Development of 131I-tositumomab

Development of

131I-Tositumomab

Valerie Lewington The median survival for patients with advanced indolent non-Hodgkin’s lymphoma (NHL) has remained at 7 to 8 years since the 1960s. Targeted treatment using radioimmunotherapy (RIT), radiolabeled monoclonal antibodies directed against tumor-specific antigens, is an attractive option for this patient population, combining the advantages of an active biologic therapy with low dose-rate irradiation of an inherently radiosensitive tumor. Two anti-CD20 RIT agents have now been approved for the treatment of refractory NHL: 90Y-ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, San Diego, CA, and Schering AG, Berlin, Germany) is approved in both the United States and Europe, and 131I-tositumomab (Bexxar; Corixa Corp, Seattle, WA) is approved only in the United States. This article discusses the development of 131I-tositumomab. Because 131I-labeled antibody clearance varies significantly among patients, prescription of 131I-tositumomab activity must be based on a calculated total-body dose derived from quantitative whole-body imaging. The maximum tolerated total-body dose has been established at 75 cGy in patients with adequate bone marrow reserves and less than 25% bone marrow involvement by lymphoma (65 cGy in patients with mild thrombocytopenia; 45 cGy in patients who have received stem cell transplantation). In a phase III trial, overall response rate (ORR) and complete response (CR) rate were significantly higher following 131I-tositumomab than following the patient’s last qualifying chemotherapy (ORR, 65% v 28%; P <.001; CR, 20% v 3%; P <.001). 131I-tositumomab has also been shown to be effective in patients who are refractory to rituximab (ORR, 70%; CR, 32%) and as first-line therapy in patients with NHL (ORR, 97%; CR, 63%). The major side effects of 131I-tositumomab are hematologic. In the phase III study, 20% of patients experienced grade 4 neutropenia and 22% experienced grade 4 thrombocytopenia. Myelodysplastic syndromes or secondary acute myeloid leukemia have been reported in 8.4% of patients with chemotherapy-refractory disease treated with 131I-tositumomab, but have not been observed to date in patients receiving 131I-tositumomab as first-line therapy. Future progress in NHL management is likely to include RIT as part of a multi-modality approach; trials are planned or currently underway to investigate the combination of RIT with chemotherapy regimens. Semin Oncol 32(suppl 1):S50-S56 © 2005 Elsevier Inc. All rights reserved.

C

urrent management of advanced non-Hodgkin’s lymphoma (NHL) relies on chemotherapy with or without radiotherapy. Although remission rates are high, only 25% of patients are cured, the majority of whom have intermediateor high-grade (aggressive) tumors. In contrast, the clinical course of low-grade NHL is characterized by multiple relapses with inevitable, progressive chemoresistance. Median survival for patients with advanced-stage low-grade (indolent) lymphomas has remained virtually static at 7 to 8 years since the 1960s.1 Targeted therapy using radiolabeled monoclonal antibodies directed against tumor-specific antigens is

Royal Marsden Hospital, Sutton, UK. Address reprint requests to Valerie Lewington, MD, Nuclear Medicine Department, Royal Marsden Hospital, Downs Rd, Sutton, Surrey SM2 5PT, UK.

S50

0093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.01.014

an attractive option for this patient population, combining the advantages of an active biologic therapy with low doserate irradiation in an inherently radiosensitive tumor. This article focuses specifically on 131I-tositumomab (Bexxar; Corixa Corp, Seattle, WA) for the treatment of NHL. Several antigens have been identified as potential targets for radioimmunotherapy (RIT) (Table 1). The antibodies Lym-1 and LL2, which target HLA-DR (MHC class II antigen) and CD22, respectively, are rapidly internalized following antigen binding. The development of Lym-1 is discussed elsewhere in this issue,2 and developmental studies with LL2 are still ongoing.3 CD20 is considered to be one of the most promising target antigens for RIT: it is expressed on more than 90% of all B-cell NHLs4,5 and is not internalized. Two anti-CD20 RIT agents have been developed: 90Y-ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, San Diego, CA,

Development of

131I-tositumomab

S51

Table 1 Monoclonal Antibodies That Have Been Developed to Target Antigens for Radioimmunotherapy Target Antigen HLA-DR

Monoclonal Antibody 131I-Lym-1 67Cu-Lym-1 90Y-Lym-1

CD22

131I-Re-LL2 90Y-Re-LL2 186Re-LL2

CD20

90Y-ibritumomab

tiuxetan

131I-tositumomab

Radioisotope Emission

␤- and ␥-emitter ␤- and ␥-emitter ␤-emitter ␤- and ␥-emitter ␤-emitter ␤-emitter ␤-emitter ␤- and ␥-emitter

and Schering AG, Berlin, Germany) and 131I-tositumomab. 90Y-ibritumomab tiuxetan was approved by the US Food and Drug Administration in 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab-refractory follicular lymphoma, and was subsequently approved in Europe in 2003. Studies with this agent are discussed elsewhere in this issue.6 131I-tositumomab was approved in the United States in June 2003 for the treatment of patients with relapsed, rituximab-refractory CD20⫹, follicular NHL, with or without transformation. 131I-Tositumomab

Tositumomab is a murine IgG2a antibody that exhibits high antibody-dependent cellular cytotoxicity activity, low complement-dependent cytotoxicity activity, and triggers apoptosis in vitro.7 Tositumomab is radiolabeled with 131I, which emits both ␤- and ␥-radiation. Clearance of 131I-labeled antibodies varies significantly among patients.8,9 Prescription of 131I-tositumomab activity must, therefore, be based on a calculated total-body dose (TBD) derived from quantitative whole-body imaging. The aim of whole-body imaging to calculate the TBD is to achieve the same area under the curve (AUC) in patients who clear the agent rapidly as in those in whom clearance is slow (Fig 1). This approach is necessary to ensure that a therapeutic dose is delivered and to reduce the risk of treatment-related toxicity. 131I-tositumomab is a ␥-emitter, which necessitates the use

Figure 1 Critical role of dosimetry with 131I-tositumomab to achieve an equal AUC in patients achieving (A) rapid clearance or (B) slow clearance of 131Itositumomab.

of lead shielding to protect health care workers during preparation and therapeutic procedures, and special precautions to minimize exposure of family members and caregivers following discharge. Patients first receive an infusion of ‘cold’ unlabeled tositumomab to optimize the biodistribution and tumor targeting of radiolabeled antibody. One hour after receiving cold antibody, 5 mCi of 131I-tositumomab is administered, and patients then undergo dosimetric whole-body imaging on at least three occasions during the following week. From these imaging studies, the total-body counts can be calibrated against standard activities to establish the activity necessary to deliver the prescribed TBD. Once the activity required to deliver the prescribed dose has been calculated, patients receive a second infusion of cold tositumomab, again to improve biodistribution and tumor uptake, followed by the therapeutic radiolabeled agent, usually 1 to 2 weeks after the dosimetric study.

Efficacy of

131I-Tositumomab

Some of the studies that have provided evidence of the efficacy of 131I-tositumomab in the treatment of refractory NHL are discussed here. In 1990, a single-center phase I/II dose-ranging study (131I-tositumomab 25 to 85 cGy TBD) was initiated in patients (N ⫽ 59; median age, 50 years; range, 23 to 75 years) with relapsed or refractory B-cell NHL; 88% had stage III/IV disease (47% with low-grade, 24% with transformed, and 29% with intermediate- or high-grade lymphoma).10,11 Patients were required to have less than 25% bone marrow involvement by lymphoma. Most had been heavily pretreated (median three prior chemotherapy regimens) and 48% had not responded to their most recent chemotherapy. This dose-ranging study was undertaken to establish the critical organ for treatment, which was identified as the bone marrow, and the maximum tolerated dose TBD, which was identified as 75 cGy. The overall response rate (ORR) was 71%, with complete responses (CR) in 34%; median progression-free survival (PFS) was approximately 12 months (20.3 months for those who achieved a CR). At 3.1 years of followup, the 5-year Kaplan-Meier estimates were 42% for overall survival and 14% for PFS.11 Response rates were higher in

V. Lewington

S52 patients with low-grade disease compared with intermediateor high-grade disease (83% v 41%; P ⬍.005). Serum lactate dehydrogenase (LDH) levels were predictive of response; patients with normal levels were more likely to respond than those with elevated levels (86% v 57%, respectively; P ⫽ .012). Increasing the TBD (⬍65 cGy v ⱖ65 cGy) resulted in a higher ORR (P ⫽ .012). The dose-limiting toxicity was hematologic (grade 3/4 leukopenia and thrombocytopenia). Nonhematologic adverse events were primarily fever, asthenia, nausea and chills. Human anti-murine antibodies (HAMA) developed in 17% of patients showing the wellrecognized potential of murine antibodies to elicit an immune response. Of 42 patients who responded to the initial therapeutic dose, 16 were retreated following disease progression. A second response was achieved in nine patients (56%; 5 CRs, 31%), with a median PFS of 11.4 months.11 The maximum tolerated TBD of 75 cGy was subsequently adjusted to 65 cGy in patients with mild thrombocytopenia (platelets, 100 to 149/mm3) and 45 cGy in patients who had received previous stem cell transplantation (SCT), in whom bone marrow reserve was compromised. In a multicenter phase II trial of 131I-tositumomab in patients (N ⫽ 45; median age, 49 years; median of four prior therapies) with refractory low-grade or transformed NHL, the ORR was 57% (CR, 32%) and the median response duration for all patients was 9.9 months. Among the 15 patients who achieved a CR (including five patients [50%] with transformed NHL), median duration of response was 19.9 months.12 As previously, patients were required to have less than 25% marrow involvement by lymphoma. Response rates were similar in patients with low-grade or transformed disease (ORR 57% v 60%, respectively). Median time to disease progression was 11.6 months for responders, compared with 5.3 months for nonresponders. To establish the proportions of the observed clinical activity attributable to 131I and to tositumomab, 131I-tositumomab was compared with unlabeled antibody in a multicenter, randomized phase II study involving 78 patients (97% with follicular NHL; 88% with stage III/IV disease). Forty-two patients received 131I-tositumomab (75 cGy TBD preceded by unlabeled tositumomab 485 mg) and 36 received unlabeled antibody (two doses of 485 mg).13,14 Patients (median age, 55 years; range, 28 to 85 years) with previously treated disease (median two prior chemotherapies; range, 1 to 5) had progressed within 12 months of their last chemotherapy. In this crossover study, those who failed treatment with the unlabeled agent could receive treatment with 131I-tositumomab. A greater proportion of patients achieved a response with 131I-tositumomab than with the unlabeled antibody (ORR, 55% v 19%, P ⬍.002; CR, 33% v 8%, P ⫽ .012).15 Those patients who received 131I-tositumomab after failing to achieve a response to cold antibody (N ⫽ 19) achieved an ORR of 68% (CR, 42%).13 HAMA response was detected in 19% of patients who received 131I-tositumomab and 27% of patients who received unlabeled antibody.14 131I-tositumomab was studied in a nonrandomized phase III trial of efficacy and response duration in patients with refractory low-grade or transformed NHL. This study com-

pared the response to 131I-tositumomab (75 cGy TBD) with that achieved following each patient’s last qualifying chemotherapy (LQC) in patients (N ⫽ 60; median age, 60 years; range, 38 to 82 years) with no more than 25% bone marrow involvement by lymphoma who had previously received at least two chemotherapy regimens (median, 4; range, 2 to 13).15 Significantly higher ORR and CR rates were achieved following 131I-tositumomab than with the LQC (ORR, 65% v 28%, P ⬍.001; CR, 20% v 3%, P ⬍.001). Univariate analyses showed significantly higher response rates in patients with a low tumor burden (ORR, 81%), low-grade NHL (ORR, 81%), bone marrow involvement (ORR, 82%), no prior radiotherapy exposure (ORR, 77%) and those who had received less than four prior chemotherapy regimens (ORR, 90%). The duration of response was significantly higher following 131Itositumomab compared with the LQC (6.5 months v 3.4 months; P ⬍.001). Median PFS for patients responding to their LQC was 6.3 months, compared with 8.4 months for patients responding to 131I-tositumomab. The primary endpoint of the study was the comparison of the number of patients who had a longer duration of response (greater than 30 days difference) after the LQC regimen with the number of patients who had a longer response following 131I-tositumomab therapy. Equivalent response durations (ⱕ30 days difference) were achieved in 17 patients (28%); among the remaining 43 patients, 11 (26%) had a longer duration of response after their LQC, and 32 (74%) had a longer duration of response after 131I-tositumomab (P ⬍.001). The median duration of response in patients who achieved a CR was not reached at 47 months. Adverse events associated with 131I-tositumomab therapy are primarily hematologic. Nonhematologic toxicities were found to be transient and mild to moderate in severity. The median nadirs for absolute neutrophil count (ANC) and platelet counts were 800/mm3, occurring after 43 days, and 50,000/mm3, at 34 days, respectively. Twenty percent of patients developed an ANC ⬍500/mm3, and 22% developed a platelet count of ⬍25,000/mm3. One patient required admission to hospital for febrile neutropenia (ANC ⬍1,000/mm3).15 This trial was followed by a multicenter expanded-access study involving 394 patients (80% with low-grade NHL, 20% intermediate-grade NHL, median two prior chemotherapies). In this study, 131I-tositumomab produced an ORR of 59% (CR, 26%), and the median duration of response was 15 months. The most common toxicity was reversible myelosuppression.16 131I-Tositumomab

in Rituximab-Refractory NHL

As the use of rituximab in patients with NHL becomes more commonplace, the number of patients with rituximab-refractory disease increases. The efficacy of 131I-tositumomab in this population was examined by Horning et al17,18 in a study of 40 patients in which 131I-tositumomab (75 cGy or 65 cGy TBD) produced a 68% ORR (CR, 30%), with a median duration of response for all patients of 14.7 months. Patients

Development of

131I-tositumomab

(median age, 57 years) were heavily pretreated (median, four prior chemotherapy regimens) and 32% had bone marrow involvement. However, only 28% had bulky disease, which is perhaps unusual in this population and may have contributed to the high CR rate achieved. 131I-Tositumomab

as First-Line Therapy All the studies described above involved previously treated patients. 131I-tositumomab was studied as first-line therapy in patients (N ⫽ 76) with newly diagnosed stage III/IV follicular lymphoma. The median activity of 131I-tositumomab administered in this study was 92 mCi, producing an ORR of 95% (CR, 74%).19 As expected, hematologic toxicity was lower than that reported for previously treated patients. The immunocompetence of these previously untreated patients was also reflected in a high rate of HAMA response (63%).

Toxicity The major side effects of 131I-tositumomab are hematologic. In the phase III study, 20% of patients experienced grade 4 neutropenia and 22% experienced grade 4 thrombocytopenia.15 Intervention was not generally required. The nadir in white cell and platelet counts typically occurs 4 to 6 weeks after treatment, with a slow recovery by weeks 8 to 9. The predominant nonhematologic side effects are influenza-like symptoms (fatigue, 41%; nausea, 38%; fever, 34%) arising from the infusion of antibody.12 These reactions are occasionally severe but are usually manageable with use of prophylactic antipyretics and antihistamines. Side effects such as headache, cough, malaise, edema, and rash occur with a frequency of less than 20%.12

Myelodysplasia/ Acute Myeloid Leukemia A number of studies have suggested a possible association between 131I-tositumomab therapy and the occurrence of secondary myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia (AML). MDS/AML has been reported to occur in up to 8.4% of patients with chemotherapy-refractory NHL treated with 131I-tositumomab,11,16 but no AML or MDS has been observed to date in 76 patients who received 131I-tositumomab as first-line therapy.19Further studies are required to determine the contribution of 131I-tositumomab to the observed rate of secondary MDS/AML.

HAMA Response The clinical significance of HAMA induction following RIT using murine or chimeric antibodies remains unclear. HAMA responses directed to mouse immunoglobulin G (IgG) are generally considered undesirable because they can interfere with mouse antibody-based clinical tests and have been reported to be clinically significant, compromising mouse an-

S53 Table 2 Factors Influencing Response to Treatment With Tositumomab Factor Tumor burden >500 g <500 g Prior radiotherapy Yes No Histology Low-grade Transformed Bone marrow involvement Yes No No. of prior therapies 2-3 >4 Lactate dehydrogenase (LDH) Normal Raised

131I-

N

ORR (%)

P Value

23 37

39 81

.002

16 44

31 77

.003

36 23

81 39

.004

33 26

82 42

.004

20 40

90 53

.01

70 47

.003

Data from Kaminski et al15 and Montoto et al.24

tibody therapy,20 –22 including antibody-targeted radiotherapy.21 HAMA responses of 17% to 19% have been reported with the use of 131I-tositumomab in previously treated NHL,11,12 and 63% of patients with previously untreated disease.19However, it has been reported that elicitation of HAMA may be associated with improved survival in patients with NHL treated with the murine Lym-1 antibody, possibly via an induced immune cascade.23

Factors Influencing Response to Therapy Several factors have been identified that can influence the response to treatment with 131I-tositumomab (Table 2). Adverse prognostic factors include high tumor burden (tumor load greater than 500 g), unfavorable histology (transformed lymphoma), exposure to ⱖ4 prior therapies,15 and elevated LDH levels.24

Myeloablative Approaches Using 131I-Tositumomab 131I-tositumomab

has been investigated at myeloablative doses, in combination with high-dose chemotherapy and autologous SCT, in patients with NHL. In 1993, Press et al25published the results of a phase I study in 24 patients with relapsed B-cell lymphoma, 19 of whom were treated using 131I-labeled antibodies (131I-tositumomab or anti-CD37). This dose-escalation study predicted a maximum tolerated dose of 27 Gy to critical normal organs (eg, liver, lungs, kidney). Patients received therapeutic infusions of 131I-labeled antibodies, followed by autologous stem cell reinfusion; high response rates were observed (ORR, 95%; CR, 84%) with response duration ranging from 3 to 53

V. Lewington

S54

Figure 2 (A) Progression-free and overall survival in 29 patients with NHL who received myeloablative doses of 131I-tositumomab followed by autologous SCT (ASCT). (B) Progression-free survival with 131I-tositumomab and ASCT (a) compared with that produced by the best previous treatment (b) and last previous chemotherapy (c) experienced by the same patients. (Reprinted from Liu et al,26 with permission of the American Society of Clinical Oncology.)

months. Toxicities were moderate in patients treated to the maximum tolerated TBD and included myelosuppression, nausea, infections, and two episodes of cardiopulmonary toxicity. On the basis of these results, 29 additional patients with high-grade (66%) or intermediate-grade NHL (96% stage III/IV) were treated using 131I-tositumomab.26 Patients (median age, 46 years; range, 24 to 59 years) had received at least one prior treatment (median, 3; range, 1 to 7) and received myeloablative doses of 131I-tositumomab followed by autologous SCT. Among 21 patients who underwent autologous stem cell reinfusion, the ORR was 86% (CR, 79%). The doselimiting toxicity was cardiopulmonary insufficiency. At longterm follow-up (median, 42 months), the 4-year estimated PFS was 42%, with an estimated overall survival of 68% (Fig 2A), which represented a dramatic improvement compared with the PFS following the best previous treatment and last previous chemotherapy (Fig 2B). Estimated overall survival at 4 years was 78% for patients with indolent lymphoma, and 43% for patients with aggressive histologies. Late toxicities were rare, with the exception of elevated thyroid-stimulating hormone levels, which occurred in 60% of patients. The conclusion drawn from this study was that myeloablative doses of 131I-tositumomab are relatively well tolerated when autologous hematopoietic stem cell support is provided. Despite these promising results, however, one-half of patients undergoing myeloablative treatment with 131I-tositumomab followed by autologous SCT had relapsed at 4 years. To improve response rates and the duration of remission, attempts were made to combine 131I-tositumomab myeloablative therapy with high-dose chemotherapy and stem cell support.27 In this study, 52 patients with relapsed follicular lymphoma (73%) or aggressive or transformed NHL received a myeloablative dose of 131I-tositumomab delivered to ensure that the dose-limiting organs received a dose of 20 to 27 Gy. Patients were then given etoposide (60 mg/kg) plus cyclophosphamide (100 mg/kg), followed by autologous SCT. The maximum dose of 131I-tositumomab that could be safely combined with this regimen delivered 25 Gy to critical organs.

Among 31 evaluable patients, the ORR was 83% (CR, 77%); at 2 years, overall survival and PFS for all treated patients were 83% and 68%, respectively. These findings compare favorably with those from a control group of patients who received the same chemotherapy regimen with total-body irradiation to a dose of 12 Gy substituted for 131I-tositumomab (overall survival, 53%; PFS, 36%, both at 2 years).27 All patients experienced severe myelosuppression after treatment, but all evaluable patients achieved engraftment. Adverse events associated with this treatment regimen included mucositis (92%), nausea (63%), and infections (63%). Abnormalities in liver function tests occurred in 81% of patients, but were mild and transient in all but 4%. Thyroid-stimulating hormone was elevated in 56% of patients, necessitating thyroid hormone replacement therapy. Eight of the 52 patients experienced grade 3/4 toxicity, including three patients with adult respiratory distress syndrome, three patients with mucositis or gastrointestinal toxicity, and one with reversible veno-occlusive disease. There were four fatal infections. HAMA response was initially 21% but fell to 15% in subsequent assays.

Future Investigations Trials are planned or currently underway to investigate the combination of 131I-tositumomab with chemotherapy regimens. In addition, a number of strategies have been proposed to enhance the efficacy and durability of RIT (Table 3).

Improving Uptake or Penetration of 131I-Tositumomab Tumors have a heterogeneous blood supply, which can result in variable antibody diffusion and reduce the reliability of 131I-tositumomab delivery. Furthermore, poor perfusion results in patchy hypoxia, which can contribute to radioresistance.

Development of

131I-tositumomab

Table 3 Potential Ways in Which Efficacy and Duration of Response to Radioimmunotherapy Could be Enhanced ● ● ● ● ● ● ●

Improve uptake or penetration of antibody Improve therapeutic ratio and tumor dose-rate Improve clearance of nontargeted antibody from blood Protect/rescue nontarget tissues Reduce immunogenicity by humanizing antibodies Use different radiolabels Use radiosensitizers

Several agents, such as polypropylacrylic acid, have been advocated to disrupt cell membranes, leading to increased vascular permeability to large molecules such as antibodies. This approach should facilitate antibody penetration and, in combination with the crossfire effect of long-range ␤-particles, could lead to an improved intra-tumoral dose distribution.

Improving Therapeutic Ratio and Tumor Dose-Rate Because NHL is radiosensitive and appears to have no threshold for cell injury, a higher uptake ratio of tumor to normal organs would be expected to improve efficacy. Several approaches are being investigated to improve the therapeutic ratio. Pretargeting. The efficacy of 131I-tositumomab is limited by the long half-life of circulating radiolabeled antibody, which leads to prolonged exposure of nonantigen-bearing tissues. Strategies that separate the antibody distribution phase from the period of radiation delivery (pretargeting) would be expected to improve the therapeutic ratio. Several options for pretargeting have been described in relation to NHL, the most successful of which exploits the high affinity of streptavidin for biotin.28 In this approach, streptavidin is bound to a specific antigen on the surface of the tumor cells using a monoclonal antibody. After removing unbound antibody– streptavidin complexes from the circulation using a clearing agent, a radiolabeled biotin conjugate is used to target a radioisotope to the tumor-localized streptavidin. This technique has successfully been used in 10 patients with relapsed or refractory NHL.29 Of seven patients who received a 90Ylabeled biotin conjugate, six achieved tumor regression, three achieved a CR, and there was one PR. The tumor-to-wholebody radiation dose-ratio achieved (38:1) was significantly higher than that observed in other studies using conventional RIT, and hematologic toxicity was transient. Fractionation. Fractionation involves administration of multiple, rather than single, doses of 131I-tositumomab and offers several potential advantages. First, repeated administrations mitigate the effects of heterogeneous intra-tumoral antibody uptake and ensure a more uniform radiation dose distribution. Second, radiotherapy increases vascular permeability, thereby improving antibody penetration in sequential treatments. Third, fractionation allows critical tissue recovery

S55 such that a higher cumulative activity can be administered than would be achievable using a single administration30: the therapeutic ratio and maximum tolerated TBD are therefore increased. Finally, fractionation is predicted to increase response duration for biologic therapies. Use of radiosensitizers. Agents that act as radiosensitizers have been shown to increase the efficacy of RIT in preclinical models.31 This strategy offers significant potential for enhancing the efficacy and response duration of RIT and future trials are planned.

Conclusion Future progress in NHL management is likely to include RIT as part of a multi-modality approach, but further research will be necessary to establish the optimal combination and sequence of treatments.

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