligibility required disease defined by bidimensionally measurable lesions or evaluable lesions on bone scan or radiograph with elevated serum levels of prostate-specific antigen (PSA), no severe cytopenias, and an Eastern Cooperative Oncology Group performance status less than 3. Prior chemotherapy was not allowed. Dose modifications were specified for mucositis and hematologic toxicity. RESULTS: Eighteen of 22 patients were evaluable for response and toxicity, whereas 4 were evaluable for toxicity alone. Toxicity was significant using this dose and schedule and included episodes of sudden death (one patient), paroxysmal supraventricular tachycardia (one patient), and congestive heart failure (one patient). Other Grade 3 toxicities included stomatitis (two patients) and diarrhea (one patient). Significant myelosuppression did not occur. Objective responses were not observed, but 12 patients experienced stable disease with a median duration of 4 months. CONCLUSIONS: Infusional 5-FU can not be recommended for the treatment of advanced hormone refractory prostate cancer.

Aged↗
PubMed1993

Correlation of clinical responses with immunologic and morphologic characteristics in patients with cutaneous T-cell lymphoma treated with interferon alfa-2a.

BACKGROUND: Immunophenotyping may aid in distinguishing more aggressive forms of cutaneous T-cell lymphoma (CTCL), thereby improving classification and treatment. OBJECTIVE: Our purpose was to investigate the relations between clinical, histologic, and immunophenotypic profiles in determining variables with respect to outcome. METHODS: Thirty-seven cases of histologically proven CTCL were analyzed in relation to clinical responses to treatment with interferon alfa alone or in combination with PUVA. Clinical stage, immunophenotyping, and histologic features were noted. RESULTS: All patients with no response to therapy had deletion of T-cell CD7 antigen. In contrast, only 21% of patients with a complete response had CD7 deletion. Deletion of the CD5 antigen occurred in 50% of patients with no response and in no patients with complete response. Large cell histologic features were found in 16% of patients with a complete response, 42% with a partial response, and 83% with no response. The presence or absence of other T-cell antigens and the clinical stage of disease did not correlate with outcome. CONCLUSION: Immunophenotypic analysis may be of greatest value in identifying a subset of high-risk CTCL patients, including those previously classified as low risk on the basis of clinical stage.

Antigens, CD↗
PubMed1993

Phase I trial of the diphtheria toxin/interleukin-2 fusion protein DAB486IL-2: efficacy in mycosis fungoides and other non-Hodgkin's lymphomas.

The purpose of this study was to investigate the biologic activity of DAB486IL-2 when administered three times daily, in terms of toxicity, pharmacokinetics, and anti-tumor effects in patients with IL-2R expressing hematologic malignancies, especially mycosis fungoides. 20 patients were enrolled in this dose escalation phase I trial. Patient cohorts were treated at levels of 0.03 mg/kg, 0.05 mg/kg, 0.07 mg/kg and 0.09 mg/kg every 8 hours for a total of 12 doses, every 21 days as toxicity and response warranted. Eight patients experienced transient fevers associated with DAB486IL-2 administration. One patient experienced grade 3 hypotension, and a second developed fluid retention manifested as weight gain/pedal edema. Dose limiting toxicity consisted of one episode of transient grade 4 hepatic transaminase elevation, and 8 episodes of transient asymptomatic grade 3 hepatic transaminase elevation. At the maximum tolerated dose DAB486IL-2 exhibited biphasic clearance kinetics; transient receptor saturation may be one mechanism for this observation. Initial serum concentration and apparent steady state level (plateau) directly correlated with the dose administered, but no difference in area under the concentration curve with greater dose was observed. Biologic activity was noted in patients with mycosis fungoides with skin lesion clearing and relief of pruritus. One patient with mycosis fungoides, and one patient with a relapsed intermediate grade non-Hodgkin's lymphoma achieved partial responses. The novel mechanism of action, toxicity profile, and evidence of biologic activity in refractory cancer patients, support development of more active constructs of this agent; such trials are underway.

Adult↗