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H M Vriesendorp

Publications and source records attributed to H M Vriesendorp.

At least 37 records · Page 2Linked to original sources
PubMed1995

Review of five consecutive studies of radiolabeled immunoglobulin therapy in Hodgkin's disease.

Recurrent Hodgkin's Disease (HD) provides unique opportunities to improve radiolabeled immunoglobulin therapy (RIT). Normal tissue toxicity after RIT is limited to bone marrow damage and is well documented and quantified in HD patients. Anti-antibody formation is rare in patients with HD, allowing for multiple RIT cycles. Overall, 134 patients with recurrent HD were treated on five different studies with i.v. antiferritin, labeled with 131I or with 111In for diagnostic purposes and 90Y for therapeutic purposes. Patients with recurrent, end-stage HD obtain a 60% response rate following 90Y-labeled antiferritin. One-half of the therapy responses are complete. Responses are more common in patients with longer disease histories (> 3 years) and smaller tumor volumes (< 30 cm3) and in patients receiving at least 0.4 mCi 90Y-labeled antiferritin/kg body weight. Complete responders survive significantly longer than partial responders (2 years versus 1 year). Partial responders survive longer than patients with progressive disease (1 year versus 4 months). HD in one-third of the patients recurs in new areas. A low protein dose (2-5 mg) and a moderate specific activity (10 mCi/mg) are recommended. Results obtained with 90Y-labeled antiferritin are significantly better than results with 131I-labeled antiferritin. Further translational research in vitro in the radio pharmacy and in vivo with experimental animals is ongoing to improve the therapeutic results of RIT in HD. Obviously, many permutations of RIT cannot be explored in HD patients for ethical, financial, or logistic reasons, and predictive preclinical research is required to achieve further progress. Currently, RIT is a low-toxicity, low-cost outpatient procedure for recurrent HD with a high response rate in a patient population with an unfavorable prognosis.

Animals↗
PubMed1995

Tumor targeting and pharmacokinetics of unmodified and modified F(ab)2 fragments of an anti-CEA murine monoclonal antibody (Immu-14).

Pharmacokinetic studies were performed with two different 111In-labeled F(ab)2 fragments of an anti-CEA murine monoclonal immunoglobulin G (Immun-14). Unmodified F(ab)2 and modified Fab-BMH-Fab fragments were compared in nude mice bearing a LS-174T human colon carcinoma tumor xenograft. Tumor accumulation is significantly higher for modified fragments than for unmodified fragments at all time points. At 24 h post injection, tumor uptake for modified and unmodified fragments reached 40 and 25% ID g, respectively. The retention of radioactivity in the liver was approx. 2-fold higher for modified fragments. Kidney uptake of modified fragments was at least 2-fold lower than that of unmodified fragments. Although blood radioactivity decreased rapidly for both fragments, the cumulative tumor activity was 40% higher for Fab-BMH-Fab fragment. Modified F(ab)2 fragments can deliver higher radiation doses to the tumor.

Animals↗
PubMed1995

Biodistribution and tumor localization of 111In-labeled unmodified and modified F(ab')2 fragments of human monoclonal IgM (16.88) in a nude mouse model.

Unmodified F(ab')2 and modified Fab'-BMH-Fab' fragments of human monoclonal IgM (16.88) were compared for biodistribution and tumor localization in nude mice bearing LS-174T human colon carcinoma xenografts. Although both unmodified and modified fragments of IgM cleared rapidly from the blood, the radioactivity retentions for each fragment in liver and kidney were significantly different. Kidney uptake of the modified fragment was about 4-fold lower than kidney uptake of the unmodified fragment. Radioactivity uptake in liver was 2-4-fold higher for the modified fragment. Lower liver and higher kidney uptake of unmodified fragments reflected the labile disulfide linkage of F(ab')2 in their hinge region and the subsequent behavior of the Fab' fragments resulting from the reduction of the disulfide linkage. Higher liver and lower kidney retention of modified fragments, on the other hand, resulted from the different cleavage mechanism of the stable thioether linkage. Tumor targeting was similar for unmodified and modified fragments at approx. 4% of injected dose per gram. These results indicate that the changes in fragment linkage chemistry may provide different pharmacokinetic patterns in vivo and improve the therapeutic application of radiolabeled fragments in human patients.

Animals↗
PubMed1995

Survival of patients with resistant Hodgkin's disease after polyclonal yttrium 90-labeled antiferritin treatment.

PURPOSE: A follow-up study was initiated of patients with Hodgkin's disease who were treated with yttrium 90-labeled antiferritin. Prescription method, pharmacokinetics, acute and late side effects, and survival were evaluated. METHODS: Patients had measurable disease and failed > or = two multiagent chemotherapy regimens previously (N = 44). All patients received 5-mCi indium 111-labeled antiferritin 2 mg intravenously and were scanned repeatedly by gamma camera. In five patients, polyclonal antiferritin (rabbit, pig, or baboon) failed to target the tumor. Thirty-nine patients were injected intravenously with 10-, 20-, 30-, 40-, or 50-mCi yttrium 90-labeled antiferritin 2 to 5 mg. Patients received between one and five cycles. Some patients were supported with 5 x 10(7) autologous bone marrow cells per kilogram. RESULTS: Yttrium 90-labeled polyclonal antiferritin does not produce immunologic, pharmacologic, or microbiologic complications in vivo. Bone marrow toxicity is the only side effect observed. Overall response rate is 20 of 39, or 51%. Two patients had stable disease. A significant positive correlation is found between blood radioactivity level 1 hour after radioimmunoconjugate administration and subsequent response of Hodgkin's disease. A dosage in millicuries per kilogram provides a higher positive correlation with blood radioactivity levels 1 hour after administration than a dosage in millicuries per square meter of body-surface area or in total millicuries. Fifty percent of patients survive for > or = 6 months. CONCLUSION: The low-dose protein used (2 to 5 mg) indicates that the high response rate is due to radiation and not to immunologic effects of the antibody. High-activity administrations followed by bone marrow transplantation are not required for tumor response. The therapeutic ratio of radiolabeled antiferritin is higher than the therapeutic ratio observed in most phase I studies of chemotherapeutic agents. This analysis does not identify a superior mode of treatment for patients with end-stage Hodgkin's disease. However, in a heavily pretreated patient population, prolonged survival is observed after relatively inexpensive treatment. Preclinical research with yttrium 90-labeled antiferritin indicates that significant increases in tumor dose can be obtained in the future without an increase in normal tissue toxicity.

Adolescent↗
PubMed1995

Liver toxicity induced by combined external-beam irradiation and radioimmunoglobulin therapy.

High-dose radiation therapy for liver metastases of gastrointestinal malignancies might be improved by combining external-beam irradiation and radioimmunoglobulin therapy. We studied the liver toxicity of the proposed combination in healthy beagle dogs. A total dose of 30 Gy to the whole liver, delivered in 2-Gy fractions over 3 weeks, resulted in mild, temporary veno-occlusive disease (VOD) in three of three dogs. Reversible bone marrow damage was noted after two intravenous injections of 18.5 MBq of yttrium-90-labeled monoclonal antibody ZCE025 per kg body weight in three of three dogs. Administrations of the antibody were separated by 1 week. Three dogs treated by irradiation of the liver with radioimmunoglobulin therapy added during the last 2 weeks of the irradiation showed signs of radiation hepatitis (VOD) starting around 35 days after treatment. One dog had a complete recovery, and two dogs were euthanized in a stage of terminal liver failure around day 90 after treatment. Temporary bone marrow damage was observed after the combined treatment, similar to the bone marrow damage observed after radioimmunoglobulin therapy alone. Earlier studies in the same dog model showed that bone marrow is the dose-limiting organ if radioimmunoglobulin therapy is used alone. The addition of irradiation of the liver to radioimmunoglobulin therapy changes the dose-limiting organ from bone marrow to liver. The radiation hepatitis observed in dogs is very similar to that observed in humans and is reflected in early platelet consumption in the irradiated liver plus late elevations of liver enzymes and VOD in central hepatic veins on histological analysis. Future applications of combined liver irradiation and radioimmunoglobulin therapy in humans should use radioimmunoglobulin therapy agents which show minimal uptake by normal liver.

Animals↗
PubMed1994

Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results.

PURPOSE: This study was undertaken to evaluate the feasibility and therapeutic effect of high-dose chemoradiotherapy with autologous or allogeneic bone marrow transplantation (BMT) in patients with advanced chronic lymphocytic leukemia (CLL) who relapse after fludarabine treatment. PATIENTS AND METHODS: Twenty-two patients with advanced CLL received high-dose cyclophosphamide, total-body irradiation, and BMT. Eleven patients with relapsed CLL received autologous BMT with marrow collected during a prior fludarabine-induced remission; leukemia cells were depleted from the autologous marrow in seven patients using an anti-CD19 monoclonal antibody and immunomagnetic separation. Eleven patients received allogeneic or syngeneic BMT, seven of whom had refractory Rai stage III or IV disease. RESULTS: Six autologous transplant recipients achieved a complete remission (CR), four a nodular CR (nCR), and one a partial remission (PR). Two recurred with CLL, and three developed Richter's transformation. Two patients had recurrence of immune cytopenias while in morphologic remission; one of these patients died of cytomegalovirus pneumonia. Six of 11 patients survive in remission 2 to 29 months following BMT. Of the 11 patients who received allogeneic or syngeneic BMT, seven achieved a CR, two a nCR, and one a PR; 10 survive 2 to 36 months following BMT. CONCLUSION: These data indicate that high-dose chemotherapy with allogeneic BMT is effective at producing CRs in patients with CLL. Autologous transplantation in CLL is feasible and is capable of producing remissions in patients with advanced CLL. Further studies are warranted to assess the role of BMT in the treatment of CLL.

Adult↗
PubMed1994

Etoposide, cyclophosphamide, total-body irradiation, and allogeneic bone marrow transplantation for hematologic malignancies.

PURPOSE: To determine the efficacy and toxicity of etoposide, cyclophosphamide, and fractionated total-body irradiation (TBI) as the conditioning regimen for allogeneic bone marrow transplantation (BMT) in patients with hematologic malignancies. PATIENTS AND METHODS: Seventy-nine patients underwent BMT from a human leukocyte antigen (HLA)-identical sibling using cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis. Thirty-four patients had early leukemia (acute leukemia or lymphoblastic lymphoma in first remission, chronic myelogenous leukemia [CML], or refractory anemia [RA]), and 45 patients had more advanced disease. Patients received etoposide 1,500 mg/m2 on day -8, followed by cyclophosphamide 60 mg/kg/d on days -7 and -6, and 10.2 Gy of TBI administered in six fractions of 1.7 Gy given twice daily for 3 days from day -3 to -1. Donor bone marrow was harvested and infused on day 0. RESULTS: Patients with early leukemia had a disease-free survival rate of 53% +/- 9% and an overall survival rate of 57% +/- 10% at 3 years. Patients with advanced disease had a disease-free survival rate of 15% +/- 5% and overall survival rate of 17% +/- 5%. The actuarial relapse rate for the early-leukemia group is 33% +/- 9% versus 69% +/- 9% for patients with more advanced disease. Severe toxicity was most frequently manifested as pulmonary hemorrhage followed by multiorgan failure and death. The 100-day mortality rate for the early-leukemia group was 10% versus 50% for patients with more advanced disease. CONCLUSION: The combination of cyclophosphamide, etoposide, and TBI is a relatively safe and effective preparative regimen for patients with early hematologic malignancies. Controlled trials are needed to evaluate critically this combination versus other standard preparative regimens. Greater toxicity was observed in patients with advanced disease, and this program does not appear to offer any advantage over other regimens.

Adolescent↗
PubMed1994

Radiobiology of total body radiation.

The first bone marrow transplants (BMTs) in human patients were performed after conditioning with total body irradiation (TBI). TBI remains an important part of BMT protocols. The morbidity and mortality of BMT remains significant, but can be decreased by the introduction of optimized TBI regimens. This requires dosimetric control and a detailed analysis and description of the physics of the TBI procedure in every BMT center that utilizes TBI. Recommendations for such procedures are given. Radiobiological models are of help in developing less toxic TBI procedures, but can only be effective after dosimetric control has been obtained and if the influence of other variables on the outcome of BMT are taken into account. Fractionated TBI (fraction size over 3.0 Gy or higher) appears to be more effective and better tolerated than single fraction TBI. Lung shielding is possible during TBI. Smaller organs or organs that cannot be imaged easily are not recommended for shielding. Radiolabeled immunoglobulins are but low molecular weight bone seeking radioisotopes and are not expected to improve the therapeutic ratio of TBI. Other variables in BMT are more difficult to quantify and model than TBI (e.g. high-dose chemotherapy, graft-versus-host disease) and will be more difficult to optimize.

Animals↗
PubMed1993

Preclinical evaluation of intravenously administered 111In- and 90Y-labeled B72.3 immunoconjugate (GYK-DTPA) in beagle dogs.

B72.3, a monoclonal antibody with reactivity against human adenocarcinomas was obtained from the Cytogen Corporation in the form of an immunoconjugate coupled with linker-chelator GYK-DTPA by using proprietary carbohydrate directed site specific chemistry. The immunoconjugate was radiolabeled with indium-111 or yttrium-90. A preclinical analysis was performed in 10 normal beagle dogs. The pharmacokinetics of intravenously administered indium- and yttrium-labeled immunoconjugates were compared serially in blood, bone marrow and urine samples. Compared to 90Y less of the 111In label ended up in urine and more was found in blood and bone marrow. Indium-labeled B72.3 GYK-DTPA had relatively higher uptake in most glandular tissues than 111In-labeled antiferritin immunoconjugate. Bone marrow toxicity was the dose limiting side effect after intravenous infusion of 90Y-labeled B72.3 GYK-DTPA. Toxicity was also observed in the liver but not in other organ systems. Recently other investigators obtained similar results with these immunoconjugates in human patients. A preclinical pharmacokinetic analysis of radioimmunoconjugates in beagle dogs provided useful information regarding bone marrow toxicity, liver toxicity and in vivo instability of the immunoconjugate. Data suggest that for future trials in human patients, a more stable chelated immunoconjugate for yttrium is needed to achieve less liver uptake and a better correlation with the 111In-labeled product than the 90Y-labeled B72.3 GYK-DTPA used in this investigation.

Animals↗
PubMed1993

Fractionated intravenous administration of 90Y-labeled B72.3 GYK-DTPA immunoconjugate in beagle dogs.

B72.3, a monoclonal antibody with reactivity against human adenocarcinomas, was coupled with linker-chelator GYK-DTPA using carbohydrate mediated conjugation chemistry and radiolabeled with yttrium-90. Single and double intravenous injections of radioimmunoconjugate were compared for acute and late normal tissue toxicity in 15 beagle dogs. The second injection was given 4 or 8 days after the first. Pharmacokinetics of the radioimmunoconjugate in blood, bone marrow and urine were similar for first and second injections. Only bone marrow (acute) and liver (late) toxicity were observed. Both liver and bone marrow toxicity were decreased by fractionation of the injections. After double injections, the total equitoxic dose was 15 and 60% higher for bone marrow and liver toxicity, respectively. The mechanisms of normal tissue protection offered by fractionated radioimmunoglobulin therapy (RIT) remain to be defined. Fractionated RIT will have a better therapeutic ratio than single injection RIT, if antitumor effects appear to be less susceptible to fractionation than normal tissues.

Animals↗
PubMed1993

Yttrium 90-labeled antiferritin followed by high-dose chemotherapy and autologous bone marrow transplantation for poor-prognosis Hodgkin's disease.

PURPOSE: This study was undertaken to examine the feasibility of combining radiolabeled antibody therapy with high-dose chemotherapy followed by autologous bone marrow transplantation in patients with poor-prognosis Hodgkin's disease. PATIENTS AND METHODS: Patients were entered onto this protocol if they had chemotherapy-resistant disease, bulky disease, or extensive prior therapy. Patients received yttrium-labeled antiferritin on day -13, -12, or -11, followed by high-dose cyclophosphamide, carmustine, and etoposide (CBV) on days -6 to -3, and then bone marrow infusion on day 0. RESULTS: Twelve patients received both radiolabeled antibody and high-dose chemotherapy followed by autologous transplantation. Two additional patients started the study, but were unable to complete all therapy. Four of 12 patients experienced early transplant-related mortality. Four patients are alive more than 2 years following transplantation and three are free from disease progression at 24+, 25+, and 28+ months following transplantation. The progression-free survival rate at 1 year is estimated to be 21%. Considering the poor prognostic characteristics of these patients, toxicity on this protocol was not necessarily greater than that observed with high-dose chemotherapy alone. CONCLUSION: This report demonstrates the feasibility of combining radiolabeled antibody therapy with high-dose chemotherapy and autologous bone marrow transplantation.

Adolescent↗
PubMed1993

Assessment of radiolabeled stabilized F(ab')2 fragments of monoclonal antiferritin in nude mouse model.

The biodistribution of 111In-labeled stabilized fragments of monoclonal antiferritin was studied in nude mice bearing a human hepatoma tumor xenograft. Pharmacokinetics and tumor targeting of fragment Fab'-linker-Fab' fragment molecules (stabilized F(ab')2) were compared to unmodified F(ab')2 fragment molecules and immunoglobulin G (IgG). Significant differences were observed in tumor and normal organ uptake at 12, 24, 48 and 72 hr. Tumor retention of stabilized F(ab')2 fragments was approximately 2.5-fold higher than of unmodified F(ab')2 at 48 hr. Blood clearance for stabilized F(ab')2 was relatively faster than intact IgG, while unmodified F(ab')2 cleared more rapidly from the circulation. Kidney radioactivity of unmodified F(ab')2 was at least two times higher than kidney radioactivity of stabilized F(ab')2 at all time points. Stabilized F(ab')2 demonstrated 40% less liver uptake than intact IgG. In these studies with nude mice, substantial retention of stabilized F(ab')2 in tumor and significant reduction in liver and kidney uptake of these fragments indicated that they could also have a higher therapeutic ratio than IgG or unmodified F(ab')2 in human patients.

Animals↗
PubMed1993

Evaluation of indium-111- and yttrium-90-labeled linker-immunoconjugates in nude mice and dogs.

Rapid uptake and slow transit of radioactivity from normal organs are detrimental to any clinical utilized radioimmunoconjugate because they lower the target-to-nontarget ratio and deliver undesirable radiation to normal organs. To mitigate this problem, two labile chemical linkages (EGS and DST) were introduced between a monoclonal antiferritin antibody (QCI) and a chelating agent (DTPA). The biodistribution of labile-linker immunoconjugates (EGS and DST) and stable linker immunoconjugates (DSS and ITCB) were compared. In a nude mouse model, all of the four immunoconjugates labeled with 111In targeted subcutaneously-implanted human tumor cells. Tumor-to-normal organ ratios were enhanced for the EGS linkage in comparison to the two stable linkages. Serial whole-body immunoscintigraphy confirmed the biodistribution study. The EGS and ITCB 90Y-labeled immunoconjugates had biodistributions similar to their respective 111In-labeled immunoconjugates. As the mouse model is not representative of the high uptake of monoclonal antibodies in the human liver, beagle dogs were used to further explore the retention of radiolabel in normal liver. The EGS-linked immunoconjugate significantly reduced the dog liver activity when compared to the ITCB immunoconjugate. The combination of the animal models (mouse and dog) appears to allow for a more compete and optimal preclinical analysis of chelated radiolabeled monoclonal antibodies for diagnosis or treatment and illustrates the potential clinical improvements possible with labile chemical linkages in radioimmunoconjugates.

Animals↗
PubMed1992

Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation.

Growth was assessed during the first and second years following bone marrow transplantation (BMT) in 47 children treated by either busulfan plus cyclophosphamide (BU/CY) (n = 24) or cyclophosphamide plus fractionated total body irradiation (CY/TBI) (n = 23). Before transplant, the median height was only 0.2 SD below age- and sex-adjusted means (range, -2.5 to +3.0). Height was greater than 2.0 SD below normal in only three patients (6%). The pretransplant heights were comparable in the BU/CY and CY/TBI groups (-0.1 v -0.6 SD, P = .35). Following transplant, median 1- and 2-year heights were 0.7 and 0.9 SD below normal, respectively. Growth rates were 2.2 SD and 1.4 SD below normal during the first and second years, respectively. Growth rates were greater than 2.0 SD below normal in 24 of 47 (51%) at 1 year and in 12 of 31 (39%) at 2 years after transplant. Growth rates in patients treated with BU/CY were comparable to those treated with CY/TBI during both years: -2.5 versus -1.7 SD during the first year (P = .19, Wilcoxon), and -1.5 versus -1.1 SD during the second year (P = .61). Growth rates during the second year correlated with growth rates during the first year (r = .36, P = .046). Growth rates during the first year were lower in patients who had been given prior cranial irradiation, those who were near pubertal age at the time of transplant, and those who were transplanted for a disease other than acute lymphoblastic leukemia (ALL). During the second year, poor rates of growth were associated only with the use of corticosteroids after transplant.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Survival after total body irradiation: effects of irradiation of exteriorized small intestine.

Rats receiving lethal irradiation to their exteriorized small intestine with pulsed 18 MVp bremsstrahlung radiation live about 4 days longer than rats receiving a dose of total-body irradiation (TBI) causing intestinal death. The LD50 for intestinal irradiation is approximately 6 Gy higher than the LD50 for intestinal death after TBI. Survival time after exteriorized intestinal irradiation can be decreased, by adding abdominal irradiation. Adding thoracic or pelvic irradiation does not alter survival time. Shielding of large intestine improves survival after irradiation of the rest of the abdomen while the small intestine is also shielded. The kinetics of histological changes in small intestinal tissue implicate the release of humoral factors after irradiation of the abdomen. Radiation injury develops faster in the first (proximal) 40 cm of the small intestine and is expressed predominantly as shortening in villus height. In the last (distal) 40 cm of the small intestine, the most pronounced radiation effect is a decrease in the number of crypts per millimeter. Irradiation (20 Gy) of the proximal small intestine causes 92% mortality (median survival 10 days). Irradiation (20 Gy) of the distal small intestine causes 27% mortality (median survival greater than 30 days). In addition to depletion of crypt stem cells in the small intestine, other issues (humoral factors, irradiated subsection of the small intestine and shielding of the large intestine) appear to influence radiation-induced intestinal mortality.

Animals↗
PubMed1992

Selection of reagents for human radioimmunotherapy.

Promising response rates are noted in patients with refractory Hodgkin's disease after radioimmunoglobulin therapy (RIT) with Yttrium-90 labeled polyclonal antiferritin. To explore the most efficacious selection of RIT reagents for use in humans, experimental animal data are reviewed for radiolabeled antiferritin and B72.3. Nude mice with subcutaneously implanted human malignancies provide an excellent primary screen for radiolabeled antibodies under consideration for use in humans. They provide information on the potential of a new reagent to target a human malignancy in vivo. The other determinant of the therapeutic ratio of RIT reagents--normal tissue toxicity--is best analyzed in large animals, such as dogs. Hematologic toxicity is dose limiting in all species and best predicted by a prescription of radiolabeled antibodies in mCi per kilogram body weight and the presence or absence of bone marrow targeting. Per cGy, RIT is more effective in causing BM damage in dogs than in rats. In dogs, bone marrow transplantation with autologous cryopreserved bone marrow cells or G-CSF treatment can accelerate hemopoietic recovery and granulopoiesis, respectively, after RIT. When dose escalation beyond bone marrow toxicity is performed, the liver (dog) or the intestinal tract (rat) become the next dose limiting tissue in dose escalation studies. Significant improvement in RIT results will be achieved when the normal liver uptake of chelated monoclonal antibody in dogs and in human patients can be prevented. The described animal models and continued investigations of RIT in patients with endstage Hodgkin's disease will allow for further improvement in the therapeutic ratio of RIT and the applicability of RIT in humans.

Animals↗