Radioimmunotherapy Of non-Hodgkin Lymphoma Research Articles

Radioimmunotherapy of Non-Hodgkin B-cell Lymphoma: An update.

Systemic radioimmunotherapy (RIT) is arguably the most effective and least toxic anticancer treatment for non-Hodgkin lymphoma (NHL). In treatment-naïve patients with indolent NHL, the efficacy of a single injection of RIT compares with that of multiple cycles of combination chemotherapy. However, 20 years following the approval of the first CD20-targeting radioimmunoconjugates 90Y-Ibritumomab-tiuxetan (Zevalin) and 131I-tositumomab (Bexxar), the number of patients referred for RIT in western countries has dramatically decreased. Notwithstanding this, the development of RIT has continued. Therapeutic targets other than CD20 have been identified, new vector molecules have been produced allowing for faster delivery of RIT to the target, and innovative radionuclides with favorable physical characteristics such as alpha emitters have been more widely available. In this article, we reviewed the current status of RIT in NHL, with particular focus on recent clinical and preclinical developments.

Radioimmunotherapy in non-Hodgkin lymphoma: Prediction and assessment of response.

Non-Hodgkin lymphoma (NHL) is one of the most common malignancies and a major cause of morbidity and mortality. Radioimmunotherapy (RIT) is a novel modality for treating NHL which offers the combined use of monoclonal antibodies for specific targeting of malignant cells and radiation for killing these cells. Despite the promising results favoring RIT in several clinical studies in different target populations and NHL types, Food and Drug Administration (FDA) approval for RIT agents is restricted to a limited number of indications and agents, maybe because of several ambiguities that still exist in the field. One of these ambiguities are the lack of evidence-based prognostic factors that determine what patient population would benefit most from RIT, which is essential to know in order to optimize the efficacy and safety of treatment with RIT. As well as selecting the best patient population for RIT, it is important to assess the response to RIT in order to provide further treatment strategies or avoid unnecessary therapies and diagnostic procedures. In this review we have explored the details of how to predict the efficiency of RIT based on various prognostic factors that have been investigated in the evidence, and also discussed the proposed methods and timing schedules for assessing the response to RIT. We have also pointed out the ambiguities in the aforementioned topics, which call for more investigation.

Outpatient 131I-Rituximab Radioimmunotherapy for Non-Hodgkin Lymphoma

This study aimed to establish the safety of outpatient 131I-rituximab radioimmunotherapy by measuring the radiation exposure of hospital staff, carers, and members of the public and by estimating the environmental impact of radioactive urinary excretion. Two hundred consecutive outpatients treated with 131I-rituximab radioimmunotherapy of non-Hodgkin lymphoma (NHL) with therapeutic activities between 1 and 4.5 GBq (mean, 2.3 GBq; or between 27 and 121 mCi; mean, 62 mCi) predicated on a prescribed whole-body radiation-absorbed dose of 0.75 Gy were studied. Their 279 family members/carers and 432 visitors wore thermoluminescent dosimeter badges for the week during which the patients were confined to their home after treatment. All 200 patients received 131I-rituximab activities according to the prescribed dose of 0.75 Gy to the whole body. From 200 consecutive patients, over the 7 days after therapy, mean radiation exposure of adult carers was 0.49 mSv (range, <0.01 to 3.67 mSv). To other coresiding family members, mean exposure was 0.23 mSv (range, <0.01 to 1.20 mSv), and for visitors sharing badges, the mean exposure was 0.17 mSv (range, <0.01 to 0.73 mSv). Urinary activity excreted over the week after 131I-rituximab therapy was typically less than 25% of the administered activity. 131I-rituximab radioimmunotherapy for non-Hodgkin lymphoma may be safely administered on an outpatient basis. The median radiation exposure of carers, cohabitants of the patient, and visitors is well within the limits recommended by international guidelines. Local regulatory agency-designated patient release rate limit of less than 25 μSv/h at 1 m was attained within 1 week of therapeutic 131I-rituximab administration.

Standard Operating Procedure for In-house Preparation of 131 I-rituximab for Radioimmunotherapy of Non-Hodgkin′s Lymphoma

A Standard Operating Procedure (SOP) has been formulated for in-house preparation, quality control, dispensing and administration of 131I-rituximab appropriate for the safe, effective, radioimmunotherapy of non-Hodgkin lymphoma. A decade of experience of semi-automated radioiodination of rituximab in our hospital radiopharmaceutical laboratory was analysed. The methodology was then refined for safe, practical, affordable application to radioimmunotherapy of lymphoma in departments of nuclear medicine in developing countries. This SOP has the potential to be incorporated into good laboratory practice conditions appropriate for local regulatory agency requirements.

Radioimmunotherapy in Non-Hodgkin Lymphoma: Opinions of Nuclear Medicine Physicians and Radiation Oncologists

Despite approval by the Food and Drug Administration and consistent reports of the efficacy and safety of (90)Y-ibritumomab tiuxetan and (131)I-tositumomab, these therapies are infrequently used. This study investigates the opinions and patterns of the use of radioimmunotherapy by nuclear physicians, affiliated researchers, nuclear medicine technologists, and radiation oncologists and aims to identify possible barriers to the use of this promising therapy. An e-mail-based survey with 13 broad questions related to radioimmunotherapy was sent electronically to 13,221 Society of Nuclear Medicine members and radiation oncologists throughout the United States. Six hundred thirteen individuals (4.6%) responded to the electronic survey. Two hundred fifty-one responders (40.9%) had treated patients with non-Hodgkin lymphoma (NHL) with radioimmunotherapy in the last 24 mo. Of the responders, 29.5% used only (90)Y-ibritumomab tiuxetan, 7.6% used only (131)I-tositumomab, and 24.9% used both radiopharmaceuticals; 37.9% did not treat NHL with radioimmunotherapy. Most responders said their patients came from university hospitals (33.9%) or private offices (25.6%), and they mainly treated in a second-line (42.9%), third-line (35.6%), or consolidation (23.5%) setting. Major concerns were that referring oncologists and hematologists wanted to treat by themselves with nonradioactive compounds (mean ± SD, 3.418 ± 1.49) and that (90)Y-ibritumomab tiuxetan and (131)I-tositumomab were expensive (mean ± SD, 3.413 ± 1.35). Of the responders and involved physicians, 40.4% and 35.2%, respectively, did not know if their institution accepted Medicare patients for radioimmunotherapy. Almost 30% (29.6%) of the responders thought radioimmunotherapy would probably grow and 38.0% thought it would grow in importance in the future. Responders who did not administer radioimmunotherapy for NHL thought it took too much time to administer radioimmunotherapy (P < 0.01) and had concerns about the dosimetry procedure (P < 0.01) and radiation safety (P < 0.01). Individuals who perceived a negative future for radioimmunotherapy had significantly more concerns about the time-consuming administration process (P < 0.05) and the high cost of radioimmunotherapy (P < 0.05). Responders from academic centers had significantly fewer concerns about payment (P < 0.01), dosimetry (P < 0.01), and radiation safety (P < 0.01). Radioimmunotherapy was generally viewed positively by the surveyed population. However, limited referrals due to alternative nonradioactive therapies and logistic, educational, and economic concerns played an important role for subgroups in the perception of radioimmunotherapy for NHL.

Radioimmunotherapy in Non-Hodgkin Lymphoma: Opinions of U.S. Medical Oncologists and Hematologists

Radioimmunotherapy is approved by the Food and Drug Administration for CD20 antigen-positive follicular and transformed non-Hodgkin lymphoma. The goal of this study was to obtain the opinion of hematologists and medical oncologists about CD20-directed radioimmunotherapy in the United States. An e-mail-based survey with 8 questions was sent to 4,239 oncologists and hematologists throughout the United States. Two hundred sixteen (5.0%) oncologists and hematologists responded to our survey. One hundred fifty-seven (72.7%) said they had referred patients with non-Hodgkin lymphoma for radioimmunotherapy in the last 24 mo. Different types of practices had significantly different concerns regarding this treatment. Compared with referring physicians from academic centers, those from nonacademic centers reported significantly higher concerns about the lack of a site to which to refer patients for treatment (P < 0.01), the lack of interest by nuclear physicians in this type of treatment (P < 0.01), and a referral process that they felt was too complicated (P < 0.01). They were also more concerned about an economically adverse effect on their own practices if they referred patients for radioimmunotherapy (P < 0.01). Referring physicians who perceived consolidation as a possible indication for radioimmunotherapy had significantly fewer concerns about an adverse effect on their own practice (P < 0.01) and about nonradioactive alternatives (P < 0.01). Seventy-nine (36.6%) responders thought radioimmunotherapy would probably grow in importance, and 52 (24.1%) responders thought it would definitely grow in importance. However, the group with a positive outlook about the future of radioimmunotherapy predicted a higher growth of radioimmunotherapy if they could administer it in their own offices (P < 0.05). Radioimmunotherapy was generally viewed positively by referring physicians. However, in addition to scientific concerns, barriers to the use of radioimmunotherapy included difficulty in referral, perceptions of a high cost of the treatment, concerns about negative financial outcomes related to referral, and an opinion that the treatment would be used more if given by medical oncologists in their own offices. For the growth of radioimmunotherapy, it appears crucial not only to demonstrate the treatment's safety and efficacy but also to streamline the referral process, to enhance collaboration between specialists, and-it appears-to develop economic incentives for the referring physician.

Acute Orbitocranial Inflammation Following Radioimmunotherapy for Non-Hodgkin Lymphoma

Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan may result in hemorrhagic tumor necrosis with acute orbital and intracranial inflammation.

Arterial Wall Dosimetry for Non-Hodgkin Lymphoma Patients Treated with Radioimmunotherapy

Tumors in non-Hodgkin lymphoma (NHL) patients are often proximal to the major blood vessels in the abdomen or neck. In external-beam radiotherapy, these tumors present a challenge because imaging resolution prevents the beam from being targeted to the tumor lesion without also irradiating the artery wall. This problem has led to potentially life-threatening delayed toxicity. Because radioimmunotherapy has resulted in long-term survival of NHL patients, we investigated whether the absorbed dose (AD) to the artery wall in radioimmunotherapy of NHL is of potential concern for delayed toxicity. SPECT resolution is not sufficient to enable dosimetric analysis of anatomic features of the thickness of the aortic wall. Therefore, we present a model of aortic wall toxicity based on data from 4 patients treated with (131)I-tositumomab. Four NHL patients with periaortic tumors were administered pretherapeutic (131)I-tositumomab. Abdominal SPECT and whole-body planar images were obtained at 48, 72, and 144 h after tracer administration. Blood-pool activity concentrations were obtained from regions of interest drawn on the heart on the planar images. Tumor and blood activity concentrations, scaled to therapeutic administered activities-both standard and myeloablative-were input into a geometry and tracking model (GEANT, version 4) of the aorta. The simulated energy deposited in the arterial walls was collected and fitted, and the AD and biologic effective dose values to the aortic wall and tumors were obtained for standard therapeutic and hypothetical myeloablative administered activities. Arterial wall ADs from standard therapy were lower (0.6-3.7 Gy) than those typical from external-beam therapy, as were the tumor ADs (1.4-10.5 Gy). The ratios of tumor AD to arterial wall AD were greater for radioimmunotherapy by a factor of 1.9-4.0. For myeloablative therapy, artery wall ADs were in general less than those typical for external-beam therapy (9.4-11.4 Gy for 3 of 4 patients) but comparable for 1 patient (32.6 Gy). Blood vessel radiation dose can be estimated using the software package 3D-RD combined with GEANT modeling. The dosimetry analysis suggested that arterial wall toxicity is highly unlikely in standard dose radioimmunotherapy but should be considered a potential concern and limiting factor in myeloablative therapy.

Radioimmunotherapy of Non-Hodgkin Lymphoma is Improved without Increasing Toxicity by Combination with Antibody immunotherapy.

Radioimmunotherapy (RAIT) is an effective treatment for follicular and transformed non-Hodgkin lymphoma (NHL) that combines a small amount of a radiolabeled anti-CD20 IgG with a large pre-dose of unlabeled anti-CD20 IgG (~900 mg). While a portion of this pre-dose is used to reduce radioconjugate uptake in the spleen and increase its circulation half-life, an excessive amount of unlabeled anti-CD20 IgG could interfere with the radioconjugate's uptake in the tumor, perhaps compromising RAIT's full therapeutic potential. In an animal model bearing the Burkitt human B-cell lymphoma xenografts (Ramos), we explored alternative approaches to enhance radionuclide targeting to the tumor without compromising the therapeutic benefit derived from the unconjugated anti-CD20 IgG and without increasing host toxicity. One approach utilized a 90Y-labeled, humanized anti-CD22 IgG (epratuzumab) combined with a therapeutic pre-dose of 1.0 mg of the humanized anti-CD20 IgG (veltuzumab) 1 day before the 90Y-epratuzumab (0.05 mg/0.175 mCi), with 3 additional veltuzumab doses of 0.5 mg given weekly thereafter. Biodistribution studies showed the anti-CD20 IgG did not affect tumor uptake of the 90Y-epratuzumab, but when 1.0 mg of anti-CD20 veltuzumab (human equivalent of 280 mg) was given 1 day, or even 1 h, in advance of radiolabeled veltuzumab, that tumor uptake was reduced 50%. The combination of 90Y-epratuzumab with unlabeled veltuzumab resulted in 80% (12/15) of the animals being tumor-free 18 weeks later, whereas either treatment alone was only able to induce a transient response within 1 week that lasted no more than 2 weeks. The addition of a similar treatment regimen of unlabeled epratuzumab or unlabeled veltuzumab to 90Y-veltuzumab produced similar short-term responses as 90Y-veltuzumab alone, with all tumors regrowing within 1–2 weeks of achieving their peak response. However, when the veltuzumab treatment regimen was initiated 1 week after the 90Y-veltuzumab dose, 6/10 of the animals were tumor-free 18 weeks later. This combination therapy was also evaluated for the method of pretargeted RAIT. We also have found that anti-CD20 bispecific antibody pretargeting that localizes a 90Y-labeled hapten-peptide provides improved therapeutic responses compared to the directly radiolabeled 90Y-veltuzumab without the associated severe hematologic toxicity at only 30% of its maximum tolerated dose. Tumor uptake of the 90Y-hapten-peptide was reduced by as much as 70% when 1 mg of veltuzumab was given as a pre-dose that resulted in a significant impairment of anti-tumor responses. However, therapeutic responses were enhanced when the pre-dose was lowered to 0.25 mg, despite a 50% reduction in tumor uptake of the pretargeted 90Y-hapten-peptide. Additional enhancements occurred when unlabeled veltuzumab was given after the 90Y-hapten-peptide pretargeting. These studies suggest a number of strategies that can enhance the therapeutic response of targeted radionuclides, including the use of anti-CD22 radioconjugate combined with non-competing veltuzumab, reducing the anti-CD20 pre-dose that is given with an anti-CD20 based targeting procedure (with emphasis on using the anti-CD20 IgG as a consolidation therapy), and applying RAIT with bispecific antibody pretargeting that is able to enhance anti-tumor responses with less severe hematologic toxicity that also benefits from consolidated veltuzumab therapy. Thus, combination direct RAIT or pre-targeted RAIT with non-competing antibody immunotherapy should be tested clinically. (Supported in part by a PHS grant P01 CA103985 from the NCI.)

A Phase I/II Trial of Radioimmunotherapy (RIT) with 90Yttrium-Ibritumomab Tiuxetan (Zevalin®; 90Y-Zevalin) Combined with the Redox-Active Agent Motexafin Gadolinium (MGd): Prompt and High Remission Rates in Patients with Rituximab-Refractory Non-Hodgkin's Lymphoma (NHL).

MGd is a novel anti-cancer agent that induces apoptosis in NHL cell lines in part by targeting oxidative stress related proteins and has been shown in solid tumor studies to enhance ionizing radiation. We reasoned that response rates could be improved by combining MGd concurrently with RIT in NHL. We conducted a phase I/II trial for patients (pts) with relapsed/refractory NHL using fixed-dose Zevalin® with increasing doses of MGd (2.5 mg/kg, 3.5 mg/kg, 5.0 mg/kg). Pts received 8 MGd doses on days 1 to 4 (111Indium-Zevalin day 1) and days 8 to 11 (90Y-Zevalin day 8). Restaging CTs were performed 4 weeks after MGd/ 90Y-Zevalin. Response was assessed by the International Workshop NHL response criteria (Cheson, 1999). 30 pts enrolled, and 28 are evaluable for toxicity and response (see table). 23 of 28 pts (82%) were rituximab-refractory (Rit-Ref) (defined as no response or time to progression (TTP) of <6 months). 4 pts received 0.3 mCi/kg 90Y-Zevalin (due to thrombocytopenia), while the remainder (n=24) received 0.4 mCi/kg. No dose limiting toxicity was seen and treatment was well-tolerated. No grade 4 non-hematologic toxicities were seen; hematologic toxicities included: 29% with grade 3/4 neutropenia (7% grade 4), 46% grade 3/4 thrombocytopenia (0% grade 4), and 18% grade 3/4 anemia (0% grade 4), which were similar to single-agent zevalin®.Overall response rate (ORR), complete remission (CR), and overall survival (OS) rates are shown (see table). Of note, all responses seen in this trial were documented at 4 weeks following MGd/90Y-Zevalin therapy. Among Rit-Ref follicular lymphoma (FL) pts, 5 responses are ongoing (9+, 9+, 11+, 27+, 31+). Moreover, these data in Rit-Ref FL compares favorably to prior reported data with single-agent Zevalin® (ORR 74%- CR 15%, median TTP 6.8 mo, Witzig, 2002). In conclusion, we found that MGd, when given with Zevalin®, is safe and does not appear to increase hematologic or other toxicity. Responses here were prompt, all seen by 4 weeks following MGd/90Y-Zevalin therapy. Moreover, we observed a high rate of durable remission in Rit-Ref FL pts (ORR 86%/CR 64%). Further studies designed to combine novel therapeutic agents with RIT are warranted.Pt Characteristics, Response, and SurvivalAll Patients (n=28)*Rituximab-Refractory FL (n=14)Aggressive NHL (n=10)*Median age, years (range)65 (47–87)- 32% >age 7560 (47–85)77 (48–87)Median prior treatments (range)3 (1–5)3 (1–4)2 (1–4)Stage III/IV at study entry19/28 (68%)11/14 (79%)7/10 (70%)Bulky disease (>5cm) at study entry15/28 (54%)9/14 (64%)4/10 (40%)Elevated LDH at study entry10/28 (36%)6/14 (43%)4/10 (40%)Best ORR (CR rate)57% (46% CR)86% (64% CR)20% (20% CR)ORR (CR rate) at 4 Weeks57% (21% CR)86% (21% CR)20% (20% CR)TTP, months (range)9 (2–31+)10 (2–31+)4 (2–29+)2-year OS76%93%50%*Histologies enrolled: 17 FL, 1 marginal zone, and 10 aggressive NHL (3 mantle-cell, 4 transformed large-cell, + 3 DLBCL)

Radioimmunotherapy for Non-Hodgkin Lymphoma : Historical Perspective and Current Status

Radioimmunotherapy (RIT) treatment for lymphoma is a novel targeted therapeutic approach. Several years of development of radioimmunotherapeutic compounds came to fruition in February of 2002 when (90)Y-ibritumomab tiuxetan (Zevalin, Y2B8) was approved in the USA and later in Europe, for the treatment of relapsed or refractory, low grade or transformed B-cell lymphoma. (90)Y-ibritumomab tiuxetan utilizes a monoclonal anti-CD20 antibody to deliver beta-emitting yttium-90 to the malignant B-cells. Clinical trials have demonstrated its efficacy, which is largely independent of the intrinsic activity of the anti-CD20 antibody. A similar anti-CD20 radiotherapeutic compound, (131)I-tositumomab, was subsequently approved in the USA. The advantages of increased efficacy compared to the naked antibody are gained at the expense of myelotoxicity which is dose limiting but reversible. Studies exploring expanded applications of radioimmunotherapy have been recently completed or are under way. It is hoped that RIT will be an ideal agent for consolidation after chemotherapy for both indolent and aggressive non-Hodgkin lymphoma as well as a useful addition to preparatory high dose regimens prior to transplant. RIT has been shown to be an effective and clinically relevant complementary therapeutic approach for patients with lymphoma.

Radioimmunotherapy for non-Hodgkin’s lymphoma: A review for radiation oncologists

The aim of this study was to review advances in radioimmunotherapy (RIT) for non-Hodgkin's lymphoma (NHL) and to discuss the role of the radiation oncologist in administering this important new form of biologically targeted radiotherapy. A review of articles and abstracts on the clinical efficacy, safety, and radiation safety of yttrium Y 90 (90Y) ibritumomab tiuxetan (Zevalin) and iodine I 131 tositumomab (Bexxar) was performed. The clinical efficacy of RIT in NHL has been shown in numerous clinical trials of 90Y ibritumomab tiuxetan and 131I tositumomab. Both agents have produced significant responses in patients with low-grade, follicular, or transformed NHL, including patients with disease that had not responded or had responded poorly to previous chemotherapy or immunotherapy. Reversible toxicities such as neutropenia, thrombocytopenia, and anemia are the most common adverse events with both agents. Radioimmunotherapy is safe and effective in many patients with B-cell NHL. 90Y ibritumomab tiuxetan and 131I tositumomab can produce clinically meaningful and durable responses even in patients in whom chemotherapy has failed. Treatment with RIT requires a multispecialty approach and close communication between the radiation oncologist and other members of the treatment team. The radiation oncologist plays an important role in treating patients with RIT and monitoring them for responses and adverse events after treatment.

Current status of cancer therapy with radiolabeled monoclonal antibody

Molecular targeting therapy has become a relevant therapeutic strategy for cancer. There are several monoclonal antibodies used for the treatment of malignant tumors. Radioimmunoconjugate is composed of antibody and radionuclide showing a synergistic effect of radiation and immunemediated cellular toxicity and thereby enabling increased efficacy and minimizing toxicity. Radioimmunotherapy using 131I- and 90Y-labeled anti-CD20 monoclonal antibodies is now indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low-grade or transformed non-Hodgkin's lymphoma (NHL), including patients who are refractory to anti-CD20 monoclonal antibody (rituximab) therapy in the United States. It has been exhibiting favorable anti-tumor efficacy in patients with NHL as compared with rituximab. Myelosuppression is the main side effect associated with the radioimmunotherapy but is usually reversible, and nonhematologic adverse reactions are mild to moderate. Following the impressive results of therapy using radiolabeled monoclonal antibodies for NHL, radioimmunotherapy for solid tumors has been examined; however, the results were unfavorable and did warrant further clinical trials as a single agent. Future studies on radioimmunotherapy for solid tumors should focus on the new strategies of targeting such as locoregional administration for intraperitoneal dissemination, and combination therapy with chemotherapy or cytostatic therapy. Although radioimmunotherapy for NHL has shown excellent results comparable to aggressive chemotherapy without severe adverse effects, additional clinical trials should be performed to define the proper role of radioimmunoconjugates as a relevant strategy for cure of NHL.