Biomedical subjects

Thomas Witzig

Publications and source records attributed to Thomas Witzig.

7 recordsLinked to original sources

PubMed2004

Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma: long-term follow-up of a phase 1/2 study.

We previously demonstrated that yttrium-90 (Y-90) ibritumomab tiuxetan (Zevalin) radioimmunotherapy (RIT) was safe and effective for relapsed or refractory CD20(+), B-cell, non-Hodgkin lymphoma (NHL). We now provide long-term follow-up data in responding patients based on International Workshop Response Criteria. Complete (CR), CR unconfirmed (CRu), and partial response (PR) rates were 29%, 22%, and 22%, respectively (overall response rate 73%, 51% in CR/CRu). Mean time to progression (TTP) and duration of response (DR) in responders were 12.6 months and 11.7 months, respectively. At the maximum tolerated dose (0.4 mCi/kg [14.8 MBq/kg]), TTP and DR in complete responders (CR/CRu) were 28.3 and 27.5 months, respectively. Nine patients (24% of responding patients) had a TTP of more than 3 years. Long-term responders (> 5 years) have been identified. Ibritumomab tiuxetan produces durable responses in patients with indolent and diffuse large B-cell lymphoma.

Antibodies, Monoclonal↗

PubMed2004

Elevated serum levels of IL-10 are associated with inferior progression-free survival in patients with Hodgkin's disease treated with radiotherapy.

Elevated pretreatment serum interleukin-10 (IL-10) is associated with inferior progression-free survival (PFS) in patients with Hodgkin's disease (HD) treated with ABVD or equivalent regimens. Therefore, we explored the association of serum IL-10 with presenting features and PFS in HD patients treated only by radiotherapy (RT) with curative intent. Eligible patients were previously untreated, had biopsy-proven HD, were older than 16 years, HIV-negative, and had unthawed pretreatment serum. Serum IL-10 levels were measured with ELISA and were considered high if > or = 10 pg/ml. We identified 69 patients with median age of 34 years (range 16 - 74), of who 52% were males, and 3% had B-symptoms. Ann Arbor Stage was I in 35%, II in 58%, and III in 7% of the patients. Histology was lymphocyte predominance in 26%, and classical HD in 74% of the patients. Serum IL-10 was elevated in 35% of the patients. After a median follow-up of 67 months for survivors, the 5-year PFS of patients with high vs. normal serum IL-10 was 50% vs. 81% (all patients, P = 0.006), and 43% vs. 77% for the subset with classical HD (P = 0.008). Multivariate analysis revealed that high serum IL-10 and beta2-microglobulin were independently associated with inferior PFS. Patients with none, 1, or 2 adverse features comprised 57%, 36%, and 7% of the population, and their 5-year PFS was 80%, 63%, and 0%, respectively (P < 0.0001). In conclusion, high serum IL-10 is independently associated with inferior PFS in patients with HD treated with RT.

Adolescent↗

PubMed2004

Follow-up results of a phase II study of ibritumomab tiuxetan radioimmunotherapy in patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma and mild thrombocytopenia.

This report presents updated time-to-event variables from a multicenter phase II trial of reduced-dose 90Y ibritumomab tiuxetan in patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL) and mild thrombocytopenia (platelet counts of 100 to 149 x 10(9) platelets/L). Patients received a single course of ibritumomab tiuxetan radioimmunotherapy, with 90Y ibritumomab tiuxetan administered at 0.3 mCi/kg (compared to a standard dose of 0.4 mCi/kg). In 30 patients, the overall response rate was 83%, with complete responses (confirmed [CR] and unconfirmed [CRu]) of 47%. Median follow-up time is currently 36.5 months (range: 7.5-54.9+ months). Median duration of response was 11.5 months (range: 1.0-53.9 months), median time to progression was 9.4 months (range: 1.7-54.8+ months), and median time to next lymphoma therapy was 14.6 months (range: 2.3-54.9 months). Median overall survival time has not yet been reached. Long-term responses, defined as time to progression of 12 months or greater, have been seen in 14 of 30 patients (47%) overall, and 12 of 14 CR/CRu patients (86%). Toxicities were primarily hematologic and reversible. No additional long-term adverse events have been observed in the follow-up period, and treatment did not preclude subsequent lymphoma therapies.

Adult↗

PubMed2004

Yttrium 90-labeled ibritumomab tiuxetan radioimmunotherapy produces high response rates and durable remissions in patients with previously treated B-cell lymphoma.

We report updated time-to-event variables of a phase III randomized study comparing yttrium 90-labeled ibritumomab with rituximab standard therapy in 143 rituximab-naive patients with relapsed or refractory low-grade, follicular, or transformed CD20+ non-Hodgkin's lymphoma (NHL). Most patients (79%) had follicular lymphoma. Patients were randomized to receive a single intravenous (I.V.) dose of 90Y ibritumomab tiuxetan 0.4 mCi/kg (n = 73) or rituximab 375 mg/m2 I.V. weekly for 4 doses (n = 70). The radioimmunotherapy group was pretreated with 2 rituximab doses (250 mg/m2) to improve biodistribution and one dose of Indium 111-labeled ibritumomab tiuxetan for imaging. The overall response rate was 80% versus 56% (P = 0.002) and complete response (CR)/CR unconfirmed (CRu) rates were 34% for 90Y ibritumomab tiuxetan versus 20% for rituximab. With a median follow-up of 44 months, the data are mature as all ongoing patients in both groups exceeded the median Kaplan-Meier estimated time to progression (TTP), duration of response (DR), and time to next therapy. Although this study was not powered to detect differences in time-to-event variables, the results from this randomized trial demonstrate trends toward longer median TTP (15 vs. 10.2 months; P = 0.07), DR (16.7 vs. 11.2 months; P = 0.44) and time to next therapy (21.1 vs. 13.8 months; P = 0.27) in follicular NHL patients treated with 90Y ibritumomab tiuxetan compared with the rituximab control arm. In patients achieving a CR/CRu, the median TTP was 24.7 months for patients treated with 90Y ibritumomab tiuxetan compared with 13.2 months for rituximab-treated patients (P = 0.41), and ongoing responses of > 5 years have been observed. These results confirm that 90Y ibritumomab tiuxetan produces high response rates and durable remissions in patients with previously treated low-grade, follicular, and transformed NHL.

Antibodies, Monoclonal↗

PubMed2004

Radioimmunotherapy: a new treatment modality for B-cell non-Hodgkin's lymphoma.

The field of radioimmunotherapy for the treatment of non-Hodgkin's lymphoma (NHL) has advanced significantly over the past decade, and several radioimmunoconjugates are being tested in clinical trials. Two of these antibodies target CD20: yttrium-90 (Y-90)-labeled ibritumomab tiuxetan (Zevalin) and tositumomab/iodine-131 (I-131)-labeled tositumomab (Bexxar). Other agents target either CD22 (Y-90 epratuzumab) or human leukocyte antigen (HLA)-DR (I-131 Lym-1), respectively. In February 2002, Y-90-labeled ibritumomab tiuxetan became the first radioimmunoconjugate to be approved by the US Food and Drug Administration (FDA) for the treatment of cancer. Tositumomab/I-131 tositumomab was approved in June 2003. Thus, two radioimmunoconjugates have been approved for the treatment of NHL. Both agents, when administered as a single dose, have produced impressive tumor response rates with an acceptable toxicity profile. The main side effect is reversible myelosuppression. Radioimmunotherapy produces overall response rates of approximately 80% in patients with low-grade lymphomas, and 25% to 30% of patients achieve a complete remission. Lower response rates (approximately 40%) have been reported in patients with large-cell lymphomas. This review discusses the clinical trials of radioimmunotherapeutic agents for NHL that demonstrated their safety and efficacy and outlines the current status of these agents.

Antibodies, Monoclonal↗

PubMed2003

Identifying and quantifying apoptosis: navigating technical pitfalls.

Apoptosis or programmed cell death is often altered in malignancies and is frequently determined by the terminal transferase-mediated nick end labeling technique (TUNEL). However, commercially available protocols can produce high background and false-positive staining, which renders the distinction between apoptosis and necrosis difficult. In an attempt to develop a rapid and reproducible method for detecting and quantifying apoptosis, we coupled optimization of the Apoptag Plus Peroxidase In Situ Apoptosis Detection kit with quantitative histomorphometric computer imaging software using the Bacus Laboratories Incorporated Slide Scanner (BLISS). Multiple (200-350) unique 40x images were scanned using the BLISS system and downloaded into the WebSlide Browser program, creating a permanent, scanned record of the area assessed. The stored images were counted, with the final analysis simultaneously taking into account cells that were immunohistochemically positive and the histology of the surrounding cells to reduce the possibility of false positive and negative staining. In addition, cells with equivocal staining can be simultaneously reviewed by other technologists with networked WebSlide Browser access to the same images. Our data show that the advantages offered by the BLISS imaging software greatly reduce the potential drawbacks of using the TUNEL method as a sole means of quantification.

Adenocarcinoma↗

PubMed2003

Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin's lymphoma: combined data from 4 clinical trials.

UNLABELLED: Ibritumomab tiuxetan is an anti-CD20 murine IgG1 kappa monoclonal antibody (ibritumomab) conjugated to the linker-chelator tiuxetan, which securely chelates (111)In for imaging or dosimetry and (90)Y for radioimmunotherapy (RIT). Dosimetry and pharmacokinetic data from 4 clinical trials of (90)Y-ibritumomab tiuxetan RIT for relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) were combined and assessed for correlations with toxicity data. METHODS: Data from 179 patients were available for analysis. Common eligibility criteria included <25% bone marrow involvement by NHL, no prior myeloablative therapy, and no prior RIT. The baseline platelet count was required to be > or = 100,000 cells/mm(3) for the reduced (90)Y-ibritumomab tiuxetan administered dose (7.4-11 MBq/kg [0.2-0.3 mCi/kg]) or > or = 150,000 cells/mm(3) for the standard (90)Y-ibritumomab tiuxetan administered dose (15 MBq/kg [0.4 mCi/kg]). Patients were given a tracer administered dose of 185 MBq (5 mCi) (111)In-ibritumomab tiuxetan on day 0, evaluated with dosimetry, and then a therapeutic administered dose of 7.4-15 MBq/kg (0.2-0.4 mCi/kg) (90)Y-ibritumomab tiuxetan on day 7. Both ibritumomab tiuxetan administered doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve ibritumomab tiuxetan biodistribution. Residence times for (90)Y in blood and major organs were estimated from (111)In biodistribution, and the MIRDOSE3 computer software program was used, with modifications to account for patient-specific organ masses, to calculate radiation absorbed doses to organs and red marrow. RESULTS: Median radiation absorbed doses for (90)Y were 7.42 Gy to spleen, 4.50 Gy to liver, 2.11 Gy to lung, 0.23 Gy to kidney, 0.62 Gy (blood-derived method) and 0.97 Gy (sacral image-derived method) to red marrow, and 0.57 Gy to total body. The median effective blood half-life was 27 h, and the area under the curve (AUC) was 25 h. No patient failed to meet protocol-defined dosimetry safety criteria and all patients were eligible for treatment. Observed toxicity was primarily hematologic, transient, and reversible. Hematologic toxicity did not correlate with estimates of red marrow radiation absorbed dose, total-body radiation absorbed dose, blood effective half-life, or blood AUC. CONCLUSION: Relapsed or refractory NHL in patients with adequate bone marrow reserve and <25% bone marrow involvement by NHL can be treated safely with (90)Y-ibritumomab tiuxetan RIT on the basis of a fixed, weight-adjusted dosing schedule. Dosimetry and pharmacokinetic results do not correlate with toxicity.

Adult↗