A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas.

Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 ((131)I)-tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg (131)I-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of (131)I calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total-body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of (131)I-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis.

Phase I study of (131)I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome.

Delivery of targeted hematopoietic irradiation using radiolabeled monoclonal antibody may improve the outcome of marrow transplantation for advanced acute leukemia by decreasing relapse without increasing toxicity. We conducted a phase I study that examined the biodistribution of (131)I-labeled anti-CD45 antibody and determined the toxicity of escalating doses of targeted radiation combined with 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI) followed by HLA-matched related allogeneic or autologous transplant. Forty-four patients with advanced acute leukemia or myelodysplasia received a biodistribution dose of 0.5 mg/kg (131)I-BC8 (murine anti-CD45) antibody. The mean +/- SEM estimated radiation absorbed dose (centigray per millicurie of (131)I) delivered to bone marrow and spleen was 6.5 +/- 0.5 and 13.5 +/- 1.3, respectively, with liver, lung, kidney, and total body receiving lower amounts of 2.8 +/- 0.2, 1.8 +/- 0.1, 0.6 +/- 0.04, and 0.4 +/- 0.02, respectively. Thirty-seven patients (84%) had favorable biodistribution of antibody, with a higher estimated radiation absorbed dose to marrow and spleen than to normal organs. Thirty-four patients received a therapeutic dose of (131)I-antibody labeled with 76 to 612 mCi (131)I to deliver estimated radiation absorbed doses to liver (normal organ receiving the highest dose) of 3.5 Gy (level 1) to 12.25 Gy (level 6) in addition to CY and TBI. The maximum tolerated dose was level 5 (delivering 10.5 Gy to liver), with grade III/IV mucositis in 2 of 2 patients treated at level 6. Of 25 treated patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), 7 survive disease-free 15 to 89 months (median, 65 months) posttransplant. Of 9 treated patients with acute lymphoblastic leukemia (ALL), 3 survive disease-free 19, 54, and 66 months posttransplant. We conclude that (131)I-anti-CD45 antibody can safely deliver substantial supplemental doses of radiation to bone marrow (approximately 24 Gy) and spleen (approximately 50 Gy) when combined with conventional CY/TBI.

Energy-based scatter corrections for scintillation camera images of iodine-131.

UNLABELLED: The use of high-dose 131I antibody therapy requires accurate measurement of normal tissue uptake to optimize the therapeutic dose. One of the factors limiting the accuracy of such measurements is scatter and collimator septal penetration. This study evaluated two classes of energy-based scatter corrections for quantitative 131I imaging: window-based and spectrum-fitting. METHODS: The window-based approaches estimate scatter from data in two or three energy windows placed on either side of the 364-keV photopeak using empirical weighting factors. A set of images from spheres in an elliptical phantom were used to evaluate each of the window-based corrections. The spectrum-fitting technique estimates detected scatter at each pixel by fitting the observed energy spectrum with a function that models the photopeak and scatter, and which incorporates the response function of the camera. This technique was evaluated using a set of Rollo phantom images. RESULTS: All of the window-based methods performed significantly better than a single photopeak window (338-389 keV), but the weighting factors were found to depend on the object being imaged. For images contaminated with scatter, the spectrum-fitting method significantly improved quantitation over photopeak windowing. Little difference, however, between any of the methods was observed for images containing small amounts of scatter. CONCLUSION: Most clinical 131I imaging protocols will benefit from qualitative and quantitative improvements provided by the spectrum-fitting scatter correction. The technique offers the practical advantage that it does not require phantom-based calibrations. Finally, our results suggest that septal penetration and scatter in the collimator and other detector-head components are important sources of error in quantitative 131I images.

Post therapy imaging in high dose I-131 radioimmunotherapy patients.

The biodistribution of a trace-labeled I-131 antibody is used to predict the biodistribution of a high dose I-131 antibody for therapy. Internal radiation dose estimates derived from the trace-labeled antibody have been used to determine the I-131 doses in a phase I escalating dose therapy trial for hematologic malignancy. To confirm the hypothesis that the distribution of a trace- and high-dose labeled antibodies are similar, both trace (7-11 mCi, 259-407 MBq) and high-dose (100-800 mCi, 3700-29600 MBq) I-131 radiolabeled antibody infusion were imaged in 12 patients who were treated for leukemia or lymphoma. With specialized imaging techniques using lead attenuation sheets, clearance data from organs were obtained from serial gamma camera images. Biological clearance half times of I-131 from both trace and therapy level doses were in agreement. An exception was a patient who developed human antimouse antibody before therapy, and subsequently had rapid clearance of the therapy dose. The method was feasible, yielded reproducible results, and provided critical data for relating therapy toxicity to radiation absorbed dose estimates.

Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support.

BACKGROUND: Radiolabeled monoclonal antibodies recognizing B-lymphocyte surface antigens represent a potentially effective new therapy for lymphomas. We assessed the biodistribution, toxicity, and efficacy of anti-CD20 (B1 and 1F5) and anti-CD37 (MB-1) antibodies labeled with iodine-131 in 43 patients with B-cell lymphoma in relapse. METHODS: Sequential biodistribution studies were performed with escalating doses of antibody (0.5, 2.5, and 10 mg per kilogram of body weight) trace-labeled with 5 to 10 mCi of 131I. The doses of radiation absorbed by tumors and normal organs were estimated by serial gamma-camera imaging and tumor biopsies. Patients whose tumors were estimated to receive greater doses of radiation than the liver, lungs, or kidneys (i.e., patients with a favorable biodistribution) were eligible for therapeutic infusion of 131I-labeled antibodies according to a phase 1 dose-escalation protocol. RESULTS: Twenty-four patients had a favorable biodistribution, and 19 received therapeutic infusions of 234 to 777 mCi of 131I-labeled antibodies (58 to 1168 mg) followed by autologous marrow reinfusion, resulting in complete remission in 16, a partial response in 2, and a minor response (25 to 50 percent regression of tumor) in 1. Nine patients have remained in continuous complete remission for 3 to 53 months. Toxic effects included myelosuppression, nausea, infections, and two episodes of cardiopulmonary toxicity, and were moderate in patients treated with doses of 131I-labeled antibodies that delivered less than 27.25 Gy to normal organs. CONCLUSIONS: High-dose radioimmunotherapy with 131I-labeled antibodies is associated with a high response rate in patients with B-cell lymphoma in whom antibody biodistribution is favorable.

Imaging and treatment of B-cell lymphoma.

Ten patients with non-Hodgkin's lymphoma have been evaluated as candidates for experimental radioimmunotherapy and five of those patients have been treated with a single high dose of iodine-131-(131I) labeled anti-pan B-cell antibodies. The evaluation protocol involved collecting biodistribution data by quantitation of gamma camera images and by tumor biopsy from trace labeled doses of antibody, to estimate the relative radiation dose delivered to normal organs and tumor sites. Each patient received up to three escalating mass doses (0.5 mg/kg, 2.5 mg/kg, and 10.0 mg/kg) of radioiodinated antibody for determination of the antibody amount that yielded the most favorable biodistribution for treatment. The millicuries of 131I-labeled to the optimal antibody dose for therapy was selected to deliver 1,000 rads (three patients) or 1,500 rads (two patients) to normal uninvolved organs. Because severe bone marrow toxicity was expected, all patients had their bone marrow cryopreserved prior to entry into the study. This report details the methods and results of quantitative imaging, biodistribution data collection, and absorbed radiation dose estimation in patients with lymphoma receiving high level radioimmunotherapy with 131I-labeled antibodies.

High dose radiolabeled antibody therapy of lymphoma.

A trial has been initiated testing the effects of high dose radiolabeled monoclonal antibody administered in conjunction with marrow transplantation for treatment of lymphoma. This study is based on observations in mice demonstrating that radiolabeled antibody against a normal lymphocyte-associate antigen can induce regression of lymphoma masses. These preclinical studies also showed that large amounts of antibody are needed to achieve adequate biodistribution in vivo and that potentially curative doses of radionuclide induce substantial hematopoietic toxicity. Consequently, in patients with recurrent lymphoma, we are first evaluating the influence of dose on the biodistribution of a pan B-cell antibody, MB-1 (anti-CD37). In four patients, the biodistribution studies indicated that at the highest amount of antibody tested 131I-labeled antibody MB-1 (10 mg/kg) could deliver more radiation to tumor than to normal organs. These patients were treated with antibody MB-1 labeled with 250 to 482 mCi 131I estimated to deliver 380 to 1570 cGy to normal organs and 850 to 4260 cGy to tumor. Myelosuppression occurred in all patients and required infusion of cryopreserved marrow in one patient. Complete tumor regressions were observed in each patient. In three other patients with splenomegaly and/or large tumor burden, biodistribution studies indicated that 131I-labeled antibody could not deliver more radiation to tumor than to normal organs and these patients were not treated. Thus, tumor burden and spleen size may determine the feasibility of treatment with radiolabeled antibody. Treatment with this antibody labeled with high doses of 131I was well tolerated and may prove therapeutically useful. These studies are being continued to determine the maximal doses of radiation that can be tolerated by nonhematopoietic tissues after infusion of 131I-labeled antibody.

Treatment of refractory non-Hodgkin's lymphoma with radiolabeled MB-1 (anti-CD37) antibody.

The biodistribution, toxicity, and therapeutic potential of anti-CD37 monoclonal antibody (MoAb) MB-1 labeled with iodine 131 (131I) was evaluated in ten patients with advanced-, low- or intermediate-grade non-Hodgkin's lymphomas who failed conventional treatment. Sequential dosimetric studies were performed with escalating amounts of antibody MB-1 (0.5, 2.5, 10 mg/kg) trace-labeled with 5 to 10 mCi 131I. Serial tumor biopsies and gamma camera imaging showed that the 10 mg/kg MoAb dose yielded the best MoAb biodistribution in the ten patients studied. Biodistribution studies in the five patients with splenomegaly and tumor burdens greater than 1 kg indicated that not all tumor sites would receive more radiation than normal organs, and these patients were therefore not treated with high-dose radioimmunotherapy. The other five patients did not have splenomegaly and had tumor burdens less than 0.5 kg; all five patients in this group showed preferential localization and retention of MoAb at tumor sites. Four of these patients have been treated with 131I (232 to 608 mCi) conjugated to anti-CD37 MoAb MB-1, delivering 850 to 4,260 Gy to tumor sites. Each of these four patients attained a complete tumor remission (lasting 4, 6, 11+, and 8+ months). A fifth patient, whose tumor did not express the CD37 antigen, was treated with 131I-labeled anti-CD20 MoAb 1F5 and achieved a partial response. Myelosuppression occurred 3 to 5 weeks after treatment in all cases, but there were no other significant acute toxicities. Normal B cells were transiently depleted from the bloodstream, but immunoglobulin (Ig) levels were not affected, and no serious infections occurred. Two patients required reinfusion of previously stored autologous, purged bone marrow. Two patients developed asymptomatic hypothyroidism 1 year after therapy. The tolerable toxicity and encouraging efficacy warrant further dose escalation in this phase I trial.