A phase 1 trial of 90Y-Zevalin radioimmunotherapy with autologous stem cell transplant for multiple myeloma.

This phase 1 study (clinical trial NCT00477815) was conducted to determine the maximum tolerated dose (MTD) of yttrium-90 ibritumomab tiuxetan (90Y-Zevalin) with high dose melphalan (HDM) therapy in multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). In a 3+3 trial design, 30 patients received rituximab 250 mg/m2 with indium-111 ibritumomab tiuxetan (111In-Zevalin) for dosimetry (day -22); rituximab 250 mg/m2 with escalating doses of 90Y-Zevalin (day -14); melphalan 100 mg/m2 (days -2,-1) followed by ASCT (day 0) and sargramostim (GM-CSF, day 0) until neutrophil engraftment. Each patient's 111In-Zevalin dosimetry data were used to calculate the dose of 90Y-Zevalin (in mCi) to deliver 10, 12, 14, 16, 18 or 20 Gy to the liver. Dose limiting toxicities were seen in 3 patients. The overall response rate was 73% (22/30) with stringent complete response in 2 patients; complete response, 5; very good partial response, 12; and partial response, 3. The median PFS was 16.5 months and the median overall survival was 63.4 months. In MM, the MTD of 90Y-Zevalin with HDM is 18 Gy to the liver. The addition of radiation with novel delivery methods such as radioimmunotherapy combined with standard transplant regimens warrants further study.

Stable, Fluorescent Polymethylmethacrylate Particles for the Long-Term Observation of Slow Colloidal Dynamics.

Suspensions of solid micron-scale colloidal particles in liquid solvents are a foundational model system used to explore a wide range of phase transitions, including crystallization, gelation, spinodal decomposition, and the glass transition. One of the most commonly used systems for these investigations is the fluorescent spherical particles of polymethylmethacrylate (PMMA) suspended in a mixture of nonpolar solvents that match the density and the refractive index of the particles to minimize sedimentation and scattering. However, the particles can swell in these solvents, changing their size and density, and may leak the fluorescent dye over days to weeks; this constrains the exploration of slow and kinetically limited processes, such as near-boundary phase separation or the glass transition. In this paper, we produce PMMA colloidal particles that employ polymerizable and photostable cyanine-based fluorescent monomers spanning the range of visible wavelengths and a polymeric stabilizer prepared from polydimethylsiloxane, PDMS-graft-PMMA. Using microcalorimetry, we characterize the thermodynamics of an accelerated equilibration process for these dispersions in the buoyancy- and refractive-index-matching solvents. We use confocal differential dynamic microscopy to demonstrate that they behave as hard spheres. The suspended particles are stable for months to years, maintaining fixed particle size and density, and do not leak dye. Thus, these particles enable longer term experiments than may have been possible earlier; we demonstrate this by observing spinodal decomposition in a mixture of these particles with a depletant polymer in the microgravity environment of the International Space Station. Using fluorescence microscopy, we observe coarsening over several months and measure the growth of the characteristic length scale to be a fraction of a picometer per second; this rate is among the slowest observed in a phase-separating system. Our protocols should facilitate the synthesis of a variety of particles.

Maintaining stable symptom control in inflammatory bowel disease: a retrospective analysis of adherence, medication switches and the risk of relapse.

BACKGROUND: Maintenance therapy with 5-aminosalicylic acid (5-ASA) is a key strategy for preventing relapse in many patients with inflammatory bowel disease (IBD). Factors which disrupt 5-ASA delivery, such as non-adherence and 5-ASA switches, may destabilise symptom control. AIM: To investigate the impact of non-adherence and medication switches on stable symptom control in UK patients with IBD. METHODS: A retrospective cohort study was conducted using a UK dispensing database. Adherence was analysed in randomised matched samples for each of the six leading oral mesalazine formulations, measured by medication possession ratio (MPR); MPR ≥80% was classified as adherent. Relationships among adherence, switch and relapse were analysed over 18 months in patients receiving continuous mesalazine therapy throughout a 6-month baseline period (primary subgroup analysis). Relapses of active ulcerative colitis were identified using a doubling of MPR as a proxy. RESULTS: Only 39% of patients in the matched samples (n = 1200) were classed as adherent. No significant differences in adherence were observed among mesalazine formulations. In the primary subgroup analysis (n = 568), non-adherent patients had a significantly greater risk of relapse than adherent patients (RR = 1.44, 95% CI = 1.08-1.94; P = 0.014). Among adherent patients (n = 276), those who switched had a 3.5-fold greater risk of relapse than those who did not switch (95% CI = 1.16-10.62; P = 0.008). CONCLUSIONS: Both non-adherence and mesalazine switches in adherent patients were associated with significant increases in the risk of relapse, suggesting that disruption of mesalazine maintenance therapy may destabilise symptom control. These findings provide evidence to advocate caution when considering mesalazine switches for stable patients.

Virolysis of feline calicivirus and human GII.4 norovirus following chlorine exposure under standardized light soil disinfection conditions.

The relationship between the infectivity of the feline calicivirus (FCV) vaccine strain F-9 and capsid destruction (virolysis) in response to available chlorine was investigated under standardized light soil disinfection conditions. Virolysis was measured using RNase pretreatment (in order to destroy exposed RNA following chlorine treatment) and quantitative reverse transcription PCR. A comparison between the results of plaque assays and virolysis following exposure of FCV F-9 grown in tissue culture to different concentrations of available chlorine showed a similar log-linear relationship, with >4-log reductions occurring at 48 and 66 ppm, respectively. Three non-epidemiologically linked human GII.4 noroviruses (NoVs) present in dilute clinical samples showed behavior similar to each other and were 10 times more resistant to virolysis than cultured FCV F-9. FCV F-9 when present in dilute human GII.4 samples acquired increased resistance to virolysis approaching that of human NoVs. This study represents a direct comparison between the virolysis of a surrogate virus (FCV F-9) and that of human GII.4 NoVs within the same matrix in response to available chlorine. The results support the view that matrix effects have a significant effect on virus survival.

Metastatic malignant melanoma.

Metastatic malignant melanoma is an incurable malignancy with extremely poor prognosis. Patients bearing this diagnosis face a median survival time of approximately 9 months with a probability of surviving 5 years after initial presentation at less than 5%. This is contrasted by the curative nature of surgical resection of early melanoma detected in the skin. To date, no systemic therapy has consistently and predictably impacted the overall survival of patients with metastatic melanoma. However, in recent years, a resurgence of innovative diagnostic and therapeutic developments have broadened our understanding of the natural history of melanoma and identified rational therapeutic targets/strategies that seem poised to significantly change the clinical outcomes in these patients. Herein we review the state-of-the-art in metastatic melanoma diagnostics and therapeutics with particular emphasis on multi-disciplinary clinical management.

Positron emission tomography using F-18 fluorodeoxyglucose pre- and post-autologous stem cell transplant in non-Hodgkin's lymphoma.

Positron emission tomography (PET) utilizing fluorodeoxyglucose (FDG) has an ever-increasing role in the management of numerous malignancies. FDG PET in lymphoma is being incorporated into the response assessment in lymphoma as published by the Imaging Subcommittee of International Harmonization Project in Lymphoma. The exact role of FDG PET in non-Hodgkin's lymphoma (NHL) associated with autologous stem cell transplant (ASCT) is unclear. Numerous studies have identified pretransplant PET scans as being highly prognostic with regard to overall and PFS after ASCT. Many included a wide range of histologies, including Hodgkin's lymphoma and NHL. In studies with mixed histologies, PFS at 2 years has been improved by as much as 82% in patients with negative pre-ASCT PET scans. In studies incorporating only patients with NHL, improvements in failure-free survival have been reported as high as 43% for patients with negative pre-ASCT PET imaging. Limitations have included inclusion of many histologies, different reported time points, small retrospective studies and variation in the interpretation of a positive PET. Validation is ongoing in larger prospective trials. Future directions include the potential incorporation of post-ASCT therapy, such as radiation therapy or maintenance antibody therapy, for patients with positive pre-ASCT PET scans.

A phase I study of 153Sm-EDTMP with fixed high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma.

Despite response rates of 30% after high-dose chemotherapy with autologous hematopoietic stem cell transplant, patients with multiple myeloma are not cured. 153Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP; Quadramet) is a short-range, beta-emitting therapeutic radiopharmaceutical with avid skeletal uptake. In total, 12 patients were treated with escalating doses of 153Sm-EDTMP (N=3/group; 6, 12, 19.8, and 30 mCi/kg) and a fixed dose of melphalan (200 mg/m(2)). No dose limiting toxicity was seen. To better standardize the marrow compartment radiation dose, the study was modified such that an additional six patients were treated at a targeted absorbed radiation dose to the red marrow of 40 Gy based on a trace labeled infusion 1 week prior to the therapy. Despite rapid elimination of unbound radiopharmaceutical via kidneys and bladder, no episodes of nephrotoxicity, hemorrhagic cystitis, or delayed radiation nephritis were observed with a median follow-up of 31 months (range 8.5-44). Median times to ANC>0.5 and platelet >20 x 10(6)/l were 12 and 11 days, respectively, with no graft failures. Overall response rate was 94% including seven very good partial responses and five complete responses. Addition of 153Sm EDTMP to melphalan conditioning appears to be safe, well-tolerated and worthy of further study.

Systolic and diastolic cardiac dysfunction early after the initiation of doxorubicin therapy: significance of gender and concurrent mediastinal radiation.

Diastolic and systolic left ventricular (LV) function may be affected early after the initiation of doxorubicin therapy. However, the role of mediastinal radiation and other cytotoxic agents in the production of these early cardiac effects is unclear. In this study LV diastolic and systolic function were assessed before and after doxorubicin (223+/-122 mg.m-2; range, 40-618) in 33 patients. After doxorubicin, LV ejection fraction declined (0.61+/-0.08 to 0.56+/-0.08, P=0.0008), peak filling rate decreased (3.38+/-1.10 to 2.82+/-0.62 end diastolic volumes/s, P=0.006), and time to peak filling rate increased (162+/-39 to 182+/-45 ms, P=0.04). The changes in LV systolic and diastolic function were not related to doxorubicin dose and the use of other cytotoxic agents; the decrease in LV ejection fraction with doxorubicin was more notable in men and in patients who received mediastinal irradiation concurrently with doxorubicin. It is concluded that the use of doxorubicin was associated with the simultaneous early development of LV systolic and diastolic dysfunction. Male gender and concurrent mediastinal irradiation were independent influences, but doxorubicin dose and the use of other cytotoxic agents were not associated with worse cardiac dysfunction.

Successful treatment of POEMS syndrome with autologous hematopoietic progenitor cell transplantation.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) is a plasma cell dyscrasia that differs substantially from classic multiple myeloma. It is often associated with disabling polyneuropathy in younger patients. Current therapeutic approaches are frequently inadequate and leave many patients wheelchair-bound with significant deterioration in quality and length of life. We present the case of a young man with progressive disease despite conventional therapeutic approaches. We describe a novel approach to treatment with a bone-seeking radiopharmaceutical, samarium-153 ethylene diamine tetramethylene phosphonate ((153)Sm-EDTMP), followed by myeloablative chemotherapy with autologous hematopoietic progenitor cell reconstitution. This approach resulted in regression of the organomegaly and skin changes and in neurologic improvement both clinically and electrophysiologically. The patient progressed from being wheelchair-bound to independent ambulation. An aggressive approach should be considered in patients with POEMS syndrome in whom standard therapeutic measures fail.

Role of radiation dosimetry in radioimmunotherapy planning and treatment dosing.

Cancer-seeking antibodies (Abs) carrying radionuclides can be powerful drugs for delivering radiotherapy to cancer. As with all radiotherapy, undesired radiation dose to critical organs is the limiting factor. It has been proposed that optimization of radioimmunotherapy (RIT), that is, maximization of therapeutic efficacy and minimization of normal tissue toxicity, depends on a foreknowledge of the radiation dose distributions to be expected. The necessary data can be acquired by established tracer techniques, in individual patients, using quantitative radionuclide imaging. Object-oriented software systems for estimating internal emitter radiation doses to the tissues of individual patients (patient-specific radiation dosimetry), using computer modules, are available for RIT, as well as for other radionuclide therapies. There is general agreement that radiation dosimetry (radiation absorbed dose distribution, cGy) should be utilized to establish the safety of RIT with a specific radiolabeled Ab in the early stages (i.e. phase I or II) of drug evaluation. However, it is less well established that radiation dose should be used to determine the radionuclide dose (amount of radioactivity, GBq) to be administered to a specific patient (i.e. radiation dose-based therapy). Although treatment planning for individual patients based upon tracer radiation dosimetry is an attractive concept and opportunity, particularly for multimodality RIT with intent to cure, practical considerations may dictate simpler solutions under some circumstances.

Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma.

UNLABELLED: Radiation dosimetry studies were performed in patients with non-Hodgkin's lymphoma (NHL) treated with 90Y Zevalin (90yttrium ibritumomab tiuxetan, IDEC-Y2B8) on a Phase III open-label prospectively randomized multicenter trial. The trial was designed to evaluate the efficacy and safety of 90Y Zevalin radioimmunotherapy compared to rituximab (Rituxan, MabThera) immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed NHL. An important secondary objective was to determine if radiation dosimetry prior to 90Y Zevalin administration is required for safe treatment in this patient population. METHODS: Patients randomized into the Zevalin arm were given a tracer dose of 5 mCi (185 MBq) (111)In Zevalin (111indium ibritumomab tiuxetan) on Day 0, evaluated with dosimetry, and then administered a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90Y Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve Zevalin biodistribution. Following administration of (111)In Zevalin, serial anterior and posterior whole-body scans were acquired and blood samples were obtained. Residence times for 90Y were estimated for major organs, and the MIRDOSE3 computer software program was used to calculate organ-specific and total body radiation absorbed dose. Patients randomized into the rituximab arm received a standard course of rituximab immunotherapy (375 mg/m(2) weekly x 4). RESULTS: In a prospectively defined 90 patient interim analysis, the overall response rate was 80% for Zevalin vs. 44% for rituximab. For all patients with Zevalin dosimetry data (N=72), radiation absorbed doses were estimated to be below the protocol-defined upper limits of 300 cGy to red marrow and 2000 cGy to normal organs. The median estimated radiation absorbed doses were 71 cGy to red marrow (range: 18-221 cGy), 216 cGy to lungs (94-457 cGy), 532 cGy to liver (range: 234-1856 cGy), 848 cGy to spleen (range: 76-1902 cGy), 15 cGy to kidneys (0.27-76 cGy) and 1484 cGy to tumor (range: 61-24274 cGy). Toxicity was primarily hematologic, transient, and reversible. The severity of hematologic nadir did not correlate with estimates of effective half-life (half-life) or residence time of 90Y in blood, or radiation absorbed dose to the red marrow or total body. CONCLUSION: 90Y Zevalin administered to NHL patients at non-myeloablative maximum tolerated doses delivers acceptable radiation absorbed doses to uninvolved organs. Lack of correlation between dosimetric or pharmacokinetic parameters and the severity of hematologic nadir suggest that hematologic toxicity is more dependent on bone marrow reserve in this heavily pre-treated population. Based on these findings, it is safe to administer 90Y Zevalin in this defined patient population without pre-treatment (111)In-based radiation dosimetry.

Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO(2) response to 100% oxygen, and brain uptake after (99m)Tc MAA lung scanning.

BACKGROUND: Because of the spectrum of intrapulmonary vascular dilation that characterizes hepatopulmonary syndrome (HPS), PaO(2) while breathing 100% oxygen varies. Abnormal extrapulmonary uptake of (99m)Tc macroaggregated albumin (MAA) after lung perfusion is common. GOAL: To describe relationships between (1) severity of liver disease measured by the Child-Pugh (CP) classification; (2) PaO(2) while breathing room air (RA) and 100% oxygen on 100% oxygen; and (3) extrapulmonary (brain) uptake of (99m)Tc MAA after lung scanning. METHODS AND PATIENTS: We prospectively measured PaO(2) on RA, PaO(2) on 100% oxygen, and brain uptake after lung perfusion of (99m)Tc MAA in 25 consecutive HPS patients. RESULTS: Mean PaO(2) on RA, PaO(2) on 100% oxygen, PaCO(2) on RA, and (99m)Tc MAA brain uptake were similar when categorized by CP classification. Brain uptake was abnormal (> or = 6%) in 24 patients (96%). Brain uptake was 29 +/- 20% (mean +/- SD) and correlated inversely with PaO(2) on RA (r = -0.57; p<0.05) and PaO(2) on 100% oxygen (r = -0.41; p<0.05). Seven patients (28%) had additional nonvascular pulmonary abnormalities and lower PaO(2) on 100% oxygen (215+/-133 mm Hg vs 391+/-137 mm Hg; p<0.007). Eight patients (32%) died. Mortality in patients without coexistent pulmonary abnormalities was associated with greater brain uptake of (99m)Tc MAA (48+/-18% vs 25+/-20%; p<0.04) and lower PaO(2) on RA (40+/-7 mm Hg vs 57+/-11 mm Hg; p<0.001). CONCLUSION: The degree of hypoxemia associated with HPS was not related to the CP severity of liver disease. HPS patients with additional nonvascular pulmonary abnormalities exhibited lower PaO(2) on 100% oxygen. Mortality was associated with lower PaO(2) on RA, and with greater brain uptake of (99m)Tc MAA.

Are posttherapy radioiodine scans informative and do they influence subsequent therapy of patients with differentiated thyroid cancer?

UNLABELLED: Posttherapy scans (PTS) with a gamma camera are typically used after therapeutic doses of 131I to visualize metastases that may not be seen with lower dose diagnostic scans. During a 16-month period, we studied 81 patients (64 with papillary thyroid cancer and 17 with follicular thyroid cancer), who had both a diagnostic whole-body scan (131I dose 3 mCi) and a PTS. A total of 117 PTS were evaluated. At the time of PTS, clinical or radiologic evidence of metastatic or residual disease was present in 68 patients (84%). The anatomic sites of known disease included, neck (63), mediastinum (23), lung (35), bone (14), trachea (16), esophagus (5), and brain (2). PTS showed focal areas of abnormal uptake not seen in diagnostic scans in 15 scans (13%). Areas with abnormal new uptake included: neck (5), lung (5), mediastinum (4), bone (2), and adrenal (1). In 7 patients (9%) the PTS results impacted future decisions regarding plans for subsequent diagnostic scanning and 131I therapy or changed the patient's risk group category. IN CONCLUSION: (1) 13% of 117 PTS demonstrated abnormal foci of 131I uptake not seen on pretherapy scans and (2) PTS changed management strategy in 9% of the studied patients.

Phase I/II 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin's lymphoma.

Dosimetry studies in patients with non-Hodgkin's lymphoma were performed to estimate the radiation absorbed dose to normal organs and bone marrow from 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) treatment in this phase I/II, multicenter trial. The trial was designed to determine the dose of Rituximab (chimeric anti-CD20, Rituxan, IDEC-C2B8, MabThera), the unlabeled antibody given prior to the radioconjugate to clear peripheral blood B cells and optimize distribution, and to determine the maximum tolerated dose of 90Y-Zevalin [7.4, 11, or 15 MBq/kg (0.2, 0.3, or 0.4 mCi/kg)]. Patients received (111)In-Zevalin (indium-111 ibritumomab tiuxetan, IDEC-In2B8 ) on day 0 followed by a therapeutic dose of 90Y-Zevalin on day 7. Both doses were preceded by an infusion of the chimeric, unlabeled antibody Rituximab. Following administration of (111)In-Zevalin, serial anterior/posterior whole-body scans were acquired. Major-organ radioactivity versus time estimates were calculated using regions of interest. Residence times were computed and entered into the MIRDOSE3 computer software program to calculate estimated radiation absorbed dose to each organ. Initial analyses of estimated radiation absorbed dose were completed at the clinical site. An additional, centralized dosimetry analysis was performed subsequently to provide a consistent analysis of data collected from the seven clinical sites. In all patients with dosimetry data (n=56), normal organ and red marrow radiation absorbed doses were estimated to be well under the protocol-defined upper limit of 20 Gy and 3 Gy, respectively. Median estimated radiation absorbed dose was 3.4 Gy to liver (range 1.2-7.8 Gy), 2.6 Gy to lungs (range 0.72-4.4 Gy), and 0.38 Gy to kidneys (range 0.07-0.61 Gy). Median estimated tumor radiation absorbed dose was 17 Gy (range 5.8-67 Gy). No correlation was noted between hematologic toxicity and the following variables: red marrow radiation absorbed dose, blood T(1/2), blood AUC, plasma T(1/2), and plasma AUC. It is concluded that 90Y-Zevalin administered at nonmyeloablative maximum tolerated doses results in acceptable radiation absorbed doses to normal organs. The only toxicity of note is hematologic and is not correlated to red marrow radiation absorbed dose estimates or T(1/2), reflecting that hematologic toxicity is dependent on bone marrow reserve in this heavily pretreated population.

Evaluation of macroaggregated albumin particle sizes for use in pulmonary shunt patient studies.

OBJECTIVE: To assess commercial macroaggregated albumin (MAA) reagent kits for compliance with particle-size parameters needed for proper clinical evaluation of pulmonary shunts (right-to-left). DESIGN: Comparative trial. SETTING: Nuclear pharmacy (laboratory setting). PATIENTS AND OTHER PARTICIPANTS: Not applicable. INTERVENTIONS: Minimally, 90% of the particles contained within an MAA reagent kit should be within the 10 to 90 microns range with minimal variation in particle size distribution and as few small particles (i.e., < 10 microns) as possible. Five separate vials from five commercial brands of MAA reagent kits were obtained, and 500 to 517 particles were analyzed for each sample. An additional study was performed on one of the MAA reagent kit brands, using five vials from each of five different lot numbers to determine the variability between lots. MAIN OUTCOME MEASURES: Long axis (maximum, micron), short axis (minimum, micron), and the area (micron 2) of each MAA particle. RESULTS: One MAA brand had the lowest percentage of unacceptable MAA particle sizes and maintained consistent particle sizes between vials. However, the same MAA reagent kit brand showed that only two of five lots had a low percentage of MAA particle sizes below the 10-micron limit. CONCLUSION: Particle sizes varied among the five different brands of MAA reagent kits, as did different lots of the best-performing kit. This variability in particle sizes may affect the accuracy and reproducibility of pulmonary shunt patient studies.

Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma.

PURPOSE: Yttrium-90 ibritumomab tiuxetan (IDEC-Y2B8) is a murine immunoglobulin G1 kappa monoclonal antibody that covalently binds MX-DTPA (tiuxetan), which chelates the radioisotope yttrium-90. The antibody targets CD20, a B-lymphocyte antigen. A multicenter phase I/II trial was conducted to compare two doses of unlabeled rituximab given before radiolabeled antibody, to determine the maximum-tolerated single dose of IDEC-Y2B8 that could be administered without stem-cell support, and to evaluate safety and efficacy. PATIENTS AND METHODS: Eligible patients had relapsed or refractory (two prior regimens or anthracycline if low-grade disease) CD20(+) B-cell low-grade, intermediate-grade, or mantle-cell non-Hodgkin's lymphoma (NHL). There was no limit on bulky disease, and 59% had at least one mass > or = 5 cm. RESULTS: The maximum-tolerated dose was 0.4 mCi/kg IDEC-Y2B8 (0.3 mCi/kg for patients with baseline platelet counts 100 to 149,000/microL). The overall response rate for the intent-to-treat population (n = 51) was 67% (26% complete response [CR]; 41% partial response [PR]); for low-grade disease (n = 34), 82% (26% CR; 56% PR); for intermediate-grade disease (n = 14), 43%; and for mantle-cell disease (n = 3), 0%. Responses occurred in patients with bulky disease (> or = 7 cm; 41%) and splenomegaly (50%). Kaplan-Meier estimate of time to disease progression in responders and duration of response is 12.9+ months and 11.7+ months, respectively. Adverse events were primarily hematologic and correlated with baseline extent of marrow involvement with NHL and baseline platelet count. One patient (2%) developed an anti-antibody response (human antichimeric antibody/human antimouse antibody). CONCLUSION: These phase I/II data demonstrate that IDEC-Y2B8 radioimmunotherapy is a safe and effective alternative for outpatient therapy of patients with relapsed or refractory NHL. A phase III study is ongoing.

Radioimmunotherapy of relapsed non-Hodgkin's lymphoma with zevalin, a 90Y-labeled anti-CD20 monoclonal antibody.

Approximately 55,400 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed each year, with the overall prevalence of the disease now estimated to be 243,000. Until recently, treatment alternatives for advanced disease included chemotherapy with or without external beam radiation. Based on the results of several clinical trials, the chimeric monoclonal antibody Rituximab has now been approved by the United States Food and Drug Administration as a treatment for patients with relapsed or refractory, low-grade or follicular, B-cell NHL. Several other monoclonal antibodies in conjugated and unconjugated forms have been evaluated in the treatment of NHL. Ibritumomab, the murine counterpart to Rituximab, radiolabeled with 90Y (Zevalin), is presently being evaluated in clinical trials. The success of radioimmunotherapy is dependent upon the appropriate choice of antibody, isotope, and chelator-linker. The Ibritumomab antibody targets the CD20 antigen. The antibody is covalently bound to the chelator-linker tiuxetan (MX-DTPA), which tightly chelates the isotope 90Y. To date, two Phase I/II Zevalin clinical trials have been completed in patients with low-grade, intermediate-grade, and mantle cell NHL. The overall response rate was 64% in the first trial and 67% in the later trial. Phase II and III trials are ongoing.