Biomedical subjects
Publications and source records attributed to Ola Lindén.
Radioimmunotherapy in indolent NHL is a new and promising therapy which adds a new therapeutic tool to the treatment palette. Recent advantages in RIT are described and perspectives discussed.
PURPOSE: Fractionated radioimmunotherapy may improve therapeutic outcome by decreasing heterogeneity of the dose delivered to the tumor and by decreasing hematologic toxicity, thereby allowing an increased amount of radionuclide to be administered. Because humanized anti-CD22 epratuzumab can be given repeatedly, a single-center study was conducted to establish the feasibility, safety, optimal dosing, and preliminary efficacy of weekly administrations of 90Y-labeled 1,4,7,10-tetra-azacyclodecane-N,N',N'',N'''-tetraacetic acid-conjugated epratuzumab. EXPERIMENTAL DESIGN: Cohorts of three to six patients with B-cell lymphoma received 185 MBq/m2 [90Y]epratuzumab with unconjugated epratuzumab (total protein dose 1.5 mg/kg) once weekly for two to four infusions, with [(111)In]epratuzumab coadministered at first infusion for scintigraphic imaging and dosimetry. RESULTS: Sixteen patients received treatment without significant infusional reactions. The overall objective response rate was 62% (95% confidence interval, 39-86%) in both indolent (75%) and aggressive disease (50%). Complete responses (CR/CRu) occurred in 25% of patients and were durable (event-free survival, 14-41 months). Two patients receiving four infusions had hematologic dose-limiting toxicity. Serum epratuzumab levels increased with each weekly dose. Of 13 patients with tumor cell CD22 expression determined by flow cytometry, seven of eight with strongly positive results had objective responses, versus one of five with negative or weakly positive results (P = 0.032). CONCLUSIONS: Radioimmunotherapy with weekly 185 MBq/m2 [90Y]epratuzumab achieved a high objective response rate (62%) across lymphoma subtypes, including durable CRs. The findings that three weekly infusions (555 MBq/m2, total dose) can be administered safely with only minor toxicity, that antibody levels increased during treatment weeks, and that therapeutic response predominantly occurs in patients with unequivocal CD22 tumor expression provide guidance for future studies.
Red marrow dosimetry is essential during radioimmunotherapy and a reliable method is essential in order to find a measure correlated to the toxic effect observed. The aim of this study was to calculate the absorbed dose to red marrow with different methods for the same patients and to compare the results. Patients diagnosed with B-cell lymphoma were treated with (131)I-labelled monoclonal antibodies (LL2, anti-CD22). Blood samples were collected, scintillation camera images were taken and single probe measurements were carried out at different points in time after administration of the radiopharmaceutical. The absorbed dose to red marrow per unit activity administered was calculated using four varieties of the blood method and from activity quantification in the sacrum in the scintillation camera images. The absorbed dose to the total body per unit activity, sometimes used as a measure for determining the toxic effect in red marrow, was calculated from both the scintillation camera images and the single probe measurements. The results from the different methods of calculating the absorbed dose for the same patient and treatment were compared. The ratio of the maximum and the minimum absorbed dose to red marrow calculated using the four variations of the blood method and the sacrum imaging method for one and the same patient varied between 1.8 and 2.8. The correlation coefficients for all the possible combinations of the dosimetry methods, including total body measurements, varied from 0.51 to 0.99. The results show that the variability of the absorbed dose to the bone marrow is dependent on both method and patient.
Patients with B-cell lymphoma may have disease manifestations ranging in size from more than a 1000 cm3 down to the volume of a single cell. If targeted radionuclide therapy is to become a curative treatment, all individual tumor cells must also be eliminated. Given the vast differences in particle energy of different electron- emitting radionuclides, one questions whether the mean absorbed dose is a relevant parameter for use in single-cell dosimetry and whether it would not be more accurate to adopt a stochastic approach to dosimetry. Monte Carlo simulations were performed of energy deposition from 1000, 300, 100, or 10 electrons uniformly distributed in a sphere with a radius of 7.7 microm. The simulated electrons were monoenergetic (18 keV, 28 keV, 141 keV, or 935 keV). The absorbed dose per emitted electron, the absorbed fraction, the fraction of the cellular volume in which energy is deposited, and the dose-volume histograms were calculated. Absorbed fractions varied between 0.60 (18 keV) and 0.001 (935 keV), and the absorbed dose to the cell per electron emitted varied by a factor of 10, from 0.898 mGy (18 keV) to 0.096 mGy (935 keV). The specific energy varied between 0 and 46 mGy for the case showing the best uniformity (1000 18-keV electrons). The nonuniformity of the absorbed dose to a cell increases with increasing electron energy and decreases with the number of decays inside the studied volume. The wide distribution of energy deposition should be taken into account when analyzing and designing trials for targeted radionuclide therapy.
Radioimmunotherapy is limited by the absorbed dose to radiosensitive organs. Removal of circulating radiolabeled MAbs after tumor tissue has been optimally targeted and should permit the administration of higher radioactivity to patients, resulting in a higher absorbed tumor dose. A novel "extracorporeal affinity adsorption treatment" (ECAT) device (MitraDep)was tested, with which biotinylated and radiolabeled MAbs can be removed from the circulation by passing whole blood over a filter coated with avidin. The antibodies were simultaneously radiolabeled and biotinylated using a trifunctional moiety comprising DOTA and biotin. Eight patients--all but 1 of whom with aggressive or mantle cell B-cell lymphoma-- who had failed to respond to standard therapies received infusions of 250 mg/m(2) cold rituximab and 150 MBq (111)In-rituximab-biotin for immunoscintigraphy. A week later, the patients were treated with another 250 mg/m(2) rituximab followed by (111)In/-(90)Y-rituximab-biotin (11 or 15 (90)Y MBq/kg). ECAT was performed 48 hours later. All 8 patients receiving (111)In-rituximab-biotin showed tumor uptake. Seven patients received radioimmunotherapy and subsequent ECAT. The mean depletion of (90)Y-rituximab-biotin in whole blood after ECAT was 96%, in the whole body 49%, in the lungs 62%, and in the liver and kidneys 40%. No effects on patients' vital signs and no adverse effects on hematological or coagulation parameters was observed during the ECAT procedure. A dose-escalation study is initiated.
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PURPOSE: In radionuclide therapy, cumulated activity and tumor volume/mass are the principal quantities necessary for the calculation of the absorbed dose to the tumor. When treating a fast-responding macroscopic tumor, there may be a decrease in its mass during therapy, and at any given uptake, this will result in an increase in the absorbed dose. The purpose of the present work is to demonstrate the limitations in current internal dosimetry protocols that assume a fixed tumor mass in lymphoma patients, using a fractionated radioimmunotherapy schedule and using a single infusion. EXPERIMENTAL DESIGN: Patients with B-cell lymphoma were treated with (90)Y-labeled epratuzumab (Immunomedics, Inc., Morris Plains, NJ) using a weekly dose-fractionation schedule for 2-4 weeks. They received either 185 MBq/m(2) (5 mCi/m(2)) in each infusion or, if they had a history of high-dose chemotherapy with stem cell rescue, 92.5 MBq/m(2) (2.5 mCi/m(2)) in each infusion. All patients received (111)In-labeled epratuzumab with the first infusion to verify tumor targeting and for dosimetry. The present report is based on three selected patients, in whom repeated assessments of tumor mass were possible. In two patients, (111)In-labeled epratuzumab was also coadministered with one of the subsequent treatments, i.e. during the second and third of two and three scheduled infusions. The tumor volume was determined from computer tomography images obtained before the first infusion and on different times after the infusion. An exponential equation was fitted to the decreasing mass of the tumor and implemented in the calculation of the absorbed dose. For comparison, the absorbed dose to the tumor was also calculated using the tumor volume determined from the baseline pretreatment computer tomography examination. RESULTS: The tumor volume for the patients changed rapidly. For one patient, the pretreatment volume was 19.5 ml, and for another patient, it was 840 ml. For these two patients, the ratio of tumor volume at the beginning of therapy compared with that after 8 days and 14 days of therapy was 0.7 and 0.8, respectively. This rapid decrease in volume and subsequent mass reduction result in an increase of mean absorbed dose to the tumor of as much as a factor of 1.75. CONCLUSIONS: At a given activity uptake, a decrease in tumor mass during therapy will significantly increase the calculated absorbed dose. Taking the change in tumor mass into account when calculating absorbed dose may improve the correlation between the mean absorbed dose to the tumor and the response to the therapy.
BACKGROUND: The method for red marrow dosimetry in radioimmunotherapy, in the absence of specific activity uptake in red marrow, is based on the activity measured in the blood or plasma. The activity concentration ratio of red marrow to blood is then assumed to be constant. The aim of the current study was to determine whether this ratio varies with time after injection. METHODS: Measurements were carried out with both animals and patients.Tumor-bearing rats were intravenously injected with iodine-131-, iodine-125-, indium-111-, or rhenium-188-labeled BR96, a chimeric immunoglobulin G1 monoclonal antibody. (All were chelate-labeled, except for iodine-131, which was iodogen-labeled.) Measurements were made of the activity concentration in blood and bone marrow at different points in time after injection, and the ratio of activity concentration in red marrow and blood as a function of time postinjection (RMBLR[t)]) was calculated. For patients treated with iodine-131-labeled monoclonal antibody (LL2, Immunomedics Inc., Morris Plains, NJ; anti-CD22; immunoglobulin G2 isotype of mouse origin), blood samples were drawn and scintillation camera images taken at different times after injection. The red marrow activity concentration in the sacrum was determined by activity quantification from regions of interest. The activity concentration in blood was also measured. The RMBLR(t) was calculated based on these data. RESULTS: For both patients and rats, the RMBLR(t) was increased 72 hours after injection. Furthermore, it was found that the use of a constant RMBLR can lead to an over- or underestimation of the absorbed dose in bone marrow. CONCLUSIONS: These data demonstrate the difficulty in using fixed values of the activity concentration ratio of red marrow to blood for dosimetry.
BACKGROUND: A patient with follicular lymphoma was investigated with 0.5 mg Fab' or minute anti-CD22 labeled with 1100 MBq technetium-99m ((99m)Tc). A computed tomography scan performed a week later revealed regression. This unexpected response prompted an investigation of single cell dosimetry of low-energy electron emitters. METHODS: Another patient with low-grade, unclassifiable B-cell lymphoma with a low expression of CD22 was injected with (99m)Tc anti-CD22. Blood samples were drawn 30 minutes, 4 hours, and 24 hours after injection. Lymphoma cells (CD19+) and T cells (CD3+), which served as control cells, were separated using a flow cytometer. The radioactivity of the two cell populations was measured in an NaI(Tl) well-type detector. The mean uptake per cell and absorbed dose were calculated. The CD22 expression of the patient's cells and of a B-cell lymphoma cell line (Raji) were assessed by flow cytometry for the extrapolation of the absorbed dose from the patient's cells to a cell line with higher CD22 expression. RESULTS: The average number of (99m)Tc atoms per CD19+ and CD3+ cell 4 hours postinjection were 5.4 and 0.054, respectively. Depending on the assumed ratio between antibody and CD22 molecules (1:2 or 1:1), the CD22 expression on the patient's cells and Raji cells varied from 2800 to 5700 and from 37,000 to 74,000 per cell, respectively. The average absorbed dose per cell ranged from 4 x 10(-7) to 0.1 grays (Gy). CONCLUSIONS: It seems feasible to assess the mean single tumor cell uptake of (99m)Tc targeted by Fab' or minute anti-CD22 in a patient's lymphoma using sorted cell populations, thereby allowing single cell dosimetry. Extrapolation of the absorbed dose from (99m)Tc to cells with higher CD22 expression was made and under certain conditions absorbed doses of 0.1 Gy were obtained, indicating the potential relevance of low-energy electron emitters to therapy.
The experience with radioimmunotherapy in B-cell lymphomas using the rapidly internalizing antibody, anti-CD22 (LL2), is limited. In this study we investigated the efficacy and toxicity of 131I-labelled-LL2 for radioimmunotherapy in patients with B-cell lymphomas that failed one or two cytostatic regimens. Eleven patients were treated with one or repeated cycles of 131I-anti-CD22 antibody, 1330 MBq/m2 (36 mCi/m2). Six of the 11 treated patients demonstrated an objective response, three of them with complete remission. All follicular (3 patients) and transformed lymphomas (2 patients) responded compared to one of four diffuse large B-cell lymphomas. Two out of six responders exhibited event-free survival (EFS), which was comparable with or longer than the EFS following primary anthracycline-containing chemotherapy. Non-haematological toxicity was mild. Haematological toxicity was associated with pretreatment clinical characteristics but not with estimated absorbed bone marrow doses. Objective remission following treatment with 131I-anti-CD22 can be achieved in patients with various subtypes of B-cell lymphomas, failing standard chemotherapy. Follicular or transformed lymphomas seem particularly responsive. Haematological toxicity seems to be dependent on the functional status of the bone marrow before radioimmunotherapy.