This manuscript reviews current advances in the use of radioimmunotherapy (RIT) for the treatment of B-cell non-Hodgkin’s lymphoma (NHL). RIT has been in use for more than 20 years and has progressed significantly with the discovery of new molecular targets, the development of new stable chelates, the humanization of monoclonal antibodies (MAbs), and the use of pretargeting techniques. Today, two products targeting the CD20 antigen are approved: 131I-tositumomab (Bexxar®), and 90Y-ibritumomab tiuxetan (Zevalin®). 131I-tositumomab is available in the United States, and 90Y-ibritumumab tiuxetan in Europe, the United States, Asia, and Africa. RIT can be integrated in clinical practice using non-ablative activities for treatment of patients with relapsed or refractory follicular lymphoma (FL) or as consolidation after induction chemotherapy in front-line treatment in FL patients. Despite the lack of phase III studies to clearly define the efficacy of RIT in the management of B lymphoma in the era of rituximab-based therapy, RIT efficacy in NHL has been demonstrated. In relapsing refractory FL and transformed NHL, RIT as a monotherapy induces around 30% complete response with a possibility of durable remissions. RIT consolidation after induction therapy significantly improves the quality of the response. Dose-limiting toxicity of RIT is hematological, depending on bone marrow involvement and prior treatment. Non-hematological toxicity is generally low. Different studies have been published assessing innovative protocols of RIT or new indications, in particular treatment in patients with aggressive lymphomas. High-dose treatment, RIT as consolidation after different therapeutic induction modalities, RIT in first-line treatment or fractionated RIT showed promising results. New MAbs, in particular humanized MAbs, or combinations of naked and radiolabeled MAbs, also appear promising. Personalized dosimetry protocols should be developed to determine injected activity.
radioimmunotherapy; monoclonal antibody; CD20; CD22; dosimetry
Radioimmunotherapy (RIT) combines the mechanism of action and targeting capability of monoclonal antibodies with the tumoricidal effect of radiation and has shown promising results in the treatment of various hematologic malignancies. Based on RIT’s efficacy and safety profile, many investigators have evaluated its use in transplant conditioning regimens with the goal of improving long-term disease control with limited toxicity. In lymphoma, two basic transplant approaches targeting CD20 have emerged: 1. Myeloablative doses of RIT with or without chemotherapy, and 2. Standard non-myeloablative doses of RIT combined with high-dose chemotherapy. Myeloablative RIT has been shown to be feasible and efficacious using escalated doses of I-131-Tositumomab (Bexxar), Y-90-ibritumomab tiuxetan (Zevalin), and I-131-rituximab with or without chemotherapy followed by autologous stem cell transplant (ASCT). The second approach predominantly has used standard doses of Y-90-ibritumomab tiuxetan or I-131 Tositumomab plus BEAM chemotherapy followed ASCT. RIT targeting CD-45, CD-33 and CD-66 prior to allogeneic transplantation has also been evaluated for the treatment of acute leukemia. Overall RIT-based transplant conditioning for lymphoma and leukemia has been shown to be safe, effective, and feasible with ongoing randomized trials currently underway to definitively establish its place in the treatment of hematologic malignancies.
Radioimmunotherapy; stem cell transplantation; CD20; CD45; I-131; Y-90
On the basis of results of our previous investigations on 90Y-DTPA-rituximab and in order to fulfil national demands to radioimmunoconjugates for radioscintigraphy and radioimmunotherapy of Non-Hodgkin’s Lymphoma (NHL), preparation and radiolabeling of a lyophilized formulation (kit) of DOTA-rituximab with 111In and 90Y was investigated.
111In and 90Y with high radiochemical and radionuclide purity were prepared by 112Cd (p,2n)111In nuclear reaction and a locally developed 90Sr/90Y generator, respectively. DOTA-rituximab immunoconjugates were prepared by the reaction of solutions of p-SCN-Bz-DOTA and rituximab in carbonate buffer (pH = 9.5) and the number of DOTA per molecule of conjugates were determined by transchelation reaction between DOTA and arsenaso yttrium(III) complex. DOTA-rituximab immunoconjugates were labeled with 111In and 90Y and radioimmunoconjugates were checked for radiochemical purity by chromatography methods and for immunoreactivity by cell-binding assay using Raji cell line. The stability of radiolabeled conjugate with the approximate number of 7 DOTA molecules per one rituximab molecule which was prepared in moderate yield and showed moderate immunoreactivity, compared to two other prepared radioimmunoconjugates, was determined at different time intervals and against EDTA and human serum by chromatography methods and reducing SDS-polyacrylamide gel electrophoresis, respectively. The biodistribution of the selected radioimmunoconjugate in rats was determined by measurement of the radioactivity of different organs after sacrificing the animals by ether asphyxiation.
The radioimmunoconjugate with approximate DOTA/rituximab molar ratio of 7 showed stability after 24 h at room temperature, after 96 h at 4°C, as the lyophilized formulation after six months storage and against EDTA and human serum. This radioimmunoconjugate had a biodistribution profile similar to that of 90Y-ibritumomab, which is approved by FDA for radioimmunotherapy of NHL, and showed low brain and lung uptakes and low yttrium deposition into bone.
Findings of this study suggest that further investigations may result in a lyophilized (kit) formulation of DOTA-rituximab which could be easily radiolabeled with 90Y and 111In in order to be used for radioimmunotherapy and radioscintigraphy of B-cell lymphoma in Iran.
Rituximab; 90Y; 111In; Lymphoma-B; Biodistribution; Radioimmunotherapy
Radioimmunotherapy (RIT) has been used to treat relapsed/refractory CD20+ Non-Hodgkin lymphoma (NHL). Myeloablative anti-CD20 RIT followed by autologous stem cell infusion (ASCT) enables high radiation doses to lymphoma sites. We performed a phase I/II trial to assess feasibility and survival.
Twenty-three patients with relapsed/refractory NHL without complete remission (CR) to salvage chemotherapy were enrolled to evaluate RIT with Iodine-131 labelled rituximab (131I-rituximab) in a myeloablative setting. Biodistribution and dosimetric studies were performed to determine 131I activity required to induce a total body dose of 21-27Gy to critical organs. In 6/23 patients RIT was combined with high-dose chemotherapy. 8/23 patients received a sequential high-dose chemotherapy with a second ASCT. The median follow-up is 9.5 years.
6.956-19.425GBq of 131I was delivered to achieve the limiting organ dose to lungs or kidneys. No grade III/IV non-hematologic toxicity was seen with RIT alone. Significant grade III/IV toxicity (mucositis, fever, infection, one therapy related death) was observed in patients treated with RIT combined with high-dose chemotherapy. The overall response rate was 87% (64% CR). The median progression-free (PFS) and overall survival (OS) is 47.5 and 101.5 months. An international prognostic index score >1 was predictive for OS.
Myeloablative RIT with 131I-rituximab followed by ASCT is feasible, well-tolerated and effective in high risk CD20+ NHL. Combination of RIT and high-dose chemotherapy increased toxicity significantly. Long-term results for PFS and OS are encouraging.
Non-Hodgkin lymphoma; Radioimmunotherapy; CD20; High-dose chemotherapy; Autologous stem cell transplantation
Radioimmunotherapy (RIT) represents a selective internal radiation therapy, that is, the use of radionuclides conjugated to tumor-directed monoclonal antibodies (including those fragments) or peptides. In a clinical field, two successful examples of this treatment protocol are currently extended by 90Y-ibritumomab tiuxetan (Zevalin) and 131I-tositumomab (Bexxar), both of which are anti-CD20 monoclonal antibodies coupled to cytotoxic radioisotopes and are approved for the treatment of non-Hodgkin lymphoma patients. In addition, some beneficial observations are obtained in preclinical studies targeting solid tumors. To date, in order to reduce the unnecessary exposure and to enhance the therapeutic efficacy, various biological, chemical, and treatment procedural improvements have been investigated in RIT. This review outlines the fundamentals of RIT and current knowledge of the preclinical/clinical trials for cancer treatment.
Radioimmunotherapy (RIT) for relapsed indolent non-Hodgkin lymphoma produces overall response rates (ORR) of 80% with mostly partial remissions. Synthetic CpG oligonucleotides change the phenotype of malignant B-cells, are immunostimulatory, and can produce responses when injected intratumorally and combined with conventional radiation. In this phase I trial we tested systemic administration of both CpG and RIT. Eligible patients had biopsy-proven previously treated CD20+ B-cell NHL and met criteria for RIT. Patients received rituximab 250 mg/m2 days 1,8, and 15; 111In-ibritumomab tiuxetan days 1, 8; CpG 7909 days 6, 13, 20, 27; and 0.4 mCi/kg of 90Y-ibritumomab tiuxetan day 15. The doses of CpG 7909 tested were 0.08, 0.16, 0.32 (six patients each) and 0.48 mg/kg (12 patients) IV over 2 hours without dose limiting toxicity. The ORR was 93% (28/30) with 63% (19/30) complete remission (CR); median progression free survival of 42.7 months (95% CI 18-NR); and median duration of response (DR) of 35 months (4.6-76+). Correlative studies demonstrated a decrease in IL10 and TNFα, and an increase in IL1β, in response to therapy. CpG 7909 at a dose of 0.48 mg/kg is safe with standard RIT and produces a high CR rate and long DR; these results warrant confirmation.
lymphoma; radioimmunotherapy; rituximab; ibritumomab tiuxetan; CpG 7909
Radioimmunotherapy (RIT) of lymphoma with Zevalin and Bexxar was approved by FDA in 2002 and 2003, respectively, for the treatment of relapsed or refractory CD20+ follicular B-cell non-Hodgkin´s lymphoma. In 2009, Zevalin was also approved for consolidation therapy in patients with follicular non-Hodgkin’s lymphoma that achieve a partial or complete response to first-line chemotherapy. For follicular lymphoma patients, the overall response and progression-free survival rates have significantly improved since the implementation of RIT. The predominant complication of RIT is hematological toxicity that is usually manageable. There are ongoing trials to further define the expanding role of RIT as first line or concomitant therapy in the treatment of lymphoma as well as for certain antibiotic resistant infections and aggressive malignancies. There is also growing interest in the development of newer protocols for increased and more uniform dose delivery resulting in better outcomes and improved patient survival. This review will primarily focus on the role of RIT in treatment of non-Hodgkin’s lymphoma, which is of established clinical utility and FDA approved. The mechanism of RIT, available radionuclides and pharmacokinetics, therapy administration, clinical utility and toxicities, and future directions would be discussed.
lymphoma; non-Hodgkin’s lymphoma; Hodgkin’s lymphoma; radioimmunotherapy; immunotherapy; Bexxar; Zevalin; Dosimetry; Y-90; Rituximab; monoclonal antibody; beta particle; alpha particle; Auger; biodistribution
Targeted radioimmunotherapy in non-Hodgkin’s B-cell lymphoma (NHL) offers an efficacious therapy and minimal toxicity compared to conventional chemotherapy. Iodine 131 tositumomab (131I-TST) is a murine monoclonal antibody against the CD20 cell surface protein and is directly covalently conjugated to 131I, a radioactive β and γ emitter. While initially approved for use in relapsed, refractory, or transformed low grade B-cell NHL, investigational uses with promising results include autologous stem cell transplant, intermediate grade NHL, and the frontline management of indolent NHL. This review summarizes the 131I-TST literature on mechanism of action, treatment indications, treatment delivery, efficacy, investigational uses, and future prospects.
tositumomab; radioimmunotherapy; non-Hodgkin’s lymphoma; Bexxar
Pulmonary involvement is common in patients with non-Hodgkin's lymphoma (NHL). 90Y- and 131I-anti-CD20 antibodies (ibritumomab tiuxetan and tositumomab, respectively) have been approved for the treatment of refractory low-grade follicular NHL. In this work, we used Monte Carlo–based dosimetry to compare the potential of 90Y and 131I, based purely on their emission properties, in targeted therapy for NHL lung metastases of various nodule sizes and tumor burdens.
Lung metastases were simulated as spheres, with radii ranging from 0.2 to 5.0 cm, which were randomly distributed in a voxelized adult male lung phantom. Total tumor burden was varied from 0.2 to 1,641 g. Tumor uptake and retention kinetics of the 2 radionuclides were assumed equivalent; a uniform distribution of activity within tumors was assumed. Absorbed dose to tumors and lung parenchyma per unit activity in lung tumors was calculated by a Monte Carlo–based system using the MCNP4B package. Therapeutic efficacy was defined as the ratio of mean absorbed dose in the tumor to that in normal lung. Dosimetric analysis was also performed for a lung-surface distribution of tumor nodules mimicking pleural metastatic disease.
The therapeutic efficacy of both 90Y and 131I declined with increasing tumor burden. In treating tumors with radii less than 2.0 cm, 131I targeting was more efficacious than 90Y targeting. 90Y yielded a broader distribution of tumor absorbed doses, with the minimum 54.1% lower than the average dose; for 131I, the minimum absorbed dose was 33.3% lower than the average. The absorbed dose to normal lungs was reduced when the tumors were distributed on the lung surface. For surface tumors, the reductions in normal-lung absorbed dose were greater for 90Y than for 131I, but 131I continued to provide a greater therapeutic ratio across different tumor burdens and sizes.
Monte Carlo–based dosimetry was performed to compare the therapeutic potential of 90Y and 131I targeting of lung metastases in NHL patients. 131I provided a therapeutic advantage over 90Y, especially in tumors with radii less than 2.0 cm and at lower tumor burdens. For both 90Y- and 131I-labeled antibodies, treatment is more efficacious when applied to metastatic NHL cases with lower tumor burdens. 131I has advantages over 90Y in treating smaller lung metastases.
non-Hodgkin's lymphoma; pulmonary metastases; dosimetry; Monte Carlo; 90Y; 131I
Radioimmunotherapy (RIT) is an emerging treatment option for non-Hodgkin lymphoma (NHL) producing higher overall response and complete remission rates compared with unlabelled antibodies. However, the majority of patients treated with conventional or myeloablative doses of radiolabelled antibodies relapse. The development of RIT with alpha-emitters is attractive for a variety of cancers because of the high linear energy transfer (LET) and short path length of alpha-radiation in human tissue, allowing higher tumour cell kill and lower toxicity to healthy tissues. In this study, we investigated the molecular effects of the alpha-emitter Bi-213 labelled to anti-CD20 antibodies ([Bi-213]anti-CD20) on cell cycle and cell death in sensitive and radio-/chemoresistant NHL cells. [Bi-213]anti-CD20 induced apoptosis, activated caspase-3, caspase-2 and caspase-9 and cleaved PARP specifically in CD20-expressing sensitive as well as in chemoresistant, beta-radiation resistant and gamma-radiation resistant NHL cells. CD20 negative cells were not affected by [Bi-213]anti-CD20 and unspecific antibodies labelled with Bi-213 could not kill NHL cells. Breaking radio-/chemoresistance in NHL cells using [Bi-213]anti-CD20 depends on caspase activation as demonstrated by complete inhibition of [Bi-213]anti-CD20-induced apoptosis with zVAD.fmk, a specific inhibitor of caspases activation. This suggests that deficient activation of caspases was reversed in radioresistant NHL cells using [Bi-213]anti-CD20. Activation of mitochondria, resulting in caspase-9 activation was restored and downregulation of Bcl-xL and XIAP, death-inhibiting proteins, was found after [Bi-213]anti-CD20 treatment in radio-/chemosensitive and radio-/chemoresistant NHL cells. [Bi-213]anti-CD20 seems to be a promising radioimmunoconjugate to improve therapeutic success by breaking radio- and chemoresistance selectively in CD20-expressing NHL cells via re-activating apoptotic pathways through reversing deficient activation of caspases and the mitochondrial pathway and downregulation of XIAP and Bcl-xL.
non-Hodgkin lymphoma; targeted alpha-therapy; anti-CD20; Bismuth-213; radioresistance; apoptosis
Radioimmunotherapy (RIT) is an attractive therapy for non-Hodgkin's lymphoma (NHL) as it allows targeted tumor irradiation which provides a cytotoxic effect significantly greater than that of the immune-mediated effects of a non-radioactive, or ‘cold’, antibody alone. Anti-CD20 antibodies such as rituximab are ideal for RIT, as not only is it easily iodinated, but the CD20 antigen is found on more than 95% of B-cell NHL. A standard operating procedure (SOP) has been formulated for personalized prospective dosimetry for safe, effective outpatient 131I-rituximab RIT of NHL. Over five years, experience of treatment of outpatients with 131I-rituximab was analyzed with respect to critical organ radiation dose in patients and radiation exposure of their carers. This radiation safety methodology has been refined; and offers the potential for safe, practical application to outpatient 131I-rituximab RIT of lymphoma in general and in developing countries in particular. Given endorsement and sanction of this SOP by local regulatory authorities the personalized dosimetry paradigm will facilitate incorporation of RIT into the routine clinical practice of therapeutic nuclear oncology worldwide.
Dosimetry; I-131 rituximab; non-Hodgkin's lymphoma; standard operating procedure
Combination treatment is a hallmark of cancer therapy. Although the rationale for combination radiopharmaceutical therapy was described in the mid ‘90s, such treatment strategies have only been implemented clinically recently, and without a rigorous methodology for treatment optimization. Radiobiological and quantitative imaging-based dosimetry tools are now available that enable rational implementation of combined targeted radiopharmaceutical therapy. Optimal implementation should simultaneously account for radiobiological normal organ tolerance while optimizing the ratio of two different radiopharmaceuticals required to maximize tumor control. We have developed such a methodology and applied it to hypothetical myeloablative treatment of non-hodgkin’s lymphoma (NHL) patients using 131I-tositumomab and 90Y-ibritumomab tiuxetan.
The range of potential administered activities (AA) is limited by the normal organ maximum tolerated biologic effective doses (MTBEDs) arising from the combined radiopharmaceuticals. Dose limiting normal organs are expected to be the lungs for 131I-tositumomab and the liver for 90Y-ibritumomab tiuxetan in myeloablative NHL treatment regimens. By plotting the limiting normal organ constraints as a function of the AAs and calculating tumor biological effective dose (BED) along the normal organ MTBED limits, the optimal combination of activities is obtained. The model was tested using previously acquired patient normal organ and tumor kinetic data and MTBED values taken from the literature.
The average AA values based solely on normal organ constraints was (19.0 ± 8.2) GBq with a range of 3.9 – 36.9 GBq for 131I-tositumomab, and (2.77 ± 1.64) GBq with a range of 0.42 – 7.54 GBq for 90Y-ibritumomab tiuxetan. Tumor BED optimization results were calculated and plotted as a function of AA for 5 different cases, established using patient normal organ kinetics for the two radiopharmaceuticals. Results included AA ranges which would deliver 95 % of the maximum tumor BED, which allows for informed inclusion of clinical considerations, such as a maximum allowable 131I administration.
A rational approach for combination radiopharmaceutical treatment has been developed within the framework of a proven 3-dimensional personalized dosimetry software, 3D-RD, and applied to the myeloablative treatment of NHL. We anticipate combined radioisotope therapy will ultimately supplant single radioisotope therapy, much as combination chemotherapy has substantially replaced single agent chemotherapy.
Radiopharmaceutical therapy; Dosimetry; Treatment planning; BED; Lymphoma
Background. Based on historical data we reviewed our hospital clinical database to analyse our updated information and therapy outcomes of follicular non-Hodgkin lymphoma (F-NHL) patients treated with 90Y-Ibritumomab tiuxetan. Patients and Methods. Between 2005 and 2011, 56 F-NHL patients were included in a clinical protocol conducted by a multidisciplinary team and treated in the same centre. All patients received 0.3 or 0.4 mCi/kg IV (88%) of 90Y-IT; response evaluation was performed 12 weeks after. Results. M/F 44.6%/55.4%, mean age 61.45 years (30–85); ECOG 0-1 96.9%. According to FLIPI score, distribution were good: 58.5%, intermediate: 29.2%, and poor: 12.3%. Previous therapies: >2: 40% (26). ORR was 94.6% (53/56). CR: 85.7%; CR according to previous disease: relapsed disease: 90% (27/30), refractory disease: 42.85% (3/7), consolidation with CR: 92.85% (13/14), and consolidation with PR: 100% (5/5). Global PR and NR were 8.9% (5) and 5.3% (3), respectively. Mean OS 63.86 months with a mean follow-up time of 57 months (2–73). Mean TTP: 52.65 months (95% CI: 43.83–61.48). Median OS and TTP were not achieved. No hospital submissions or deaths were registered. Conclusions. This study confirms the safety and high efficacy of 90Y-IT in F-NHL patients, RIT in early stage of disease could improve outcomes.
This study aimed at identifying clinical factors for predicting hematologic toxicity after radioimmunotherapy with 90Y-ibritumomab tiuxetan or 131I-tositumomab in clinical practice.
Hematologic data were available from 14 non-Hodgkin lymphoma patients treated with 90Y-ibritumomab tiuxetan and 18 who received 131I-tositumomab. The percentage baseline at nadir and 4 wk post nadir and the time to nadir were selected as the toxicity indicators for both platelets and neutrophils. Multiple linear regression analysis was performed to identify significant predictors (P < 0.05) of each indicator.
For both platelets and neutrophils, pooled and separate analyses of 90Y-ibritumomab tiuxetan and 131I-tositumomab data yielded the time elapsed since the last chemotherapy as the only significant predictor of the percentage baseline at nadir. The extent of bone marrow involvement was not a significant factor in this study, possibly because of the short time elapsed since the last chemotherapy of the 7 patients with bone marrow involvement. Because both treatments were designed to deliver a comparable bone marrow dose, this factor also was not significant. None of the 14 factors considered was predictive of the time to nadir. The R2 value for the model predicting percentage baseline at nadir was 0.60 for platelets and 0.40 for neutrophils. This model predicted the platelet and neutrophil toxicity grade to within ±1 for 28 and 30 of the 32 patients, respectively. For the 7 patients predicted with grade I thrombocytopenia, 6 of whom had actual grade I–II, dosing might be increased to improve treatment efficacy.
The elapsed time since the last chemotherapy can be used to predict hematologic toxicity and customize the current dosing method in radioimmunotherapy.
radioimmunotherapy; 90Y-ibritumomab tiuxetan; 131I-tositumomab; hematologic toxicity
Non-Hodgkin’s lymphoma (NHL) accounts for 4% of all cancers diagnosed in the United States. Follicular lymphoma (FL) is the most common type of indolent NHL with a survival from 5 to 15 years. Although it is very sensitive to chemotherapy and radiotherapy, relapses are the main cause of therapeutic failure, and currently there is no consensus on the first-line treatment and optimal therapeutic strategies for patients with FL. Immediate treatment offers any survival benefit for asymptomatic and more indolent disease. In order to improve outcomes in FL, extend the remission, postpone the need for chemotherapy and improve OS, maintenance therapies with rituximab and consolidation treatments represent very attractive strategies. 90Y-ibritumomab tiuxetan (90Y-IT, Zevalin®) is approval as consolidation therapy in previously untreated FL patients who achieve response to first-line chemotherapy. Consolidation therapy with 90Y-IT after initial induction treatment has shown improved activity compared with induction chemotherapy alone, even in patients previously treated with rituximab, in one phase III and several phase II trials, improving progression-free survival (PFS) and rate of conversion from partial response (PR) to complete response (CR). The phase III international FIT trial shows an improvement in PFS that is maintained after a median follow up of 7.3 years. Several phase II trials show high rate of conversion from PR to CR and a significant improvement in PFS. Treatment is feasible and well tolerated although myelodysplastic syndrome cases has been observed in some trials. 90Y-IT should be considered for the initial treatment of FL in patients who are unable to tolerate standard chemotherapy, e.g., elderly or frail patients and otherwise in high-risk patients who achieve a PR or CR due to improvements in CR rate and PFS.
90Y-ibritumomab tiuxetan; consolidation treatment; follicular lymphoma
Several studies have indicated that radioimmunotherapy is an effective and clinically relevant complementary therapeutic approach for patients with B-cell non-Hodgkin’s lymphoma (NHL) and may convert partial to complete response when given as consolidation after induction chemotherapy. Yttrium-90(90Y)-ibritumomab tiuxetan (90Y-IT, Zevalin®, Y2B8) has documented efficacy for both indolent and aggressive NHL. Patients considered eligible for 90Y-IT treatment should satisfy several screening criteria. A recently completed randomized study for patients with follicular lymphoma has demonstrated that 90Y-ibritumomab consolidation also produced a marked prolongation of the median time to progression from 13.5 to 37 months, while partial responders seem to derive relatively more benefit. Other published and ongoing studies explore a similar use for patients with aggressive lymphoma. Studies are comparing the use of 90Y-IT consolidation with the anti-CD20 antibody rituximab maintenance, which is also gaining acceptance. In conclusion, the documented benefit of radioimmunotherapy should be viewed in the context of the goals of treatment and the changing standards of care for lymphoma.
radioimmunotherapy; 90Y-ibritumomab tiuxetan; follicular lymphoma; consolidation
With the success of targeted monoclonal antibody therapy in non-Hodgkin’s lymphoma, attempts were made to further improve efficacy through the addition of a radioisotope. A goal of radioimmunotherapy is to utilize the monoclonal antibody to deliver radiation to a tumor bed with relatively limited toxicity to the surrounding normal tissues. I-131 Tositumomab is an iodine-131 labeled anti-CD20 murine IgG2a monoclonal antibody and is one of two FDA-approved radioimmunotherapeutic drugs for patients with non-Hodgkin’s lymphoma (NHL). For more than a decade now, radiolabeled tositumomab has principally been evaluated in low-grade and transformed low-grade NHL patients with proven efficacy in both the up-front and salvage settings. Studies have included its use as a single agent, in combination with chemotherapy and as part of a conditioning regimen for autologous stem cell transplantation. These data suggest that this agent has an important role in the treatment of patients with B cell lymphoma.
non-Hodgkin’s lymphoma; tositumomab; iodine-131-labeled tositumomab; B-cell lymphoma
After nearly three decades with little change in the treatment for B-cell non-Hodgkin’s lymphoma, the addition of immunotherapy has had a profound effect on the treatment of this group of diseases. A more subtle addition to the armentarium has been the radiolabeled monoclonal antibodies, 90yttrium ibritumomab tiuxetan and 131iodine tositumomab. Unfortunately these drugs have been underutilized. This is, in part, because of the need for coordination between specialties, concern about long-term effects, possible limitations on the tolerance of subsequent therapies and, in part, because of reimbursement factors. In this review, the studies in relapsed and refractory disease are discussed and the very promising results reported from phase II studies using radioimmunotherapy as first-line. Potential mechanisms of resistance to monoclonal antibodies are postulated based on alterations in cell signaling pathways that have been observed in lymphoma cell lines resistant to rituximab. It is anticipated that as mechanisms of resistance are better understood for both unlabeled and labeled monoclonal antibodies, biomarkers will not only predict their efficacy but also lead to the development of therapies to overcome resistance.
immunotherapy; radioimmunotherapy; ibritumomab; zevalin; non-Hodgkin lymphoma
Radioimmunoconjugates are radioisotope-bound monoclonal antibodies that target radiation specifically to sites of lymphoma involvement. Initial studies of 131I–tositumomab in non-Hodgkin lymphoma (nhl) have suggested benefit in patients with relapsed or refractory indolent disease. However, the routine adoption of this agent is tempered by concerns about associated toxicities and unclear long-term benefit. Based on a comprehensive search for studies on 131I–tositumomab use in lymphoma, this systematic review summarizes and evaluates the evidence on
the benefits and risks of this novel therapy,the predictors for response and toxicity, andthe role of dosimetry and imaging studies before treatment.
We identified 18 trials investigating the use of 131I–tositumomab for the treatment of adult patients with nhl. In trials of patients with relapsed or refractory indolent nhl, overall response rates ranged from 67% to 83%. In patients with follicular nhl refractory to the monoclonal antibody rituximab, response rates remained high (65%–72%). However, in rituximab-naïve patients with relapsed or refractory indolent or transformed nhl, improvements in time to progression or survival have not been clearly established. 131I–Tositumomab is an active agent in relapsed and refractory non-Hodgkin lymphoma that should be considered in selected patients.
131I–Tositumomab; Bexxar; indolent lymphoma; systematic review
We report a case that demonstrates the efficacy of radioimmunotherapy (RIT) with radioiodinated rituximab (131I-rituximab) for relapsed diffuse large B-cell lymphoma (DLBCL). A 79-year-old male patient with DLBCL initially achieved a complete response (CR) after six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. However, the lymphoma relapsed 20 months later. Although the patient had achieved a second and a third CR after two cycles of 90Y-ibritumomab tiuxetan, he experienced a third relapse approximately 3 years later. Between March and June 2011, the patient received three cycles of 131I-rituximab. Although he had achieved partial response after the second cycle, the disease progressed after the third cycle, and the total progression–free survival was thus 5 months. The patient suffered only relatively mild toxicity (grade 1 thrombocytopenia) during treatment. RIT with 131I-rituximab is therefore potentially effective in patients with relapsed DLBCL, even after the failure of 90Y-ibritumomab tiuxetan therapy.
131I-rituximab; Rituximab; Radioimmunotherapy; Diffuse large B-cell lymphoma; Refractory
To determine the maximum-tolerated radiation-absorbed dose (RAD) to critical organs delivered by yttrium-90 (90Y) ibritumomab tiuxetan in combination with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy with autologous transplantation.
Patients and Methods
Eligible patients had relapsed or refractory CD20+ non-Hodgkin's lymphoma (NHL). Individualized 90Y activities were based on dosimetry and were calculated to deliver cohort-defined RAD (1 to 17 Gy) to critical organs with three to six patients per cohort. The therapeutic dose of 90Y ibritumomab tiuxetan was followed by high-dose BEAM and autologous transplantation.
Forty-four patients were treated. Thirty percent of patients had achieved less than a partial remission to their most recent therapy and would not have been eligible for autologous transplantation at most centers. The toxicity profile was similar to that associated with high-dose BEAM chemotherapy. Two dose-limiting toxicities occurred at the 17 Gy dose level, which made 15 Gy the recommended maximum-tolerated RAD. Although eight patients received at least twice the conventional dose of 0.4 mCi/kg, a weight-based strategy at 0.8 mCi/kg would have resulted in a wide range of RAD; nearly 25% of patient cases would have received 17 Gy or more, and many would have received less than 10 Gy. With a median follow-up of 33 months for all patients, the estimated 3-year progression-free and overall survivals were 43% and 60%, respectively.
Dose-escalated 90Y ibritumomab tiuxetan may be safely combined with high-dose BEAM with autologous transplantation and has the potential to be more effective than standard-dose radioimmunotherapy. Careful dosimetry is required to avoid toxicity and undertreatment.
Positron emission tomography (PET) with 89Zr-ibritumomab tiuxetan can be used to monitor biodistribution of 90Y-ibritumomab tiuxetan as shown in mice. The aim of this study was to assess biodistribution and radiation dosimetry of 90Y-ibritumomab tiuxetan in humans on the basis of 89Zr-ibritumomab tiuxetan imaging, to evaluate whether co-injection of a therapeutic amount of 90Y-ibritumomab tiuxetan influences biodistribution of 89Zr-ibritumomab tiuxetan and whether pre-therapy scout scans with 89Zr-ibritumomab tiuxetan can be used to predict biodistribution of 90Y-ibritumomab tiuxetan and the dose-limiting organ during therapy.
Seven patients with relapsed B-cell non-Hodgkin’s lymphoma scheduled for autologous stem cell transplantation underwent PET scans at 1, 72 and 144 h after injection of ~70 MBq 89Zr-ibritumomab tiuxetan and again 2 weeks later after co-injection of 15 MBq/kg or 30 MBq/kg 90Y-ibritumomab tiuxetan. Volumes of interest were drawn over liver, kidneys, lungs, spleen and tumours. Ibritumomab tiuxetan organ absorbed doses were calculated using OLINDA. Red marrow dosimetry was based on blood samples. Absorbed doses to tumours were calculated using exponential fits to the measured data.
The highest 90Y absorbed dose was observed in liver (3.2 ± 1.8 mGy/MBq) and spleen (2.9 ± 0.7 mGy/MBq) followed by kidneys and lungs. The red marrow dose was 0.52 ± 0.04 mGy/MBq, and the effective dose was 0.87 ± 0.14 mSv/MBq. Tumour absorbed doses ranged from 8.6 to 28.6 mGy/MBq. Correlation between predicted pre-therapy and therapy organ absorbed doses as based on 89Zr-ibritumomab tiuxetan images was high (Pearson correlation coefficient r = 0.97). No significant difference between pre-therapy and therapy tumour absorbed doses was found, but correlation was lower (r = 0.75).
Biodistribution of 89Zr-ibritumomab tiuxetan is not influenced by simultaneous therapy with 90Y-ibritumomab tiuxetan, and 89Zr-ibritumomab tiuxetan scout scans can thus be used to predict biodistribution and dose-limiting organ during therapy. Absorbed doses to spleen were lower than those previously estimated using 111In-ibritumomab tiuxetan. The dose-limiting organ in patients undergoing stem cell transplantation is the liver.
Immuno-PET; Molecular imaging; Radioimmunotherapy; Ibritumomab tiuxetan; 89Zr; 90Y; Dosimetry; Lymphoma
Radioimmunotherapy agents have a highly significant role in autologous stem cell transplantation as they improve tolerability and increase the efficacy of the conditioning regimen.
We retrospectively analyzed the efficacy and toxicity of yttrium-90 ibritumomab tiuxetan (Zevalin) combined with intravenous busulfan, cyclophosphamide, and etoposide (Z-BuCyE) compared with those of BuCyE alone followed by autologous stem cell transplantation in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). The efficacy, toxicity, and engraftment characteristics were compared between 19 patients who received Z-BuCyE and 19 historical controls who received BuCyE.
The 2 treatment groups shared similar baseline characteristics. The median time to platelet engraftment (>20×109/L) and neutrophil engraftment (>0.5×109/L) did not significantly differ between the Z-BuCyE group (12 days and 10 days, respectively) and the BuCyE group (12 days and 10 days, respectively). No significant differences were observed between the groups with respect to toxicities and treatment-related mortality. The median follow-up period was 30.4 months, and median event-free survival was generally better in the Z-BuCyE group (12.5 months) vs. the BuCyE group (6.2 months, P=0.236). No significant difference in overall survival between the groups was noted.
Adding ibritumomab tiuxetan to BuCyE high-dose chemotherapy may benefit patients with relapsed or refractory B-cell NHL with no risk of additional toxicity.
Yttrium-90 ibritumomab tiuxetan; BuCyE; Autologous stem cell transplantation; Non-Hodgkin lymphoma
To present a possible coincidence of cytomegalovirus retinitis and intraocular lymphoma in a patient with systemic non-Hodgkin’s lymphoma.
A 47-year-old woman presented with decreased visual acuity associated with white retinal lesions in both eyes. A history of pneumonia of unknown aetiology closely preceded the deterioration of vision. Five years previously the patient was diagnosed with follicular non-Hodgkin’s lymphoma. She was treated with a chemotherapy regimen comprised of cyclophosphamide, adriamycin, vincristin, and prednisone with later addition of the anti-CD20 antibody rituximab. She experienced a relapse 19 months later with involvement of the retroperitoneal lymph nodes, and commenced treatment with rituximab and 90Y-ibritumomab tiuxetan. A second relapse occurred 22 months after radioimmunotherapy and was treated with a combination of fludarabine, cyclophosphamide, and mitoxantrone followed by rituximab. The patient experienced no further relapses until the current presentation (April, 2010).
Pars plana vitrectomy with vitreous fluid analysis was performed in the right eye. PCR testing confirmed the presence of cytomegalovirus in the vitreous. Atypical lymphoid elements, highly suspicious of malignancy were also found on cytologic examination. Intravenous foscarnet was administered continually for three weeks, followed by oral valganciclovir given in a dose of 900 mg twice per day. In addition, the rituximab therapy continued at three monthly intervals. Nevertheless, cessation of foscarnet therapy was followed by a recurrence of retinitis on three separate occasions during a 3-month period instigating its reinduction to the treatment regime after each recurrence.
Cytomegalovirus retinitis is an opportunistic infection found in AIDS patients as well as in bone marrow and solid organ transplant recipients being treated with systemic immunosuppressive drugs. This case presents a less common incidence of cytomegalovirus retinitis occurring in a patient with non-Hodgkin’s lymphoma. We demonstrated a possible coexistence of cytomegalovirus retinitis and intraocular lymphoma in this particular patient. The final diagnosis was based on clinical manifestations together with the course of uveitis and its response to treatment alongside the results of vitreous fluid analysis. This report highlights the importance of intraocular fluid examination in cases with nonspecific clinical manifestations. Such an examination allows for the detection of simultaneously ongoing ocular diseases of differing aetiologies and enables the prompt initiation of effective treatment.
Cytomegalovirus; Cytomegalovirus retinitis; Foscarnet; Non-Hodgkin’s lymphoma; Rituximab; Valganciclovir
Therapeutic strategies to enhance the efficacy of radioimmunotherapy have not been explored. Motexafin gadolinium (MGd) is a novel anti-cancer agent that targets redox-dependent pathways and enhances sensitivity of tumor cells to ionizing radiation.
We performed pre-clinical studies examining MGd combined with rituximab and/or radiation in lymphoma cells. We subsequently completed a phase I clinical trial combining escalating doses of MGd concurrently with standard yttrium-90 (90Y)-ibritumomab tiuxetan for patients with relapsed/refractory non-Hodgkin lymphoma.
In HF1 lymphoma cells, MGd and rituximab resulted in synergistic cytotoxicity (combination index 0.757) through a mitochondrial-mediated caspase-dependent pathway, while cell death in Ramos and SUDHL4 cells was additive. MGd/rituximab combined with radiation (1–3Gy) resulted in additive apoptosis. Twenty-eight of 30 patients were evaluable on the phase I clinical trial. Median age was 65 years (47–87), and histologies were: marginal-zone (n=1), mantle-cell (n=3), diffuse large-cell (n=6), and follicular lymphoma (n=18). 86% of all patients were rituximab-refractory. Therapy was well-tolerated and no dose limiting toxicity was seen. Overall response rate (ORR) was 57% (complete remission (CR) 43%) with median time-to-treatment failure (TTF) of 10 months (1–48+) and median duration-of-response of 17 months. Of note, all responses were documented at 4 weeks. Furthermore, in rituximab-refractory follicular lymphoma (n=14), ORR was 86% (CR 64%) with median TTF of 14 months (2–48+).
This represents the first report of a novel agent to be combined safely concurrently with radioimmunotherapy. Further, tumor responses with 90Y-ibritumomab tiuxetan/MGd were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma.
lymphoma; radioimmunotherapy; rituximab-refractory; oxidative stress; MGd