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Radioimmunotherapy for Stem Cell Transplantation in Non-Hodgkin's Lymphoma: In Pursuit of a Complete Response

^aHôpital Saint-Louis, Paris, France; ^bUniversity of Nebraska Medical Center, Omaha, Nebraska, USA; ^cCity of Hope National Medical Center, Duarte, California, USA; ^dIstituto Nazionale Tumori, Milan, Italy; ^eBMT & CBB, Chaim Sheba Medical Center, Tel Hashomer, Israel

Key Words. Stem cell transplantation • Lymphoma • Non-Hodgkin's lymphoma • Radioimmunotherapy • Iodine-131 tositumomab • Yttrium-90 ibritumomab tiuxetan

Correspondence: Christian Gisselbrecht, Ph.D., Hôpital Saint-Louis, Hémato-oncologie, 1 Avenue Claude Vellefaux, Paris 75010, France. Telephone: 33-1-4249-9296; Fax: 33-1-4249-9641; e-mail: christian.gisselbrecht{at}sls.ap-hop-paris.fr

Received March 27, 2009; accepted for publication June 1, 2009.

Disclosures: Christian Gisselbrecht: Research funding/contracted research: Bayer Schering Pharma; Julie Vose: Research funding/contracted research: GlaxoSmithKline, Biogen/IDEC; Auayporn Nademanee: None; Alessandro M. Gianni: None; Arnon Nagler: None.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

	ABSTRACT

Top Abstract Introduction The Role of Radioimmunotherapy... Standard-Dose Nonmyeloablative... High-Dose Myeloablative RIT With... Can RIT Be Used... Does RIT Have a... Conclusion Author Contributions References

 
High-dose chemotherapy (HDC) conditioning given in association with autologous stem cell transplantation (ASCT) or reduced-intensity conditioning (RIC) with allogeneic stem cell transplantation (alloSCT) are established treatment approaches for patients with chemotherapy-sensitive, relapsed, aggressive, or low-grade non-Hodgkin's lymphoma (NHL). These approaches have been shown to be the only curative option for patients with relapsed NHL. Despite data suggesting that prolonged event-free survival can be achieved with SCT combined with HDC, there are problems that may limit the utility of this approach for a broad patient population. For example, older patients, who make up the majority of the NHL population, may not be able to withstand the toxicities associated with this intensive regimen, and this therapy combination, especially when it includes the use of total-body irradiation, has been associated with a greater risk for secondary malignancies. Furthermore, relapse is the most common cause of treatment failure after HDC with ASCT and there is a poor success rate for those patients with either chemotherapy-refractory or heavily pretreated, multiple-relapsed disease. Consequently, there is an urgent need for other effective and well-tolerated approaches that will eradicate the residual disease that may persist before SCT, thus improving outcomes for patients with this life-threatening disease. In addition, approaches with better safety profiles would allow older patients to benefit from this therapeutic option. Because lymphomas are highly sensitive to radiation, radioimmunotherapy (RIT) has been used with great success in consolidation therapy and, as a result, there is great interest in exploring the use of RIT, either as a single agent or as augmentation of HDC, as part of a conditioning regimen for ASCT. The flexibility of including RIT as part of conditioning therapy also allows it to be combined with RIC to reduce the toxic effects of HDC. This treatment option replaces any concomitant loss of chemotherapy efficacy with a gain in RIT efficacy. The data so far suggest that the use of RIT in the autologous setting can improve clinical outcome with no added toxicity in these patients, whereas similar positive findings have been reported in preliminary studies of yttrium-90 ibritumomab tiuxetan combined with RIC and alloSCT in high-risk patients.

	INTRODUCTION

Top Abstract Introduction The Role of Radioimmunotherapy... Standard-Dose Nonmyeloablative... High-Dose Myeloablative RIT With... Can RIT Be Used... Does RIT Have a... Conclusion Author Contributions References

 
The principle of stem cell transplantation (SCT) is to eliminate residual disease, thus resulting in a complete response (CR). Elimination of residual disease can be achieved either by using a myeloablative approach, involving intensive (high-dose) immunochemotherapy with or without radiotherapy followed by stem cell replacement from the patients themselves (autologous SCT [ASCT]), or with an immunological approach using stem cells from a matched donor (allogeneic SCT [alloSCT]). AlloSCT is usually performed with a reduced-intensity conditioning (RIC) regimen because it is the immunological process that eliminates residual disease. Although most patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), the two most common types of non-Hodgkin's lymphoma (NHL), achieve a partial response (PR) or a CR following primary combination chemotherapy, 15%–40% of patients with DLBCL treated with rituximab and almost all patients with FL relapse [1, 2]. Indeed, NHL is characterized by continued relapse and shorter duration of response, and high-dose chemotherapy (HDC) with SCT is the standard treatment approach in patients who have aggressive types of NHL with high-risk features, or who have relapsed or are resistant to chemotherapy. The National Comprehensive Cancer Network guidelines [3] indicate that ASCT or alloSCT should be used in FL as second-line and subsequent therapy (Fig. 1) and in DLBCL as second-line and first-line consolidation in patients with a poor prognosis. However, these recommendations may not be the standard for all countries, and many patients do not qualify because of the intensity of treatment.

View larger version (51K): [in this window] [in a new window]   Figure 1. Autologous stem cell transplantation in relation to other treatment choices for follicular lymphoma. These data are based on guidelines from the National Comprehensive Cancer Network [3]. Abbreviation: NHL, non-Hodgkin's lymphoma.

DLBCL
The PARMA trial demonstrated that ASCT in chemotherapy-sensitive but incurable DLBCL provides a survival benefit over conventional chemotherapy [8]. Furthermore, long-term follow-up after ASCT shows that achievement of a CR in high-grade B-cell NHL (mainly DLBCL) correlates with longer progression-free survival (PFS) and overall survival (OS) times, and that the probability of relapse after achieving a CR is only 16% at 10 years [9]. Consequently, the introduction of SCT as a salvage regimen for NHL has provided a much-needed new and effective treatment approach for this challenging disease.

FL
The European Bone Marrow Transplantation Registry CUP trial also demonstrated that ASCT provides a survival benefit in chemotherapy-sensitive FL patients [10, 11]. Long-term follow-up of FL patients receiving HDC and ASCT also demonstrated that achieving a CR translated into a significant event-free survival (EFS) benefit. At the 7-year follow-up, the EFS rate among patients who achieved a CR was 56% (95% confidence interval [CI], 43%–69%), compared with 36% (95% CI, 31%–43%) for patients who achieved a PR only (p < .001) [7]. In second-relapse FL, myeloablative therapy plus ASCT resulted in 48% of patients still in remission at 12 years, further supporting the beneficial effect of SCT regimens in controlling disease progression [12]. In addition, early intervention using ASCT resulted in a significantly longer survival duration for patients in second remission when compared with the survival time of patients who were treated later in the course of their treatment [12].

These data from both DLBCL and FL patients suggest that SCT can improve survival outcomes for patients with NHL, but an incomplete elimination of residual disease, or less than a CR, may be one reason for the high relapse rates that are still observed in the transplant setting.

Limitations of SCT
Despite significant advances in radiation therapy and chemotherapy regimens over the past 25 years, few randomized studies have been carried out and no consensus has been reached to define the optimal conditioning regimen for leukemias or lymphomas. Relapses occur in many patients receiving HDC in conjunction with ASCT because of a contaminated graft or cancer cells remaining in the patient following ablative chemotherapy [13]. Therefore, several approaches have been attempted to reduce relapse after ASCT for NHL by eliminating residual disease, including in vivo purging of the marrow graft [14], approaches to manage side effects of HDC to maintain dose intensity [15], pre- and post-use of radiotherapy for bulky disease [16], and post-ASCT maintenance treatment with rituximab [13, 17]. Data from trials in mantle cell lymphoma (MCL) and FL have demonstrated that rituximab alone or added to chemotherapy can reduce the contamination of the graft given to the recipient [13].

HDC conditioning regimens (which typically contain strong alkylating agents and topoisomerase II inhibitors) are used in combination with ASCT for patients with aggressive or bulky lymphoma. Generally, the use of HDC is limited to younger and healthier patients, because many compromised and frail patients cannot withstand the toxicities associated with these HDC regimens. Therefore, to overcome the limitations of ASCT and improve survival, there is a need to purge residual disease in the graft and patient prior to administration, thus improving the efficacy of therapy without increasing the toxicity and enhancing treatment options for patients who are not traditional candidates for ASCT as a result of the toxicity associated with HDC.

	THE ROLE OF RADIOIMMUNOTHERAPY AS A PRETRANSPLANT CONDITIONING REGIMEN

Top Abstract Introduction The Role of Radioimmunotherapy... Standard-Dose Nonmyeloablative... High-Dose Myeloablative RIT With... Can RIT Be Used... Does RIT Have a... Conclusion Author Contributions References

 
Radioimmunotherapy (RIT) is comprised of a monoclonal antibody conjugated to a radionuclide that targets a tumor-specific cell-surface antigen. RIT for NHL specifically targets cells expressing the CD20 antigen that is present exclusively on mature B cells and B-cell lymphomas [18]. Two agents are currently used for RIT of NHL [19]: yttrium-90 (⁹⁰Y)-ibritumomab tiuxetan (Zevalin®; Spectrum Pharmaceuticals, Inc., Irvine, CA; Bayer Schering Pharma AG, Berlin, Germany) and iodine-131 (¹³¹I)-tositumomab (Bexxar®; GlaxoSmithKline, Research Triangle Park, NC). ⁹⁰Y-ibritumomab tiuxetan received approval in the European Union (EU) in 2004 for the treatment of relapsed or refractory, low-grade NHL or FL, and more recently received regulatory approval in the EU for use as first-line consolidation of first remission in FL patients. ¹³¹I-tositumomab is only indicated in the U.S. as part of the treatment regimen for relapsed or refractory, low-grade NHL, FL, or transformed NHL.

There is a strong rationale for using RIT as a part of preconditioning treatment for SCT. For example, total-body irradiation (TBI) has traditionally been integrated into transplant regimens for many NHL patients, with the exclusion of the elderly who are unable to tolerate its toxicity. This is especially pertinent because the majority of patients with relapsed or refractory B-cell NHL are >60 years old, and yet are often denied potentially curative HDC and/or TBI and ASCT because of the risk for excessive treatment-related morbidity and mortality [20, 21]. In contrast to TBI, and by virtue of its targeted activity, RIT (conventional and high dose) can be used in elderly patients with comorbidities undergoing SCT, making it appropriate as a pretransplant regimen for a wider patient population [19]; as such, a dramatic decrease in TBI-containing regimens has been observed in data from the European Group for Blood and Marrow Transplantation registry since 2000 [22, 23]. In two studies, ⁹⁰Y-ibritumomab tiuxetan was used to treat patients with NHL who were not eligible for HDC- and/or TBI-containing therapies prior to ASCT. Data demonstrated better disease control in relapsed and refractory FL and transformed B-cell NHL (such as DLBCL and MCL), with no unexpected additional toxicities [24, 25]. Because RIT delivers targeted radiation, it is feasible that any additional therapeutic benefit would be delivered without adding to the HDC-associated toxicity, which could increase the treatment options for older and frailer patients. In recent years, reduced-intensity regimens have been used in conjunction with alloSCT for the treatment of NHL in such patients [26]. Currently, there are two approaches to using RIT in the SCT setting. The first combines standard-dose, nonmyeloablative RIT with either conventional-dose chemotherapy (i.e., a reduced-intensity regimen) in the alloSCT setting, as mentioned above, or HDC prior to ASCT. The second is to use high-dose myeloablative RIT, with or without chemotherapy, mostly based on accurate dosimetry to ensure that enough radiation is delivered directly to the tumor sites while limiting radiation exposure to the rest of the body, particularly the critical organs.

By minimizing the levels of residual disease without increasing the toxicity of HDC, approaches that incorporate RIT in pretransplant conditioning may improve outcomes following SCT [27]. Information on the utility of RIT in the SCT setting is currently evolving and growing, and this paper summarizes data that were presented on this topic at the 6th meeting of the International Workshop on Nuclear Oncology.

	STANDARD-DOSE NONMYELOABLATIVE RIT IN COMBINATION WITH HDC

Top Abstract Introduction The Role of Radioimmunotherapy... Standard-Dose Nonmyeloablative... High-Dose Myeloablative RIT With... Can RIT Be Used... Does RIT Have a... Conclusion Author Contributions References

 
The rationale for combining RIT and chemotherapy is to further minimize the risk for residual disease in SCT and to improve safety by targeting radiation exposure directly to the tumor site. Data from Lenz et al. [6] (German Low Grade Lymphoma Study Group), Deconinck et al. [5] (Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang), and Sebban et al. [7] (Groupe d'Etude des Lymphomes de l'Adulte [GELA]) show that chemotherapy as myeloablative conditioning prior to ASCT is beneficial in patients with FL in terms of PFS. However, the OS advantage remains uncertain because it is as yet unclear whether or not chemotherapy can sufficiently decrease tumor burden and the risk for relapse. Thus, new treatment approaches need to be developed that not only improve remission rates but are also better tolerated, in order to accommodate the older patient population [5–7].

Preliminary data suggest that RIT may be able to replace adjuvant radiotherapy or TBI as a conditioning regimen for SCT in B-cell lymphoma. Promising results from numerous trials (Table 1) suggest that incorporating RIT may significantly improve disease control with negligible added toxicity. Particularly in aggressive lymphomas, the high rates of OS with RIT and HDC seen in the studies below compare favorably with those from historical controls. The superior outcomes observed in the chemotherapy-sensitive NHL population are also attributed to the addition of RIT to SCT conditioning regimens [8]. Combining HDC regimens with ⁹⁰Y-ibritumomab tiuxetan has produced impressive long-term OS rates of 81%–92% in chemotherapy-sensitive patients in preliminary trials in a variety of histologic lymphoma subtypes [28–30]. In the largest preliminary trial to date, in patients with low-grade lymphoma, the inclusion of ⁹⁰Y-ibritumomab tiuxetan with HDC achieved an 80% PFS rate [23]. Recent reports investigating RIT in combination with HDC regimens in patients with chemotherapy-refractory disease have demonstrated higher OS rates of 55% and 87% at 38 months [31] and 30 months [32], respectively; a remarkable result considering that such patients have a 3-year estimated survival rate of <20% when treated with standard HDC and ASCT [27, 33]. Vose et al. [31] also reported an estimated 2-year OS rate of 67%, and another study investigating RIT and high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy with ASCT reported estimated 2-year OS and PFS rates of 67% (95% CI, 46%–87%) and 52% (95% CI, 31%–72%), respectively [34]. Altogether, such improvements in OS rates demonstrate the benefit of adding RIT to ASCT for patients with chemotherapy-refractory NHL. Such promising preliminary data have led to a number of studies investigating different, specific ASCT conditioning regimens that include RIT. The discussion below focuses on data from several key studies that have been reported recently.

View larger version (9K): [in this window] [in a new window]   Figure 2. Overall survival and disease-free survival with 90-yttrium ibritumomab tiuxetan plus high-dose carmustine, etoposide, cytarabine, and melphalan (Z-BEAM regimen) in older patients undergoing autologous stem cell transplantation for poor-risk non-Hodgkin's lymphoma [35]. Adapted from Krishnan A, Nademanee A, Fung HC et al. Phase II trial of a transplantation regimen of yttrium-90 ibritumomab tiuxetan and high-dose chemotherapy in patients with non-Hodgkin's lymphoma. J Clin Oncol 2008;26:90–95, with permission. ©2008 American Society of Clinical Oncology. All rights reserved.

The data above demonstrate that both ⁹⁰Y-ibritumomab tiuxetan and ¹³¹I-tositumomab can significantly improve survival rates without additional toxicity when added to HDC and ASCT.

Safety of Combination Regimens
Secondary malignancies are observed in some patients treated with chemotherapy, and the addition of radiation may increase this risk; for example, a long-term follow-up of 693 FL patients undergoing HDC (including 378 patients receiving a TBI-containing regimen) demonstrated that of the 39 patients who developed these secondary malignancies, 34 had received TBI as the conditioning regimen (p = .04) [20]. Another recent report that retrospectively analyzed 563 patients with indolent lymphoma demonstrated a higher incidence of myelodysplastic syndromes/acute myeloid leukemia, which was associated with fludarabine-containing therapy after a 16-year follow-up [21]. Concerns that the incidence of secondary malignancies would increase with a combination of ⁹⁰Y-ibritumomab tiuxetan plus BEAM followed by ASCT have not been settled [38]. However, data from a larger number of patients with a longer follow-up are needed to establish whether or not there is cause for concern. Interestingly, patients receiving RIT with HDC may be at no greater risk for secondary malignancies than those treated with HDC alone; this has been demonstrated in a number of studies in which the addition of RIT to HDC showed that adverse events were similar to those seen with high-dose BEAM alone and that there was no greater toxicity level [31, 37]. Furthermore, no secondary malignancies have been reported with standard-dose ⁹⁰Y-ibritumomab tiuxetan [36].

	HIGH-DOSE MYELOABLATIVE RIT WITH OR WITHOUT CHEMOTHERAPY

Top Abstract Introduction The Role of Radioimmunotherapy... Standard-Dose Nonmyeloablative... High-Dose Myeloablative RIT With... Can RIT Be Used... Does RIT Have a... Conclusion Author Contributions References

 
Data from studies of high-dose RIT plus HDC and ASCT are promising, but the use of HDC in this setting may still be too aggressive for many patients who may benefit from ASCT. Therefore, high-dose, single-agent RIT prior to ASCT may be a promising new approach for patients with relapsed B-cell lymphoma. Because of the acceptable tolerability of RIT, a conditioning regimen that includes high-dose RIT but excludes HDC may be appropriate for a broader range of patients for whom myeloablative chemotherapy regimens are too toxic. This hypothesis has been, and still is being, evaluated in clinical trials [32, 39–42] (Table 1). In the following section, we review data that have recently emerged on the safety and efficacy of high-dose RIT prior to ASCT.

Safety of High-Dose Myeloablative RIT
At therapeutic doses, high-dose RIT is well tolerated [39, 40, 43, 44]. In dose-finding studies, the maximum-tolerated dose and dose-limiting toxicities of RIT were defined. This approach provided the opportunity to identify doses that gave the highest radiation concentration in the tumor while minimizing total-body radiation exposure. For high-dose ⁹⁰Y-ibritumomab tiuxetan prior to ASCT, 1.2 mCi/kg (45 MBq/kg) was defined as the maximum recommended dose because the radiation absorbed by nonhematologic critical organs approached the protocol-defined upper safety limit. In a recent publication by Devizzi et al. [32], the maximum dose given to 17 patients was 1.2 mCi/kg (45 MBq/kg), and no further dose escalation was attempted because 11 of these patients exhibited an absorbed dose close to the upper tolerance limits for the absorbed dose.

In phase I dose-escalation studies of ¹³¹I-tositumomab, 27 Gy was determined to be the maximum-tolerated level of radiation that can be delivered to normal critical organs, with limited nonhematologic toxicity and maintained efficacy [40, 45]. These data established the optimal therapeutic dose as 2.5 mg/kg antibody labeled with 5–10 mCi ¹³¹I. However, in practice, and as a result of the fact that iodine is absorbed by the thyroid, the use of high-dose ¹³¹I-tositumomab treatment can be complicated for both health care professionals and patients, because therapeutic doses may have a long total-body residence time and patients may require radiation isolation in specialist hospital facilities [46]. When patients are released, they may also have to adhere to instructions outside their normal daily activities, for example, sleeping in a separate bed, minimizing close contact with others, and delaying their return to work [46]. In contrast, following treatment with ⁹⁰Y-ibritumomab tiuxetan, patients are readily discharged with advice on how to properly manage bodily fluid spillages [47]. Furthermore, unlike treatment with ¹³¹I-tositumomab, patients are not required to minimize contact with others [48, 49].

Efficacy of High-Dose ⁹⁰Y-Ibritumomab Tiuxetan
Preliminary data suggest that ⁹⁰Y-ibritumomab tiuxetan, when used at two to three times the registered dose, is a well-tolerated and effective conditioning regimen prior to ASCT. In a very recent report, in 30 patients with CD20⁺ NHL that was either relapsed/refractory or de novo high risk (FL, 12; DLBCL, 10; lymphocytic lymphoma, 2; MCL, 3; MZL, 2; Richter syndrome, 1), ⁹⁰Y-ibritumomab tiuxetan administered at doses of 0.8 mCi/kg or 1.2 mCi/kg was well tolerated [32]. Hematologic toxicities were mild to moderate and of short duration. Only eight (27%) patients experienced infections, and only three (10%) patients required short hospital stays for grade 3 febrile neutropenia; no secondary myeloid malignancies/chromosomal abnormalities were evident after a mean observation time of 30 months. A disease-free status was achieved by 25 (83%) patients, two patients had a PR, and three had disease progression. The projected OS and EFS rates after a median follow-up of 30 months were 87% and 69%, respectively. These data are extremely promising because these patients are historically associated with an extremely poor prognosis [50]. The good tolerability of ⁹⁰Y-ibritumomab tiuxetan demonstrated in that study suggests that the agent may be appropriate for the majority of NHL patients as an outpatient treatment [32, 43].

High-dose ⁹⁰Y-ibritumomab tiuxetan plus HDC (high-dose etoposide and cyclophosphamide) was also investigated as a conditioning regimen before SCT in 42 patients (median age, 51 years) with poor-risk or refractory B-cell NHL [30]. The median dose of ⁹⁰Y-ibritumomab tiuxetan used was 70.8 mCi. The regimen showed promising long-term efficacy, especially for FL and DLBCL patients, and an excellent safety profile without additional toxicity. At a median follow-up of 55 months (range, 25–84 months) for the surviving patients, the 4-year estimated OS and disease-free survival rates were 81% and 65%, respectively (Fig. 3). Engraftment was achieved in all but one patient, and the incidence of second malignancy (7%) with high-dose ⁹⁰Y-ibritumomab tiuxetan plus HDC was similar to that of high-dose regimens that did not include RIT [30, 51].

View larger version (9K): [in this window] [in a new window]   Figure 3. Overall survival and disease-free survival in poor-risk or refractory B-cell non-Hodgkin's lymphoma patients treated with high-dose 90-yttrium ibritumomab tiuxetan plus high-dose chemotherapy followed by autologous stem cell transplantation [30].

The results from the studies above demonstrate that high-dose myeloablative RIT with or without chemotherapy and ASCT is a promising and effective treatment option for patients unable to tolerate HDC. Furthermore, the excellent tolerability demonstrated even by patients with poor-risk characteristics suggests that this approach may broaden the patient population who would benefit from SCT, thus offering a curative potential to a larger number of NHL patients.

	CAN RIT BE USED POST-TRANSPLANT?

Top Abstract Introduction The Role of Radioimmunotherapy... Standard-Dose Nonmyeloablative... High-Dose Myeloablative RIT With... Can RIT Be Used... Does RIT Have a... Conclusion Author Contributions References

 
Currently, few data are available for the use of RIT in patients who have relapsed after HDC and transplantation (Table 2). However, these preliminary studies with ⁹⁰Y-ibritumomab tiuxetan [52, 53] and ¹³¹I-tositumomab [54] suggest that RIT may be a viable option for some patients after ASCT failure. In a study by Vose et al. [53], 19 patients who failed transplant (DLBCL, 58%; FL, 32%; MCL, 5%; MZL, 5%) were treated with ⁹⁰Y-ibritumomab tiuxetan (0.10–0.20 mCi/kg). The response rate was 47% and, at a median follow-up of 37 months, the 1-year EFS and OS rates were 26% and 57%, respectively. Although hematologic toxicities were dose limiting, the EFS and OS rates were higher with higher doses in the overall study population and also in the subset of patients with FL. In a second preliminary study (n = 13) of RIT (¹³¹I-tositumomab, 45 cGy total-body dose) in chemotherapy-relapsed or chemotherapy-refractory B-cell lymphoma patients (histology not specified), the objective response rate was 50% (compared with 78% for nonperipheral SCT failures), and at 4.7 years, the median PFS time of responders had not been reached. Notably, 31% of patients were disease free at 3 years post-therapy [54]. Although these preliminary data are promising, further investigation is needed to clarify the appropriate dose of ⁹⁰Y-ibritumomab tiuxetan and ¹³¹I-tositumomab to be used and the level of risk for myelodysplasia, acute myeloid leukemia, and hematologic toxicities in this setting.

	DOES RIT HAVE A ROLE IN NONMYELOABLATIVE CONDITIONING IN ALLOSCT?

Top Abstract Introduction The Role of Radioimmunotherapy... Standard-Dose Nonmyeloablative... High-Dose Myeloablative RIT With... Can RIT Be Used... Does RIT Have a... Conclusion Author Contributions References

⁹⁰Y-Ibritumomab Tiuxetan Case Study
A ⁹⁰Y-ibritumomab tiuxetan case study (Fig. 4) illustrates the long-term effectiveness of RIT as a component of an RIC regimen for alloSCT in a 27-year-old patient with mediastinal large B-cell lymphoma (Dr. Dolores Caballero, Transplant Unit, University Hospital, Salamanca, Spain, personal communication).

View larger version (23K): [in this window] [in a new window]   Figure 4. Schematic figure of case study. aOral beclometasone (2 mg every 6 hours) and i.v./oral prednisone (1 mg/kg every 6 hours). Abbreviations: AlloSCT, allogeneic stem cell transplantation; CR, complete response; CT, computed tomography; FDG, 18F-fluoro-2-deoxyglucose; gvh, graft versus host; HLA, human lymphocyte antibody; PET-CT, positron emission tomography–computed tomography; PR, partial response; RIC, reduced-intensity conditioning (fludarabine, 30 mg/m2 per day on day –8 to day –3, plus melphalan, 70 mg/m2 per day on day –2 to day –1); R-IFE, rituximab, ifosfamide, and etoposide; R-MegaCHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

	CONCLUSION

Top Abstract Introduction The Role of Radioimmunotherapy... Standard-Dose Nonmyeloablative... High-Dose Myeloablative RIT With... Can RIT Be Used... Does RIT Have a... Conclusion Author Contributions References

All these studies indicate a promising role for RIT-based conditioning regimens for SCT, particularly in patients who cannot tolerate HDC and/or TBI. Based on these data, large-scale trials should be performed to investigate and further confirm these key observations.

	AUTHOR CONTRIBUTIONS

Top Abstract Introduction The Role of Radioimmunotherapy... Standard-Dose Nonmyeloablative... High-Dose Myeloablative RIT With... Can RIT Be Used... Does RIT Have a... Conclusion Author Contributions References

 
Conception/Design: Auayporn Nademanee, Alessandro M. Gianni, Arnon Nagler

Provision of study materials: Christian Gisselbrecht, Julie Vose, Auayporn Nademanee, Alessandro M. Gianni, Arnon Nagler

Collection/assembly of data: Christian Gisselbrecht, Alessandro M. Gianni, Arnon Nagler

Data analysis: Christian Gisselbrecht, Julie Vose, Auayporn Nademanee, Alessandro M. Gianni

Manuscript writing: Christian Gisselbrecht, Julie Vose, Auayporn Nademanee, Alessandro M. Gianni, Arnon Nagler

Final approval of manuscript: Christian Gisselbrecht, Julie Vose, Auayporn Nademanee, Alessandro M. Gianni, Arnon Nagler

The authors take full responsibility for the scope, direction, and content of the manuscript and have approved the submitted manuscript. They would like to thank Lynda Chang, Ph.D., and Maxine Holland, B.Sc., Complete HealthVizion, for their assistance in the preparation and revision of the draft manuscript, based on detailed discussion and feedback from all the authors. Editorial assistance was supported by a grant from Bayer HealthCare Pharmaceuticals.

	REFERENCES

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1. Feugier P, Van Hoof A, Sebban C et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 2005;23:4117–4126.[Abstract/Free Full Text]
2. Armitage JO. Treatment of non-Hodgkin's lymphoma. N Engl J Med 1993;328:1023–1030.[Free Full Text]
3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin's Lymphomas. Available at http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. accessed October 13, 2008.
4. Baron F, Maris MB, Sandmaier BM et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 2005;23:1993–2003.[Abstract/Free Full Text]
5. Deconinck E, Foussard C, Milpied N et al. High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: A randomized multicenter study by GOELAMS. Blood 2005;105:3817–3823.[Abstract/Free Full Text]
6. Lenz G, Dreyling M, Schiegnitz E et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: Results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 2004;104:2667–2674.[Abstract/Free Full Text]
7. Sebban C, Mounier N, Brousse N et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: The GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 2006;108:2540–2544.[Abstract/Free Full Text]
8. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 1995;333:1540–1545.[Abstract/Free Full Text]
9. Bertz H, Zeiser R, Lange W et al. Long-term follow-up after high-dose chemotherapy and autologous stem-cell transplantation for high-grade B-cell lymphoma suggests an improved outcome for high-risk patients with respect to the age-adjusted International Prognostic Index. Ann Oncol 2004;15:1419–1424.[Abstract/Free Full Text]
10. Schouten HC, Kvaloy S, Sydes M et al. The CUP trial: A randomized study analyzing the efficacy of high dose therapy and purging in low-grade non-Hodgkin's lymphoma (NHL). Ann Oncol 2000;11(suppl 1):91–94.[Abstract/Free Full Text]
11. Schouten HC, Qian W, Kvaloy S et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: Results from the randomized European CUP trial. J Clin Oncol 2003;21:3918–3927.[Abstract/Free Full Text]
12. Rohatiner AZS, Nadler L, Davies AJ et al. Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: Long-term follow-up. J Clin Oncol 2007;25:2554–2559.[Abstract/Free Full Text]
13. Gianni AM, Berinstein NL, Evans PA et al. Stem-cell transplantation in non-Hodgkin's lymphoma: Improving outcome. Anticancer Drugs 2002;13(suppl 2):S35–S42.[Medline]
14. Gribben JG, Freedman AS, Neuberg D et al. Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med 1991;325:1525–1533.[Abstract]
15. Moskowitz CH, Hamlin PA, Gabrilove J et al. Maintaining the dose intensity of ICE chemotherapy with a thrombopoietic agent, PEG-rHuMGDF, may confer a survival advantage in relapsed and refractory aggressive non-Hodgkin lymphoma. Ann Oncol 2007;18:1842–1850.[Abstract/Free Full Text]
16. Weaver CH, Petersen FB, Appelbaum FR et al. High-dose fractionated total-body irradiation, etoposide, and cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma. J Clin Oncol 1994;12:2559–2566.[Abstract/Free Full Text]
17. Gisselbrecht C, Mounier N. Rituximab: Enhancing outcome of autologous stem cell transplantation in non-Hodgkin's lymphoma. Semin Oncol 2003;30(suppl 2):28–33.[Medline]
18. Stashenko P, Nadler LM, Hardy R et al. Characterization of a human B lymphocyte-specific antigen. J Immunol 1980;125:1678–1685.[Abstract]
19. Gregory SA, Hohloch K, Gisselbrecht C et al. Harnessing the energy: Development of radioimmunotherapy for patients with non-Hodgkin's lymphoma. The Oncologist 2009;14(suppl 2):4–16.[Abstract/Free Full Text]
20. Montoto S, Canals C, Rohatiner AZS et al. Long-term follow-up of high-dose treatment with autologous haematopoietic progenitor cell support in 693 patients with follicular lymphoma: An EBMT registry study. Leukemia 2007;21:2324–2331.[CrossRef][Medline]
21. Sacchi S, Marcheselli L, Bari A et al. Secondary malignancies after treatment for indolent non-Hodgkin's lymphoma: A 16-year follow-up study. Haematologica 2008;93:398–404.[Abstract/Free Full Text]
22. Gisselbrecht C, Bethge W, Duarte RF et al. Current status and future perspectives for yttrium-90 (90Y)-ibritumomab tiuxetan in stem cell transplantation for non-Hodgkin's lymphoma. Bone Marrow Transplant 2007;40:1007–1017.[CrossRef][Medline]
23. Gisselbrecht C. Completing the picture: Results of the GELA-Z-BEAM trial in follicular lymphoma. Presented at the EBMT 2008; Month dd,-dd 7777; location. Painting a brighter future: Improving clinical outcomes in transplant patients with NHL and CLL.
24. Schilder R, Molina A, Bartlett N et al. Follow-up results of a phase II study of ibritumomab tiuxetan radioimmunotherapy in patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma and mild thrombocytopenia. Cancer Biother Radiopharm 2004;19:478–481.[Medline]
25. Morschhauser F, Illidge T, Huglo D et al. Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation. Blood 2007;110:54–58.[Abstract/Free Full Text]
26. Gopal AK, Pagel JM, Rajendran JG et al. Improving the efficacy of reduced intensity allogeneic transplantation for lymphoma using radioimmunotherapy. Biol Blood Marrow Transplant 2006;12:697–702.[CrossRef][Medline]
27. Shimoni A, Nagler A. Radioimmunotherapy and stem-cell transplantation in the treatment of aggressive B-cell lymphoma. Leuk Lymphoma 2007;48:2110–2120.[CrossRef][Medline]
28. Khouri IF, Saliba RM, Hosing C et al. Efficacy and safety of yttrium 90 (⁹⁰Y) ibritumomab tiuxetan in autologous and nonmyeloablative stem cell transplantation (NST) for relapsed non-Hodgkin's lymphoma (NHL). Blood 2006;108:Abstract 315.
29. Nademanee A, Forman S, Molina A et al. A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood 2005;106:2896–2902.[Abstract/Free Full Text]
30. Nademanee A, Raubitschek A, Molina A et al. Updated results of high-dose yttrium 90 (⁹⁰Y) ibritumomab tiuxetan with high-dose etoposide (VP-16) and cyclophosphamide (CY) followed by autologous hematopoietic cell transplant (AHSCT) for poor-risk or refractory B-cell non-Hodgkin's lymphoma. Blood 2007;110:Abstract 1891.
31. Vose JM, Bierman PJ, Enke C et al. Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin's lymphoma. J Clin Oncol 2005;23:461–467.[Abstract/Free Full Text]
32. Devizzi L, Guidetti A, Tarella C et al. High-dose yttrium-90-ibritumomab tiuxetan with tandem stem-cell reinfusion: An outpatient preparative regimen for autologous hematopoietic cell transplantation. J Clin Oncol 2008;26:5175–5182.[Abstract/Free Full Text]
33. Philip T, Armitage JO, Spitzer G et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med 1987;316:1493–1498.[Abstract]
34. Shimoni A, Zwas ST, Oksman Y et al. Yttrium-90-ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin's lymphoma. Exp Hematol 2007;35:534–540.[CrossRef][Medline]
35. Krishnan A, Nademanee A, Fung HC et al. Phase II trial of a transplantation regimen of yttrium-90 ibritumomab tiuxetan and high-dose chemotherapy in patients with non-Hodgkin's lymphoma. J Clin Oncol 2008;26:90–95.[Abstract/Free Full Text]
36. Shimabukuro-Vornhagen A, Josting A, Hübel K et al. Yttrium-90 ibritumomab tiuxetan combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for relapsed/refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol 2008;26(15 suppl. Abstract 8615.
37. Vose J, Bierman P, Bociek G et al. Radioimmunotherapy with 131-I tositumomab enhanced survival in good prognosis relapsed and high-risk diffuse large B-cell lymphoma (DLBCL) patients receiving high-dose chemotherapy and autologous stem cell transplantation. J Clin Oncol 2007;25(18 suppl. Abstract 8013.
38. Seshadri T, Pintilie M, Tsang R et al. Second cancers after autologous hematopoietic stem cell transplantation (ASCT) for relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL). Blood 2007;110:Abstract 1673.
39. Gopal AK, Rajendran JG, Gooley TA et al. High-dose ¹³¹I tositumomab (anti-CD20) radioimmunotherapy and autologous hematopoietic stem-cell transplantation for adults 60 years old with relapsed or refractory B-cell lymphoma. J Clin Oncol 2007;25:1396–1402.[Abstract/Free Full Text]
40. Liu SY, Eary JF, Petersdorf SH et al. Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue. J Clin Oncol 1998;16:3270–3278.[Abstract]
41. Vanazzi A, Ferrucci P, Grana C et al. High dose ⁹⁰yttrium ibritumomab tiuxetan with PBSC support in refractory-resistant NHL patients [abstract 1890]. Presented at the 2008 American Society for Hematology Annual Meeting; December 6–9, 2008; San Francisco, CA.
42. Swinnen LJ, Flinn IW, Kahl B et al. Phase I trial of yttrium 90 ibritumomab tiuxetan ⁹⁰Y-RIT with autologous stem cell transplantation (ASCT) in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). J Clin Oncol 2008;26(15 suppl. Abstract 8565.
43. Devizzi L, Seregni E, Guidetti A et al. High-dose myeloablative Zevalin radioimmunotherapy with tandem stem-cell autografting has promising activity, minimal toxicity and full feasibility in an outpatient setting. Blood 2006;108:Abstract 3047.
44. Press OW, Eary JF, Appelbaum FR et al. Phase II trial of ¹³¹I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas. Lancet 1995;346:336–340.[CrossRef][Medline]
45. Press OW, Eary JF, Appelbaum FR et al. Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support. N Engl J Med 1993;329:1219–1224.[Abstract/Free Full Text]
46. Cole WC, Barrickman J, Bloodworth G. Essential role of nuclear medicine technology in tositumomab and ¹³¹I-tositumomab therapeutic regimen for non-Hodgkin's lymphoma. J Nucl Med Technol 2006;34:67–73.[Abstract/Free Full Text]
47. Wagner HN Jr, Wiseman GA, Marcus CS et al. Administration guidelines for radioimmunotherapy of non-Hodgkin's lymphoma with ⁹⁰Y-labeled anti-CD20 monoclonal antibody. J Nucl Med 2002;43:267–272.[Abstract/Free Full Text]
48. Meredith RF. Logistics of therapy with the ibritumomab tiuxetan regimen. Int J Radiat Oncol Biol Phys 2006;66(2 suppl):S35–S38.[Medline]
49. Emmanouilides C. Radioimmunotherapy for non-Hodgkin lymphoma: Historical perspective and current status. J Clin Exp Hematop 2007;47:43–60.[CrossRef][Medline]
50. Press OW. Evidence mounts for the efficacy of radioimmunotherapy for B-cell lymphomas. J Clin Oncol 2008;26:5147–5150.[Free Full Text]
51. Krishnan A, Bhatia S, Slovak ML et al. Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: An assessment of risk factors. Blood 2000;95:1588–1593.[Abstract/Free Full Text]
52. Jacobs SA, Vidnovic N, Joyce J et al. Full-dose ⁹⁰Y ibritumomab tiuxetan therapy is safe in patients with prior myeloablative chemotherapy. Clin Cancer Res 2005;11(19 Suppl):7146s–7150s.[Abstract/Free Full Text]
53. Vose JM, Bierman PJ, Loberiza FR Jr et al. Phase I trial of ⁹⁰Y-ibritumomab tiuxetan in patients with relapsed B-cell non-Hodgkin's lymphoma following high-dose chemotherapy and autologous stem cell transplantation. Leuk Lymphoma 2007;48:683–690.[CrossRef][Medline]
54. Kaminski MS, Estes J, Zasadny KR et al. Radioimmunotherapy with iodine ¹³¹I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: Updated results and long-term follow-up of the University of Michigan experience. Blood 2000;96:1259–1266.[Abstract/Free Full Text]
55. Shimoni A, Zwas ST, Oksman Y et al. Ibritumomab tiuxetan (Zevalin) combined with reduced-intensity conditioning and allogeneic stem-cell transplantation (SCT) in patients with chemorefractory non-Hodgkin's lymphoma. Bone Marrow Transplant 2008;41:355–361.[CrossRef][Medline]
56. Winter JN, Inwards DJ, Spies S et al. Yttrium-90 ibritumomab tiuxetan doses calculated to deliver up to 15 Gy to critical organs may be safely combined with high-dose BEAM and autologous transplantation in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol 2009;27:1653–1659.[Abstract/Free Full Text]
57. Press OW, Eary JF, Gooley T et al. A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas. Blood 2000;96:2934–2942.[Abstract/Free Full Text]

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