131I-tositumomab therapy as initial treatment for follicular lymphoma.

BACKGROUND: Advanced-stage follicular B-cell lymphoma is considered incurable. Anti-CD20 radioimmunotherapy is effective in patients who have had a relapse after chemotherapy or who have refractory follicular lymphoma, but it has not been tested in previously untreated patients. METHODS: Seventy-six patients with stage III or IV follicular lymphoma received as initial therapy a single course of treatment with 131I-tositumomab therapy (registered as Tositumomab and Iodine I 131 Tositumomab [the Bexxar therapeutic regimen]). This consisted of a dosimetric dose of tositumomab and 131I-labeled tositumomab followed one week later by a therapeutic dose, delivering 75 cGy of radiation to the total body. RESULTS: Ninety-five percent of the patients had any response, and 75 percent had a complete response. The use of polymerase chain reaction (PCR) to detect rearrangement of the BCL2 gene showed molecular responses in 80 percent of assessable patients who had a clinical complete response. After a median follow-up of 5.1 years, the actuarial 5-year progression-free survival for all patients was 59 percent, with a median progression-free survival of 6.1 years. The annualized rate of relapse progressively decreased over time: 25 percent, 13 percent, and 12 percent during the first, second, and third years, respectively, and 4.4 percent per year after three years. Of 57 patients who had a complete response, 40 remained in remission for 4.3 to 7.7 years. Hematologic toxicity was moderate, with no patient requiring transfusions or hematopoietic growth factors. No cases of myelodysplastic syndrome have been observed. CONCLUSIONS: A single one-week course of 131I-tositumomab therapy as initial treatment can induce prolonged clinical and molecular remissions in patients with advanced follicular lymphoma.

A Phase 1 dose-escalation trial of glufosfamide in combination with gemcitabine in solid tumors including pancreatic adenocarcinoma.

PURPOSE: To evaluate safety and pharmacokinetics and to establish the maximum tolerated dose of glufosfamide when administered in combination with gemcitabine in advanced solid tumors. METHODS: This Phase 1 dose-escalation study evaluated the combination of glufosfamide + gemcitabine in patients with advanced solid tumors. Cohorts of three to six patients were treated with glufosfamide doses from 1,500 to 4,500 mg/m(2) i.v. over 4 h on Day 1 and gemcitabine 1,000 mg/m(2) i.v. over 30 min on Days 1, 8 and 15 of every 28-day cycle. Detailed PK sampling was performed on days 1 and 8 of the first two cycles. RESULTS: Nineteen patients were enrolled. Two patients had dose-limiting toxicity: Grade 3 fatigue at 2,500 mg/m(2) and Grade 4 thrombocytopenia at 4,500 mg/m(2). Five patients completed six cycles and one patient remained on study for ten cycles. Two patients discontinued for adverse events. Grade 3/4 neutropenia and thrombocytopenia occurred in seven patients and five patients, respectively. The CrCL fell below 60 mL/min in two patients. There was one unconfirmed partial response and 10 of 19 (52.6%) patients had stable disease or better at 8 weeks and three patients had continuing stable disease at 24 weeks. Pharmacokinetic analyses suggest no interaction between glufosfamide and gemcitabine. CONCLUSION: Phase I data indicate that full dose glufosfamide (4,500 mg/m(2)) can be given safely in combination with gemcitabine. A Phase II study in patients with pancreatic adenocarcinoma is ongoing.

Dose-attenuated radioimmunotherapy with tositumomab and iodine 131 tositumomab in patients with recurrent non-Hodgkin's lymphoma (NHL) and extensive bone marrow involvement.

Radioimmunotherapy (RIT) with tositumomab and iodine 131 tositumomab can produce durable and complete responses in relapsed/refractory low-grade Non-Hodgkin's lymphoma. Patients with bone marrow involvement (BMI) with tumor >25% of the intertrabecular space are generally excluded from RIT because of risk of excessive hematologic toxicity. The authors conducted a dose-escalation study of tositumomab and iodine 131 tositumomab to determine whether RIT is feasible in this population. Patients had baseline BMI of >25% and platelet count of >or=150,000/mm3. In contrast to the usual 75 cGy total body dose of radiation, dose escalation of Iodine I 131 tositumomab began at a total body dose of 45 cGy, and increased to 55 cGy in a second cohort. Dose-limiting toxicity (DLT) was defined as absolute neutrophil count <500 cells/mm3 or platelets <25,000/mm3 for >17 days, or absolute neutrophil count <750/mm3 or platelets <50,000/mm3 for >24 days. Eleven subjects were enrolled (8 at 45 cGy and 3 at 55 cGy). Estimated BMI ranged from 30 to 65% (median approximately 40%). Patients had received a median of three prior chemotherapies (range 1 - 6). One of the six evaluable patients treated at 45 cGy experienced DLT. Three patients received 55 cGy, one had hematologic DLT concurrent with lymphoma progression and extensive BMI at relapse. Three of 11 (27%) patients received hematologic supportive care. Two patients had objective responses of 1 and 42.4+ months, respectively. RIT with attenuated dose iodine 131 tositumomab for patients with >25% BMI has acceptable toxicity and can result in lymphoma responses.

Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab.

PURPOSE: To determine overall response (OR) and complete response (CR) rates, response duration, progression-free (PFS) and overall survival and safety with the tositumomab and iodine-131 tositumomab ((131)I tositumomab) therapeutic regimen in patients with indolent, follicular large-cell, or transformed B-cell lymphoma, progressive after rituximab. PATIENTS AND METHODS: From July 1998 to November 1999, 40 patients (24 rituximab nonresponders: 11 with response < 6 months, and five with response > or = 6 months) received a therapeutic dose (0.65 to 0.75 Gy per platelet count) of (131)I tositumomab based on total-body dosimetry in this prospective phase II study. The median number of prior treatments was four; 59% of patients were chemotherapy-resistant. RESULTS: Confirmed OR (65%) and CR (38%) rates were not significantly associated with prior rituximab response. With a median follow-up of 3.3 years, the median PFS was 10.4 months, 24.5 months for responders, and not reached for CR patients. Among follicular grade 1 or 2 patients with tumors < or = 7 cm (n = 21), the OR and CR rates were 86% and 57%. Estimated 3-year PFS in this subgroup was 48%, compared with 11% for all others (P = .002). Transient grade 3 to 4 marrow toxicity was seen in 50% of patients. Two patients, one of whom received two subsequent chemotherapy regimens, developed secondary myelodysplasia. CONCLUSION: (131)I tositumomab is effective in CD20-positive lymphoma progressive after rituximab, with a 65% OR rate and median PFS of 24.5 months for responders. Patients with follicular grade 1 or 2 histology and tumors < or = 7 cm achieved very high OR and CR rates, with 48% PFS at 3 years.

Re-treatment with I-131 tositumomab in patients with non-Hodgkin's lymphoma who had previously responded to I-131 tositumomab.

PURPOSE: To study efficacy and safety of re-treatment with I-131 tositumomab in patients with low-grade, follicular, or transformed low-grade B-cell lymphoma who relapsed following a response to I-131 tositumomab. PATIENTS AND METHODS: A prior response > or = 3 months to I-131 tositumomab was required. The single therapeutic dose following a dosimetric dose was adjusted to give the same total body dose (in Gy) as that used for the original dose, or was attenuated if the platelet count was less than 150,000 per mm(3) or if the prior treatment resulted in grade 4 cytopenias lasting longer than 7 days. RESULTS: Of 32 patients enrolled, 28 completed the therapeutic dose. A median of four therapies were given before re-treatment. Eighteen (56%) of 32 patients had a complete or partial response (median duration, 15.2 months); eight (25%) had a complete response (median duration, 35 months). Five continue in response from 1.8 to 5.7 years, with a median follow-up of 35 months. The overall median response duration was not significantly different for the two treatments, with no clinical factors predicting response or its duration. Ten of 18 re-responders had longer responses with re-treatment, with five having responses > or = 1.5 years longer. Grade 3/4 neutropenia and thrombocytopenia occurred in 50% and 43% of patients, respectively, similar to initial treatment. Antimouse antibodies developed in 10% of patients, and 12% developed elevated serum thyroid-stimulating hormone. Six patients were diagnosed with second malignancies, including four patients who developed myelodysplastic syndrome (one who had not received the therapeutic dose) and one with acute myelogenous leukemia. CONCLUSION: Re-treatment with I-131 tositumomab following a previous response can produce second responses that can be durable.

Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas.

PURPOSE: This study is an integrated efficacy analysis of the five clinical trials of tositumomab and iodine-131 tositumomab in patients with relapsed or refractory low-grade, follicular, or transformed low-grade non-Hodgkin's lymphoma (NHL) that resulted in the regulatory approval of the iodine-131 tositumomab by the US Food and Drug Administration. PATIENTS AND METHODS: This integrated analysis included 250 patients. Patients received a single course of iodine-131 tositumomab. Responses were assessed by an independent panel of radiologists and oncologists. RESULTS: Response rates in the five trials ranged from 47% to 68%; complete response rates ranged from 20% to 38%. With a median follow-up of 5.3 years, the 5-year progression-free survival was 17%. Eighty-one (32%) of 250 patients had a time to progression of > or = 1 year (termed durable response population). For the durable response population, 44% had not progressed at > or = 2.5 to > or = 9.5 years and had a median duration of response of 45.8 months. The median duration of complete response was not reached. The durable response population had many poor prognostic characteristics, including bone marrow involvement (41%), bulky disease > or = 5 cm (49%), and transformed histology (23%). Forty-three percent of the patients had been treated with more than four prior therapies and 36% had not responded to their most recent therapy. CONCLUSION: The tositumomab and iodine-131 tositumomab therapeutic regimen produces high response rates in patients with relapsed or refractory low-grade, follicular, and transformed low-grade NHL, with a sizable subgroup of patients achieving long-term durable responses.

Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma.

PURPOSE: To evaluate the safety and efficacy of a sequential chemotherapy plus radioimmunotherapy (RIT) regimen in previously untreated follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS: Thirty-five patients received an abbreviated course (three cycles) of fludarabine followed 6 to 8 weeks later by tositumomab and iodine I 131 tositumomab. RESULTS: After fludarabine, 31 (89%) of 35 patients responded, with three (9%) of 31 patients achieving a complete response (CR). After the full regimen of fludarabine and iodine I 131 tositumomab, all 35 patients responded; 30 (86%) of 35 patients achieved CR, and five (14%) of 35 achieved partial response. After a median follow-up of 58 months, the median progression-free survival (PFS) had not been reached (95% CI, 27 months to not reached), but it will be at least 48 months. The 5-year estimated PFS rate is 60%. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) was significantly associated (P = .003) with PFS. Five of six patients with more than 25% bone marrow involvement at baseline achieved adequate bone marrow cytoreduction to receive standard-dose iodine I 131 tositumomab. Ten (77%) of 13 patients with baseline bone marrow Bcl-2 positivity demonstrated molecular remissions at month 12. Toxicities were manageable and principally hematologic. Two (6%) of 35 patients developed human antimurine antibodies (HAMA) after RIT. CONCLUSION: Use of abbreviated fludarabine before iodine I 131 tositumomab can reduce bone marrow involvement, when needed, to allow the use of RIT and can suppress HAMA responses. This sequential treatment regimen is highly effective as front-line therapy for follicular lymphoma, particularly for low- or intermediate-risk FLIPI patients.

Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients.

PURPOSE: Standard therapies for non-Hodgkin's lymphoma (NHL) are associated with an increased risk of developing treatment-related myelodysplastic syndrome or acute myelogenous leukemia (tMDS/AML). However, there is considerable debate over the incidence or risk of tMDS/AML in NHL patients treated with any particular modality and the factors that contribute to malignant transformation. DESIGN: Conclusions were based on thorough analysis of data reported in the peer-reviewed literature and careful examination of the statistical methodology and methods for identifying cases of tMDS/AML. Unless noted, data are reported only for NHL patients, excluding Hodgkin's disease patients. RESULTS: Despite differences in methods used to identify cases and to estimate the cumulative incidence over time (actuarial v cumulative calculations), up to 10% of NHL patients treated with either conventional-dose chemotherapy or high-dose therapy and autologous stem-cell transplantation may develop tMDS/AML within 10 years of primary therapy. Kaplan-Meier estimates of the actuarial incidence, which are based on censoring of patients who died without developing tMDS/AML, can lead to artificially high estimates with large confidence intervals at later time points. Although there is much debate about the cause(s) of tMDS/AML, there is compelling evidence that alkylating agents, certain other leukemogenic agents, and total-body irradiation (TBI) cause chromosomal damage that can lead to tMDS/AML. CONCLUSION: Limiting exposure to alkylating agents and eliminating TBI from transplantation conditioning regimens may reduce the relative risk of tMDS/AML.

The radioisotope contributes significantly to the activity of radioimmunotherapy.

PURPOSE: A multicenter, randomized study was undertaken to estimate the single agent activity of Tositumomab and to determine the contribution of radioisotope-labeling with (131)I to activity and toxicity by comparing treatment outcomes for Tositumomab and Iodine I 131 Tositumomab (BEXXAR) to an equivalent total dose of unlabeled Tositumomab. EXPERIMENTAL DESIGN: Seventy-eight patients with refractory/relapsed non-Hodgkin's lymphoma were randomized to either unlabeled Tositumomab or Iodine I 131 Tositumomab. Patients progressing after unlabeled Tositumomab could cross over to receive Iodine I 131 Tositumomab. The median follow-up at analysis was 42.6 months (range 1.9 to 71.5 months). RESULTS: Responses in the Iodine I 131 Tositumomab versus unlabeled Tositumomab groups: overall response 55% versus 19% (P = 0.002); complete response 33% versus 8% (P = 0.012); median duration of overall response not reached versus 28.1 months (95% confidence interval: 7.6, not reached); median duration of complete response not reached in either arm; and median TTP 6.3 versus 5.5 months (P = 0.031), respectively. Of the patients who had a complete response after initial Iodine I 131 Tositumomab therapy, 71% (10 of 14) continued in complete response at 29.8 to 71.1 months. Two patients who achieved a complete response after unlabeled Tositumomab had ongoing responses at 48.1 to 56.9 months. Nineteen patients received Iodine I 131 Tositumomab crossover therapy. Responses after crossover versus prior response to unlabeled Tositumomab were as follows: complete response rates of 42% versus 0% (P = 0.008); overall response 68% versus 16% (P = 0.002); median durations of overall response 12.6 versus 7.6 months (P = 0.001); and median TTP 12.4 versus 5.5 months (P = 0.01), respectively. Hematologic toxicity was more severe and nonhematologic adverse events were more frequent after Iodine I 131 Tositumomab than after Tositumomab alone. Elevated thyrotropin occurred in 5% of patients. Seroconversion to human antimurine antibody after Iodine I 131 Tositumomab, unlabeled Tositumomab, and Iodine I 131 Tositumomab-crossover was 27%, 19%, and 0%, respectively. CONCLUSIONS: Unlabeled Tositumomab showed single agent activity, but in this direct comparison, all of the therapeutic outcome measures were significantly enhanced by the conjugation of (131)I to Tositumomab.

A practical methodology for patient release after tositumomab and (131)I-tositumomab therapy.

UNLABELLED: A methodology was developed determining patient releasability after radioimmunotherapy with tositumomab and (131)I-tositumomab for the treatment of non-Hodgkin's lymphoma. METHODS: Dosimetry data were obtained and analyzed after 157 administrations of (131)I-tositumomab to 139 patients with relapsed or refractory non-Hodgkin's lymphoma. Tositumomab and (131)I-tositumomab therapy included dosimetric (low activity) and therapeutic (high activity) administrations. For each patient, the total-body residence time was calculated after the dosimetric administration from total-body counts obtained over 6 or 7 d and was then used to determine the appropriate therapeutic activity to deliver a specific total-body radiation dose. Patient dose rates at 1 m were measured immediately after the therapeutic infusion. Patient-specific calculations based on the measured total-body residence time and dose rate for (131)I-tositumomab were derived to determine the patient's maximum releasable dose rate at 1 m, estimated radiation dose to maximally exposed individuals, and the amount of time necessary to avoid close contact with others. RESULTS: The mean administered activity (+/-SD), determined by dosimetry studies for each patient before therapy, was 3,108 +/- 1,073 MBq (84 +/- 29 mCi) (range, 1,221 +/- 5,957 MBq [33--161 mCi]). Immediately after treatment, the mean measured dose rate (+/- SD) at 1 m was 0.109 +/- 0.032 mSv/h (10.9 +/- 3.2 mrem/h; range, 0.04--0.24 mSv/h [4--24 mrem/h]). The measured dose rates were 60% (range, 37%--90%; P < 0.0001) of the theoretic dose rates from a point source in air predicted using the dose equivalent rate per unit activity of (131)I (5.95 x 10(-5) mSv/MBq h [0.22 mrem/mCi h] at 1 m). The mean estimated radiation dose to the maximally exposed individual was 3.06 mSv (306 mrem) (range, 1.95--4.96 mSv [195--496 mrem]). On the basis of current regulatory patient-release criteria, all (131)I-tositumomab--treated patients were determined to be releasable by comparing the dose rate at 1 m with a predetermined maximum releasable dose rate. Detailed instructions were provided to limit family members' exposure. CONCLUSION: A methodology has been developed for the release of patients administered radioactive materials based on the new Nuclear Regulatory Commission regulations. This approach uses a patient-specific dose calculation based on the measured total-body residence time and dose rate. This analysis shows the feasibility of outpatient radioimmunotherapy with tositumomab and (131)I-tositumomab.

A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors.

PURPOSE: This phase I trial was initiated to evaluate the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of the glycolytic inhibitor, 2-deoxy-D-glucose (2DG) in combination with docetaxel, in patients with advanced solid tumors. METHODS: A modified accelerated titration design was used. 2DG was administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg and docetaxel was administered intravenously at 30 mg/m(2) for 3 of every 4 weeks beginning on day 1 of week 2. Following the completion of dose escalation, cohorts of patients were then treated with 2DG for 21 days or every day of each 4-week cycle for up to 12 cycles. RESULTS: Thirty-four patients were enrolled: 21 on every other week, 6 on a 21 of 28-day cycle and 7 on the continuous 2DG dosing schedule. There were no dose-limiting toxicities which met the MTD criteria. The most common adverse events were fatigue, sweating, dizziness and nausea mimicking the hypoglycemic symptoms expected from 2DG administration. Therefore, 63 mg/kg was selected as the clinically tolerable dose. The most significant adverse effects noted at 63-88 mg/kg doses were reversible hyperglycemia (100 %), gastrointestinal bleeding (6 %) and reversible grade 3 QTc prolongation (22 %). Eleven patients (32 %) had stable disease, 1 patient (3 %) partial response and 22 patients (66 %) progressive disease as their best response. There was no PK interaction between 2DG and docetaxel. CONCLUSION: The recommended dose of 2DG in combination with weekly docetaxel is 63 mg/kg/day with tolerable adverse effects.

A phase 2 trial of glufosfamide in combination with gemcitabine in chemotherapy-naive pancreatic adenocarcinoma.

OBJECTIVES: A dose-escalation study of glufosfamide plus gemcitabine showed that the combination could be administered safely at full doses. The purpose of this phase II study was to evaluate the safety and efficacy of this combination in chemotherapy-naive pancreatic adenocarcinoma. METHODS: Eligible patients had metastatic and/or locally advanced pancreatic adenocarcinoma, Karnofsky performance status >or=70, creatinine clearance (CrCL) >or=60 mL/min, and acceptable organ function. Patients received glufosfamide 4500 mg/m intravenous on day 1 and gemcitabine 1000 mg/m intravenous on Days 1, 8, and 15 of every 28-day cycle. The primary end point was response rate. RESULTS: Twenty-nine patients were enrolled; 14 male, median age 58 years. Twenty-three (79%) patients had distant metastases. Median cycles on treatment was 4 (range: 1-18+). Of 28, 5 (18%; 95% CI: 6%-37%) patients had a confirmed partial response (median duration: 8.4 months) and 1 had an unconfirmed partial response. Eleven patients (39%) had stable disease. Median progression-free survival was 3.7 months, median overall survival was 6 months, and 1-year survival was 32%. Grade 3/4 neutropenia occurred in 23 (79%) patients and grade 3/4 thrombocytopenia in 10 (34%) patients. The CrCL fell below 60 mL/min in 10 of 27 (37%) patients. Renal failure occurred in 4 patients. Decrease in CrCL was correlated with glufosfamide and isophosphoramide mustard pharmacokinetic area under the curve. CONCLUSIONS: The combination of glufosfamide plus gemcitabine is active in pancreatic cancer; however, hematologic and renal toxicity were pronounced. Alternative dosing of glufosfamide plus gemcitabine should be explored.

A randomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic adenocarcinoma previously treated with gemcitabine.

PURPOSE: There are currently no approved therapies for patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine. This Phase III trial evaluated the efficacy and safety of glufosfamide as compared with best supportive care (BSC) in this patient population. METHODS: Patients were randomised to glufosfamide plus BSC or to BSC alone with baseline performance status as a stratification factor. The primary end-point was overall survival. RESULTS: Three hundred and three patients were randomised: 148 to glufosfamide plus BSC and 155 to BSC alone. There was an 18% increase in overall survival for glufosfamide that was not statistically significant: hazard ratio (HR) 0.85 (95% confidence interval (CI) 0.66-1.08, p=0.19). Median survival was 105 (range 5-875) days for glufosfamide and 84 (range 2+ to 761) days for BSC. Grade 3/4 creatinine increase occurred in 6 patients on glufosfamide, including 4 with dosing errors. CONCLUSION: These results suggest low activity of glufosfamide in this very refractory patient population.

A randomized, blinded, parallel group, placebo controlled pilot study evaluating the effect of PVAC treatment in patients with diffuse systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a disorder characterized by progressive thickening of the skin; there is no effective therapy. PVAC, a potential therapeutic agent derived from delipidated, deglycolipidated Mycobacterium vaccae, has shown effects on cutaneous disease in animal models of SSc. We evaluated the safety and possible biologic effect of intradermal injections of PVAC in patients with diffuse SSc. METHODS: Eighteen patients enrolled in this double blind, placebo controlled, randomized, 24 week pilot study. All patients met criteria for diffuse SSc without evidence of significant renal dysfunction, pulmonary fibrosis, pulmonary hypertension, or congestive heart failure. Patients received 8 intradermal injections of 15 microg PVAC, 50 microg PVAC, or placebo at 3 week intervals. The primary efficacy endpoint was the change in Modified Rodnan Skin Score (MRSS) at Week 24. Each of the active drug arms was compared to placebo. RESULTS: Baseline demographic and disease characteristics were similar across the 3 treatment groups. The median age was 48 years and 14 of 18 (78%) patients were female. The regimens were well tolerated with no reported serious adverse events; however, grade 1 or 2 injection site reactions occurred in the majority of patients receiving PVAC. The MRSS improved by 20.6% in the 15 microg PVAC arm, while it worsened by 29.8% in the placebo arm and by 16.7% in the 50 microg arm. Change in physician and patient global assessments followed similar trends. CONCLUSION: In this pilot study, use of PVAC in patients with SSc appeared safe and was associated with a trend toward improved skin scores in the 15 microg treatment group. Additional evaluation of this therapeutic approach is warranted.

Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin lymphoma treated with tositumomab and iodine I131 tositumomab.

The incidence of treatment-related myelodysplastic syndromes and acute myeloid leukemia (tMDSs/tAML) after tositumomab and iodine I(131) tositumomab administration to previously treated and untreated patients with non-Hodgkin lymphoma (NHL) was evaluated. A total of 1071 patients were enrolled in 7 studies: 995 with relapsed/refractory low-grade NHL, +/- transformation (median, 3 prior regimens [range, 1-13 regimens]) and 76 patients with previously untreated low-grade follicular NHL. A single dose of iodine tositumomab and I(131) tositumomab was administered. For tMDS/tAML patients, baseline and posttherapy peripheral blood and marrow specimens were reviewed in a blinded fashion. Median follow-up was 6 years from diagnosis and 2 years from radioimmunotherapy (RIT) for previously treated patients, and 4.6 years from radioimmunotherapy for previously untreated patients. tMDS/tAML was reported in 35 (3.5%) of 995 patients (annualized incidence, 1.6%/y [95% confidence interval, 1.0%-2.0%/y]), and 52% of the tMDS/tAML diagnoses of tMDS/tAML were confirmed in a blinded review (annualized incidence of 1.1%/y [95% confidence interval, 0.7%-1.6%/y]). Of the 25 cases, 10 patients (40%) were diagnosed with tMDS/tAML prior to receiving radioimmunotherapy; 2 (8%) had no pathologic or clinical evidence to support such a diagnosis; and 13 (52%) were confirmed to have developed tMDS/tAML following RIT. This incidence is consistent with that expected on the basis of patients' prior chemotherapy for NHL. With a median follow-up approaching 5 years, no case of tMDS/tAML has been reported in any of the 76 patients receiving iodine I(131) tositumomab as their initial therapy (P = .011 compared with previously treated patients).

Late radiation failures after iodine 125 brachytherapy for uveal melanoma compared with charged-particle (proton or helium ion) therapy.

OBJECTIVE: To evaluate late (more than 5 years) radiation failures after uveal melanoma treatment. DESIGN: Comparison of three retrospective, interventional, partially randomized case series. PARTICIPANTS: Nine hundred ninety-six patients who were treated in several phase I, II, and III trials of uveal melanoma radiation. MAIN OUTCOME MEASURES: Follow-up period, treatment history, recurrence rates, type of recurrence, and mortality associated with late local recurrences. RESULTS: Eleven of 996 irradiated uveal melanoma patients experienced intraocular recurrence more than 5 years after radiation. All 11 of these patients were treated with iodine 125 ((125)I) brachytherapy. Late recurrences were detected between 5.5 to 15.3 years after treatment. These patients did not have either high-risk clinical parameters (thin, posterior tumors in proximity to the optic nerve) or radiation dosimetry characteristics (low dose-delivery radiation) associated with a known increased risk for tumor recurrence after radioactive plaques. The annualized incidence rate for regrowth was 1.9% per year between 5 and 15 years after (125)I brachytherapy. In contrast to charged particles, the risk of late recurrence after (125)I brachytherapy continued with increased follow-up. CONCLUSIONS: There was a significantly higher late recurrence rate with (125)I brachytherapy as compared with charged particle radiation. Although tumor enlargement 5 or more years after radiation can be the result of intratumor hemorrhage, in a patient treated with radioactive plaque, a late failure is a distinct possibility.

Volume reduction versus radiation dose for tumors in previously untreated lymphoma patients who received iodine-131 tositumomab therapy. Conjugate views compared with a hybrid method.

BACKGROUND: A Phase II study of previously untreated patients with malignant low grade follicular lymphoma given a combination of unlabeled tositumomab and tositumomab labeled with iodine-131 has recently been completed. The responses of these patients have been characterized, and for some of them tumor dosimetry during therapy has been estimated not only by pretherapy tracer conjugate views but also by a hybrid method. METHODS: Available patients were studied if they had had a pelvic or abdominal tumor evaluation by single photon emission computed tomography (SPECT) and achieved a partial response. A tumor outlined on the iodine-131 conjugate-view images was called a composite tumor. Its volume estimate came from multiple, not necessarily contiguous, regions of interest (ROI) on the pretherapy computed tomography (CT) scan. Its radiation dose was estimated from the weeklong series of pretherapy images and standard Medical Internal Radiation Dose methods. Computed tomography ROI were also grouped into smaller, contiguous volumes that defined individual tumors. Their radiation doses were estimated by the hybrid method. This method employed the activity measured for each individual tumor by a single intratherapy SPECT scan, as well as the tumor's volume, to individually normalize the composite time-activity curve as appropriate. The individual normalization factors then converted the composite radiation dose to radiation doses for individual tumors. Reduction in tumor volume was calculated for both composite and individual tumors at 12 weeks posttherapy. RESULTS: For 14 composite tumors in 10 patients, the median pretherapy volume was 170 cm(3). Application of a sigmoidal curve function to the plot of volume reduction versus radiation absorbed dose resulted in degeneration of the curve into a straight line with a negative slope. There was no statistical significance in the relationship (P = 0.73). For 43 individual tumors, the median pretherapy tumor volume was 26 cm(3). The plot of volume reduction versus dose was fairly well fit by a sigmoidal curve, and the relationship approached statistical significance (P = 0.06). The representation assigned 56% of the shrinkage to the effects of unlabeled tositumomab. For the subset of individual tumors with a pretherapy volume less than 10 cm(3) from 6 patients (n = 15), the relationship was significant (P = 0.03). The sigmoidal representation assigned only 12% of the shrinkage to unlabeled tositumomab, as contrasted with 72% for tumors with pretherapy volume greater than 10 cm(3). CONCLUSIONS: For patients who attained a partial response, analysis of individual tumors by a hybrid dosimetric method led to a dependence between volume reduction at 12 weeks and radiation dose that tended to be significant. The same was not true with dosimetry of composite tumors based on pretherapy conjugate views alone. It appeared that volume reductions from both unlabeled antibody and radiation dose were important in tositumomab therapy of lymphoma patients, with unlabeled antibody relatively more important for larger tumors.