Allogeneic hematopoietic cell transplant (HCT) is a widely used therapy for hematologic malignancy. It is important to give the option of HCT to patients without an HLA-matched donor; this is most acute for ethnic minorities. Haploidentical HCT may offer the best or only chance for cure but often fails due to persistant malignancy or fatal toxicity. It is important to improve disease control without increased toxicity of the regimen. We have shown that CD45 radioimmunotherapy (RIT) delivers radiation to leukemic sites, sparing normal organs. We hypothesize haploidentical HCT may be enhanced via CD45 RIT by maximizing delivery to target tissue with minimal toxicity by reducing total-body irradiation (TBI) and chemotherapy. We performed studies to find the maximal intensity of anti-leukemic RIT combined with haploidentical HCT while preserving graft-versus-leukemia effects. We established an HCT regimen in B6SJLF1/J mice (H-2Db haplotype) conditioned with fludarabine (FLU, days -6 to -2), followed by TBI (250, 500, 750 cGy; day -1). Mice received 15 million donor (CB6F1/J, H-2Dd) BM cells (day 0), then cyclophosphamide (CY) for graft-versus-host disease (GvHD) prophylaxis (day +2). Chimerism was TBI dose-dependent; mice receiving ≥500 cGy were fully chimeric 4 weeks post-HCT, persisting ≥8 months. We then treated B6SJLF1/J mice with or without FLU and 200-400 μCi of 90Y-labeled anti-murine CD45 Ab (30F11, day -3), followed by 15 million donor BM cells (day 0) and CY (day +2). All mice receiving 200 or 300 μCi 90Y-CD45 Ab survived 30 days after HCT with no evidence of toxicity or GvHD. Four of 10 mice receiving 400 μCi 90Y-CD45 Ab died by day 25 due to toxicity. At day 25 blood was taken to detect chimerism via flow cytometry. Three of 5 mice that received 200 μCi 90Y-CD45 Ab and FLU showed chimerism with 23-77% CD8+ T-cells expressing H-2Dd. Four of 5 (80%) mice receiving 300 μCi 90Y-30F11 and 2/3 (67%) receiving 400 μCi 90Y-30F11, in the presence of FLU, were chimeric with 22-89% and 25-64% CD8+ donor cells, respectively. Mice receiving 200, 300, or 400 μCi 90Y-CD45 Ab without FLU were chimeric with 10-71% donor cells in 4/5 (80%), 2/5 (40%) and 1/4 (25%) mice, respectively. These data suggest anti-CD45 RIT may be a well-tolerated regimen allowing engraftment of haploidentical marrow without TBI and chemotherapy. Current studies testing pretargeted RIT may improve targeting of malignant CD45+ cells with reduced TBI and FLU, and increased therapeutic index.

In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a phase 1/2 study in which targeted irradiation delivered by 131I-anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/mL) and cyclophosphamide (CY; 120 mg/kg). Fifty-two (88%) of 59 patients receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ. Forty-six patients were treated with 102 to 298 mCi (3774-11 026 MBq) 131I, delivering an estimated 5.3 to 19 (mean, 11.3) Gy to marrow, 17-72 (mean, 29.7) Gy to spleen, and 3.5 Gy (n = 4) to 5.25 Gy (n = 42) to the liver. The estimated 3-year nonrelapse mortality and disease-free survival (DFS) were 21% and 61%, respectively. These results were compared with those from 509 similar International Bone Marrow Transplant Registry patients who underwent transplantation using BU/CY alone. After adjusting for differences in age and cytogenetics risk, the hazard of mortality among all antibody-treated patients was 0.65 times that of the Registry patients (95% CI 0.39-1.08; P = .09). The addition of targeted hematopoietic irradiation to conventional BU/CY is feasible and well tolerated, and phase 2 results are sufficiently encouraging to warrant further study.

PURPOSE Radioimmunotherapy may improve the outcome of hematopoietic cell transplantation for hematologic malignancies by delivering targeted radiation to hematopoietic organs while relatively sparing nontarget organs. We evaluated the organ localization of yttrium-90-labeled anti-CD45 ((90)Y-anti-CD45) antibody in macaques, a model that had previously predicted iodine-131-labeled anti-CD45 ((131)I-anti-CD45) antibody biodistribution in humans. EXPERIMENTAL DESIGN Twelve Macaca nemestrina primates received anti-CD45 antibody labeled with 1 to 2 mCi of (90)Y followed by serial blood sampling and marrow and lymph node biopsies, and necropsy. The content of (90)Y per gram of tissue was determined by liquid scintillation spectrometry. Time-activity curves were constructed using average isotope concentrations in each tissue at measured time points to yield the fractional residence time and estimate radiation absorbed doses for each organ per unit of administered activity. The biodistribution of (90)Y-anti-CD45 antibody was then compared with that previously obtained with (131)I-anti-CD45 antibody in macaques. RESULTS The spleen received 2,120, marrow 1,060, and lymph nodes 315 cGy/mCi of (90)Y injected. The liver and lungs were the nontarget organs receiving the highest radiation absorbed doses (440 and 285 cGy/mCi, respectively). Yttrium-90-labeled anti-CD45 antibody delivered 2.5- and 3.7-fold more radiation to marrow than to liver and lungs, respectively. The ratios previously observed with (131)I-anti-CD45 antibody were 2.5-and 2.2-fold more radiation to marrow than to liver and lungs, respectively. CONCLUSIONS This study shows that (90)Y-anti-CD45 antibody can deliver relatively selective radiation to hematopoietic tissues, with similar ratios of radiation delivered to target versus nontarget organs, as compared with the (131)I immunoconjugate in the same animal model.

The poor survival of elderly patients with advanced AML or high-risk MDS following conventional chemotherapy, as well as their poor tolerance for high-dose regimens used in conventional myeloablative hematopoietic cell transplantation (HCT) demands innovative therapeutic approaches. Recent success achieving stable donor chimerism following infusion of allogeneic peripheral blood stem cells (PBSC) after reduced intensity (non-myeloablative) conditioning regimens affords an opportunity to safely induce a graft-vs-leukemia (GVL) effect with minimal acute morbidity. GVL effects, however, appear to be most potent in patients with low tumor burdens at the time of transplantation. We have therefore conducted a Phase I clinical trial of targeted hematopoietic irradiation delivered by an 131I-labeled anti-CD45 antibody (BC8) to determine the feasibility, safety and efficacy of this approach toward reducing the burden of disease before an established non-myeloablative regimen. In this dose escalation study designed to estimate the maximum tolerated dose of 131I-BC8 antibody that can be combined with fludarabine (FLU) and low dose total body irradiation (TBI), 33 patients over 50 years of age with advanced AML or high-risk MDS (> 5% blasts) were treated with 246 to 932 mCi 131I delivering an estimated 5.2 to 45.9 (mean 27.5) Gy to bone marrow, 17.3 to 155 (mean 81.2) Gy to spleen, and 12–24 Gy to the liver (dose-limiting organ). Patients then received FLU (30 mg/m2 daily for 3 days), 2 Gy TBI, and HLA-matched related (n = 10) or unrelated (n = 23) PBSC grafts with graft-vs-host disease prophylaxis provided by cyclosporine and mycophenolate mofetil. The median age of patients was 61 (50–71) years. Twenty-four patients had AML, with 6 (13%) patients in second or third complete remission, 2 (4%) with primary refractory disease, and 16 (35%) in relapse. Nine (20%) patients had MDS with >5% blasts. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a remission in all patients, and all had 100% donor CD3+ and CD33+ cell engraftment by day 28 post-transplant. The absolute neutrophil count surpassed 500/uL at a median of 14 (range, 10–19) days, and the self-sustained platelet count surpassed 20,000/uL at a median of 17 days (range, 15–43). Eighteen patients (55%) are surviving disease-free 2 to 16 months (median 9.5 months) post-transplant. In 9 (27%) patients, the disease relapsed 3 to 38 months after HCT. The day-100 non-relapse mortality was 12%. This study demonstrates that at least an average of 27 Gy of targeted radiotherapy can be delivered to bone marrow and an average of 81 Gy to the spleen, in addition to a standard reduced intensity transplant regimen, without a marked increase in day 100 mortality. Whether this approach will reduce post-transplant relapse rates for older patients with high-risk AML/MDS remains to be determined.

Patients with AML in first remission undergoing conventional matched related hematopoietic cell transplantation (HCT) have a significant risk of both relapse and non-relapse mortality following transplant. In an attempt to improve outcome by decreasing relapse, we conducted a Phase I/II study in which targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody is combined with busulfan (BU) and cyclophosphamide (CY). Patients (median age 41) received a trace (~5mCi) 131I-labeled dose of 0.5 mg/kg anti-CD45 (BC8) murine monoclonal antibody followed by serial quantitative gamma camera imaging and a bone marrow biopsy for estimation of radiation absorbed doses to target organs (marrow and spleen) and non-target organs (liver, lung, and kidney). Fifty-two of 59 patients (88%) had a higher estimated radiation absorbed dose to marrow and spleen than to any normal organ. Forty-six of these were treated with 102 to 298 mCi 131I delivering an estimated 5.3 to 19 (mean 11.3) Gy to bone marrow, 17 to 72 (mean 29.7) Gy to spleen, and 3.5 Gy (n = 4) to 5.25 Gy (n = 42) to the liver. Patients then received targeted BU (AUC 600–900 ng/ml), CY (120 mg/kg), and infusion of HLA-matched related marrow (n = 40) or peripheral blood stem cells (n = 6). The non-relapse mortality (NRM) was 17%, as eight patients died of transplant-related causes (sepsis-2, idiopathic pneumonia syndrome-1, viral pneumonia-3, and fungal pneumonia-2). Nine patients (20%) relapsed 3 to 38 months post-transplant, and 28 patients (61%) are surviving disease-free 7 to 124 months (median 49 months) post-transplant. For 26 patients (62%) with intermediate risk cytogenetics, 18 (69%) are surviving disease-free, with only 3 (12%) relapsing. Fifteen patients (33%) were considered high risk based on unfavorable cytogenetics or secondary AML; 7 of these 15 (46%) are surviving disease-free and 5 (33%) have relapsed. Because of the known impact of features such as age and cytogenetic risk group on post-HCT outcome, we compared our data to data from the International Bone Marrow Transplant Registry (IBMTR) on first remission AML patient conditioned with BU/CY alone prior to HCT. Over a 10-year period, 980 IBMTR patients (median age 28) were transplanted using a median BU dose of 16 mg/kg (range 8–21 mg/kg) and a median CY dose of 120 (range 62–232). Of the 509 IBMTR patients with known cytogenetics at diagnosis, 466 (92%) had intermediate-risk cytogenetics. Using a Cox regression model for overall mortality and adjusting for age and cytogenetics risk differences, the hazard for mortality among 131I-BC8 Ab/BU/CY patients is 0.65 times that of registry patients receiving BU/CY only (95% CI 0.35 to 1.08, p = 0.09). The addition of targeted hematopoietic irradiation to conventional BU/CY is both feasible and well tolerated, and has the potential to improve survival for patients undergoing HCT for AML in first remission.

UNLABELLEDRadioimmunotherapy (RIT) using (131)I-tositumomab has been used successfully to treat relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). Our approach to treatment planning has been to determine limits on radiation absorbed dose to critical nonhematopoietic organs. This study demonstrates the feasibility of using CT to adjust for actual organ volumes in calculating organ-specific absorbed dose estimates.METHODSRecords of 84 patients who underwent biodistribution studies after a trace-labeled infusion of (131)I-tositumomab for RIT (January 1990 and April 2003) were reviewed. Serial planar gamma-camera images and whole-body NaI probe counts were obtained to estimate (131)I-antibody source-organ residence times as recommended by the MIRD Committee. The source-organ residence times for standard man or woman were adjusted by the ratio of the MIRD phantom organ mass to the CT-derived organ mass.RESULTSThe mean radiation absorbed doses (in mGy/MBq) for our data using the MIRD model were lungs = 1.67; liver = 1.03; kidneys = 1.08; spleen = 2.67; and whole body = 0.3; and for CT volume-adjusted organ volumes (in mGy/MBq) were lungs = 1.30; liver = 0.92; kidneys = 0.76; spleen = 1.40; and whole body = 0.22. We determined the following correlation coefficients between the 2 methods for the various organs: lungs, 0.49 (P = 0.0001); liver, 0.64 (P = 0.004); kidneys, 0.45 (P = 0.0004); spleen, 0.22 (P = 0.0001); and whole body, 0.78 (P = 0.0001), for the residence times. For therapy, patients received mean (131)I administered activities of 19.2 GBq (520 mCi) after adjustment for CT-derived organ mass compared with 16.0 GBq (433 mCi) that would otherwise have been given had therapy been based only using standard MIRD organ volumes-a statistically significant difference (P = 0.0001).CONCLUSIONWe observed large variations in organ masses among our patients. Our treatments were planned to deliver the maximally tolerated radiation dose to the dose-limiting normal organ. This work provides a simplified method for calculating patient-specific radiation doses by adjusting for the actual organ mass and shows the value of this approach in treatment planning for RIT.

The goal of this work was to determine an optimal radioimmunotherapy agent for further development against non-Hodgkin's lymphoma. We sought to establish the stability profile of Y-90-labeled humanized LL2 (hLL2) monoclonal antibody (mAb) when prepared with different chelating agents and, from these data, to estimate the dosimetric improvement to be expected from use of the most stable Y-90-chelate-hLL2 complex. Methods: The complementarity-determining region-grafted (humanized) anti-CD22 mAb, hLL2 (epratuzumab), was conjugated to 3 different chelating agents, 2 of which were derivatives of diethylenetriaminepentaacetic acid (DTPA) and 1 of which was the macrocyclic chelate 1,4,7,10-tetraazacyclododecane-NN',N",N"'-tetraacetic acid (DOTA). The 3 hLL2 conjugates were radiolabeled with Y-90 and tested for stability in vitro against a 10,000fold molar excess of free DTPA over 9 d. They were also tested against normal human serum at 37degreesC over 12 d. Each conjugate was radiolabeled with the gamma-emitting radionuclide, Y-88, and compared for biodistribution in normal and lymphoma xenograft-bearing athymic mice. In vivo data were analyzed for statistical differences in the uptake of yttrium in bone and washed bone when either the DOTA or the Mx-DTPA chelates were used, and closimetry calculations were made for each complex. Results: Y-90-DOTA complex of the hLL2 mAb was completely stable to either DTPA or serum challenge for the duration of either experiment (equivalent to 3.3-4.5 half-lives of Y-90 radionuclide or >90% of possible Y-90 decays from an initial starting activity). Complexes of hLL2 that had been prepared using the DTPA-type chelates lost 3%-4% of initially bound Y-90 over the first few days and about 10%-15% over the duration of the challenges. In vivo, these stability differences manifested as significantly lower yttrium uptake in bone and cortical bone over a 10-d period when DOTA was used as the yttrium chelating agent. Absorbed doses per 37 MBq (1 mCi) of Y-90-mAb were 3,555 and 5,405 cGy for bone and 2,664 and 4,524 cGy for washed bone for Y-90-DOTA-hLL2 and 90Y-lVlxDTPA-hLL2, respectively, amounting to 52.0% and 69.8% increases in absorbed radiation doses for bone and washed bone, respectively, when a DOTA chelate was switched to a Mx-DTPA chelate. Conclusion: Y-90-hLL2 prepared with the DOTA chelate represents an improved agent for radioimmunotherapy of nonHodgkin's lymphoma, with an in vivo model demonstrating a large reduction in bone-deposited yttrium, compared with (90)YhLL2 agents prepared with open-chain DTPA-type chelating agents. Dosimetry suggests that this benefit will result in a substantial toxicologic advantage for a DOTA-based hLL2 conjugate.

Pretargeted radioimmunotherapy (PRIT) was investigated in patients with non-Hodgkin's lymphoma (NHL). The PRIT approach used in this study is a multi-step delivery system in which an antibody is used to target streptavidin to a tumor associated antigen receptor, and subsequently biotin is then used to target 90Y radioisotope to the tumor localized streptavidin. A chimeric, IgG1, anti-CD20 antibody, designated C2B8 or Rituximab, was conjugated to streptavidin (SA) and administered to patients with NHL. Thirty-four hours later, a clearing agent, synthetic biotin-N-acetyl-galactosamine, was administered to remove non-localized conjugate from the circulation. Finally, a DOTA-biotin ligand, labeled with 111In for imaging and/or 90Y for therapy was administered. Ten patients with relapsed or refractory NHL were studied. In three patients, the C2B8/SA conjugate was radiolabeled with a trace amount of 186Re in order to assess pharmacokinetics and biodistribution using gamma camera imaging. Seven patients received 30 or 50 mCi/m2 90Y DOTA-biotin. Re-186 C2B8/SA images confirmed that the conjugate localized to known tumor sites and that the clearing agent removed > 95% of the conjugate from the circulation. Radiolabeled biotin localized well to tumor. Unbound radiobiotin was rapidly excreted from the whole body and normal organs. The mean tumor dose calculated was 29 +/- 23 cGy/mCi 90Y and the average whole body dose was 0.76 +/- 0.3 cGy/mCi 90Y, resulting in a mean tumor to whole body dose ratio of 38:1. Only grade I/II non-hematologic toxicity was observed. Hematologic toxicity was also not severe; i.e., five of the seven patients who received 30 or 50 mCi/m2 of 90Y-DOTA-biotin experienced only transient grade III (but no grade IV) hematologic toxicity. Although six of ten patients developed humoral immune responses to the streptavidin, these were delayed and transient and hence may not preclude retreatment. Six of seven patients who received 30 or 50mCi/m2 90Y achieved objective tumor regression, including three complete and one partial response. The estimate of tumor to whole body dose ratio (38:1) achieved with PRIT in these NHL patients is higher than has been achieved in other studies using conventional RIT. Toxicity was mild and tumor response encouraging. PRIT clearly deserves additional study in patients with NHL.

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 (131I)–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 131I-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 of131I 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 of131I-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.

UNLABELLED:Pretargeted radioimmunotherapy permits the administration of doses of 90Y five times higher than is possible with antibodies directly labeled with 90Yttrium (90Y). These high doses of 90Y introduced new issues for dosimetry that were not encountered in prior studies using conventional radioimmunotherapy. We have addressed these issues here and correlated dosimetry estimates with observed toxicity and tumor responses.METHODS:The pretargeted radioimmunotherapy (PRIT) system employed the antibody NR-LU-10 conjugated with streptavidin, a glycoprotein clearing agent and 90Y-DOTA-biotin. A single dose of 90Y was escalated to 140 mCi/m2. Indium-111(111In) (3-5 mCi) DOTA-biotin was co-injected for gamma camera imaging and dosimetry assessment. The effect of bremsstrahlung radiation from increasing 90Y activity levels with a constant dose of 111In was studied using a phantom. Patient images identified the intestinal tract and the kidneys as potential organs at risk of clinically significant radiation toxicity. A method of measuring the activity localized in the intestinal tract was developed, and S values were calculated to estimate intestinal wall dose from radioactivity present in the intestine. Intestinal, bone marrow and renal toxicity were observed. Coefficients were derived for correlating the relationships between observed intestinal and marrow toxicity and the estimated radiation absorbed doses.RESULTS:At an 90Y:111In ratio of 50:1, bremsstrahlung radiation accounted for 12% of the counts in the images. Grade IV diarrhea was observed in patients estimated to have received 6850-14,000 cGy to the large intestinal wall. The correlation coefficient of intestinal toxicity with absorbed dose was 0.64. Myelotoxicity (measured as grade of suppression of absolute neutrophil count) correlated better with marrow dose (r = 0.72) than with the whole body dose, (r = 0.44). Delayed renal toxicity was observed in two patients 8 and 11 months following therapy. Tumor response was seen in the two patients with the highest estimated dose to tumor, 4,000-6,000 cGy.CONCLUSION:Dosimetry is feasible using 111In as a tracer in the presence of high 90Y activity. The absorbed dose estimates derived in the PRIT schema correlated moderately well with clinically observed toxicity and response.

UNLABELLED:Estimates of radiation absorbed dose to the red marrow (RM) would be valuable in treatment planning for radioimmunotherapy if they could show a correlation with clinical toxicity. In this study, a correlation analysis was performed to determine whether estimates of radiation absorbed dose to the bone marrow could accurately predict marrow toxicity in patients who had received 186Re-labeled monoclonal antibody.METHODS:White blood cell and platelet count data from 25 patients who received 186Re-NR-LU-10 during Phase I radioimmunotherapy trials were analyzed, and the toxicity grade, the fraction of the baseline counts at the nadir (percentage baseline) and the actual nadir were used as the indicators of marrow toxicity. Toxicity was correlated with various predictors of toxicity. These predictors included the absorbed dose to RM, the absorbed dose to whole body (WB) and the total radioactivity administered.RESULTS:Percentage baseline and grade of white blood cells and platelets all showed a moderate correlation with absorbed dose and radioactivity administered (normalized for body size). The percentage baseline platelet count was the indicator of toxicity that achieved the highest correlation with the various predictors of toxicity (r = 0.73-0.79). The estimated RM absorbed dose was not a better predictor of toxicity than either the WB dose or the total radioactivity administered. There was substantial variation in the blood count response of the patients who were administered similar radioactivity doses and who had similar absorbed dose estimates.CONCLUSION:Although there was a moderately good correlation of toxicity with dose, the value of the dose estimates in predicting toxicity is limited by the patient-to-patient variability in response to internally administered radioactivity. In this analysis of patients receiving 186Re-labeled monoclonal antibody, a moderate correlation of toxicity with dose was observed but marrow dose was of limited use in predicting toxicity for individual patients.

PURPOSE Radioimmunotherapy (RIT) is a promising treatment approach for B-cell lymphomas. This is our first opportunity to report long-term follow-up data and late toxicities in 29 patients treated with myeloablative doses of iodine-131-anti-CD20 antibody (anti-B1) and autologous stem-cell rescue. PATIENTS AND METHODS Trace-labeled biodistribution studies first determined the ability to deliver higher absorbed radiation doses to tumor sites than to lung, liver, or kidney at varying amounts of anti-B1 protein (0.35, 1.7, or 7 mg/kg). Twenty-nine patients received therapeutic infusions of single-agent (131)I-anti-B1, given at the protein dose found optimal in the biodistribution study, labeled with amounts of (131)I (280 to 785 mCi [10.4 to 29.0 GBq]) calculated to deliver specific absorbed radiation doses to the normal organs, followed by autologous stem-cell support. RESULTS Major responses occurred in 25 patients (86%), with 23 complete responses (CRs; 79%). The nonhematopoietic dose-limiting toxicity was reversible cardiopulmonary insufficiency, which occurred in two patients at RIT doses that delivered > or = 27 Gy to the lungs. With a median follow-up time of 42 months, the estimated overall and progression-free survival rates are 68% and 42%, respectively. Currently, 14 of 29 patients remain in unmaintained remissions that range from 27+ to 87+ months after RIT. Late toxicities have been uncommon except for elevated thyroid-stimulating hormone (TSH) levels found in approximately 60% of the subjects. Two patients developed second malignancies, but none have developed myelodysplasia (MDS). CONCLUSION Myeloablative (131)I-anti-B1 RIT is relatively well tolerated when given with autologous stem-cell support and often results in prolonged remission durations with few late toxicities.

To optimize the efficacy of radioimmunotherapy (RIT), the ideal antibody-radioisotope combinations should be used to deliver the highest tumor and the lowest normal tissue doses. In a mouse model, tumor and critical organ-absorbed doses delivered by different radioimmunoconjugates were calculated and compared. We used a Medical Internal Radiation Dosimetry (MIRD)-style mouse dosimetry model that incorporates cross-organ beta doses to make refined estimates of the radiation absorbed dose to tissues. Biodistribution data from neuroblastoma xenografted nude mice were used to estimate tumor, organ and bone marrow absorbed dose values for 90Y-3F8, 131I-3F8 and 131I-F(ab′)2 fragments. Immunoreactive fractions of the radiolabeled antibodies were comparable. Although tumor uptake of the radioiodinated and radiometal labeled 3F8 was much higher than that of the radioiodinated F(ab′)2 fragments (maximum percent injected dose per gram values were 39.4, 33.2 and 20.1 for 131I-3F8, 90Y-3F8 and 131I-F(ab′)2, respectively), tumor to nontumor ratios were higher for radioiodinated fragments (with the exception of tumor to kidney ratio). For the minimum tumor dose necessary for complete ablation, the bone marrow received 195, 278 and 401 cGy for 131I-F(ab′)2, 131I-3F8 and 90Y-3F8, respectively. Tumor doses were 50.1, 232 and 992 cGy/MBq for 131I-F(ab′)2, 131I-3F8 and 90Y-3F8, respectively. Tumor to bone marrow dose, which is defined as the therapeutic index, was 21.5, 14.7 and 10.4 for 131I-F(ab′)2, 131I-3F8 and 90Y-3F8. 131I-F(ab′)2 fragments produced the highest therapeutic index but also the lowest tumor dose for radioimmunotherapy. Radiometal conjugated IgG produced the highest tumor dose but also the lowest therapeutic index.