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- MATERIALS AND METHODS
- FUNDING SOURCES
High-dose chemotherapy combined with autologous stem cell transplantation (ASCT) is the standard therapy for patients with relapsed or refractory aggressive lymphoma who are chemosensitive to second-line chemotherapy. The PARMA study, reported in 1995, is the only randomized study comparing salvage chemotherapy with salvage chemotherapy followed by ASCT in this setting. The 5-year progression-free survival (PFS) in patients randomized to ASCT in this study was 46%, compared with 12% in the nontransplant group.1 However, the PARMA trial was conducted in the prerituximab era. The use of rituximab, an anti-CD20 monoclonal antibody, in frontline chemotherapy has dramatically changed the outcome of patients with aggressive lymphoma, increasing both response and survival rates.2-4 However, despite this progress a significant proportion of patients with aggressive lymphoma are still refractory or relapse after frontline rituximab-containing therapy. Moreover, it is increasingly more difficult to rescue these patients with current salvage chemotherapy and ASCT approaches.
The recently reported Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) identified prior treatment with rituximab as an adverse prognostic factor in relapsed/refractory aggressive lymphoma, especially in those relapsing within 12 months of diagnosis.5 The 3-year event-free survival was 21% in patients previously treated with rituximab, compared with 47% in rituximab-naive patients. Novel approaches are in need to improve outcome in these patients. Theoretically, these can include better salvage regimens, better conditioning regimens for ASCT, and/or maintenance treatment after ASCT. Rituximab-containing salvage regimens have been shown to be more effective, but mostly in rituximab-naive patients.5-8 Rituximab maintenance or consolidation after SCT to target minimal residual disease is another appealing approach.9-11 The results of the second randomization study in the CORAL trial are awaited to confirm this strategy.
No single preparative regimen before ASCT has been shown to have an advantage in disease eradication over the others. Lymphomas are inherently radiosensitive malignancies. Total body irradiation (TBI) has been used as part of conditioning regimens for ASCT. However, there are concerns about toxicity and long-term effects associated with TBI, and there are no data to support TBI-containing regimens over regimens containing high-dose chemotherapy alone. Radiolabeled antibodies such as yttrium-90 ibritumomab tiuxetan (Zevalin) and iodine-131 tositumomab (Bexxar) are increasingly used in indolent lymphomas, but are also effective in aggressive lymphomas.12 Several studies used radioimmunotherapy in combination with high-dose chemotherapy and ASCT with promising results (reviewed in Shimoni and Nagler13 and Gisselbrecht et al14).
In this randomized multicenter study, we evaluated the safety and efficacy of standard-dose ibritumomab tiuxetan combined with high-dose BEAM chemotherapy (Z-BEAM) and ASCT in patients with relapsed/refractory aggressive non-Hodgkin lymphoma in the era of rituximab-containing frontline therapy.
- Top of page
- MATERIALS AND METHODS
- FUNDING SOURCES
This is the first reported randomized study to evaluate the safety and efficacy of the combination of radioimmunotherapy with high-dose chemotherapy in patients with relapsed/refractory aggressive lymphoma. It suggests that the addition of ibritumomab tiuxetan to BEAM high-dose chemotherapy is safe and possibly more effective in disease eradication. The 2-year PFS was 59% and 30% in the Z-BEAM and BEAM arms, respectively (P = .20). The 2-year OS was 91% and 62%, respectively (P = .05). There was no significant added toxicity with the Z-BEAM regimen.
There are 3 potential approaches for the use of radioimmunotherapy in ASCT. The radioconjugate can be administered in the standard treatment dose combined with high-dose chemotherapy, as in this study. Krishnan et al reported the use of Z-BEAM in 60 patients with various types of lymphoma.18 The 2-year PFS in the 20 patients with diffuse large B-cell lymphoma was 68%, compared with 48% in historical controls. In a following report, they compared 46 patients with aggressive lymphoma given Z-BEAM to a matched control cohort given TBI-based conditioning.19 Z-BEAM had a similar relapse incidence to TBI with lower toxicity, resulting in improved survival. The 4-year survival was 81% and 53%, respectively. This regimen was also used safely in patients with low-grade lymphoma.20
The second approach is to escalate the radioconjugate dose beyond the standard dose. Winter et al used an individualized ibritumomab tiuxetan dose calculated to deliver a maximum of 15 grays to critical organs.21 The 4-year PFS in a group of 44 patients, 30% with less than a partial response to prior chemotherapy, was 43%. This approach requires accurate dosimetry to calculate a dose that will not deliver excess radiation to critical organs. The third approach is to use high doses of the radioconjugate alone, followed by stem cell support with no additional high-dose chemotherapy.22, 23 This approach was used mostly in patients considered not eligible for standard ASCT. Devizzi et al used ibritumomab tiuxetan at 0.8 to 1.2 mCi/kg, 2 to 3× the standard dose, in 30 patients.23 The regimen was safe, with promising results: a 2-year PFS of 69%. Similar approaches have been used with iodine-131 tositumomab (Bexxar) as the radioconjugate, with similar outcomes.13, 14, 24 A large Blood and Marrow Transplant Clinical Trials Network randomized study comparing iodine-131 tositumomab-BEAM and BEAM has completed accrual, and results are eagerly awaited.
The first approach was used in the current study because there is no evidence to support 1 approach over the others, and we were seeking a regimen that will be widely applicable. Ibritumomab tiuxetan dosing was used without prior imaging, as is the common practice in Europe. Ibritumomab tiuxetan in standard dose is dosed based on body weight alone. Dosimetric studies demonstrated that in this dose there is minimal exposure to nontargeted tissues. No significant correlation was found between biodistribution of the radionuclide and toxicity. Therefore, ibritumomab tiuxetan was approved in the European Union without the necessity for imaging studies. The use of a fixed standard dose is easier, does not require specific expertise, allows ambulatory treatment, and limits the costs related to dosimetry and escalated doses of the radioconjugate, which may become prohibitive. Ibritumomab tiuxetan, being a pure beta emitter, is not associated with radiation risk to the patient family and health care providers, and can routinely be given to ambulatory patients.
This randomized study confirmed the previously reported observations that the addition of ibritumomab tiuxetan to high-dose chemotherapy is safe and not associated with excess toxicity. Although there was a trend for more mucositis and more serious infections in the Z-BEAM arm, there was no excess in critical organ toxicities, and all toxicities were reversible, with no early deaths. The cause of increased rate of infections is not clear, but they did not result in any mortality or irreversible morbidity. Engraftment was not significantly affected by ibritumomab tiuxetan, as the residual radiation dose at the time of stem cell infusion, 14 days after treatment, or >5 half-lives of the agent, was reported by other groups to be very low.21, 23 Two patients in the Z-BEAM group had protracted poor graft function. Theoretically, targeting radiation to the marrow in patients with active marrow involvement at ASCT may cause stromal damage. However, none of these patients had such involvement, and other causes may have contributed to this finding. Long-term safety requires longer follow-up. Several group reported few patients with myelodysplastic syndrome, but this can be related to ASCT itself. The risk of myelodysplastic syndrome after ibritumomab tiuxetan therapy was reported to be low,25 and Devizzi et al reported no cytogenetic abnormalities after high-dose ibritumomab tiuxetan and ASCT.23
PFS after ASCT is highly dependant on several prognostic factors. This makes the results of different studies difficult to compare and strengthens the need for randomized studies. Chemosensitivity to the salvage regimen is the most important factor for the success of ASCT, such that patients who do not have at least a partial response to second-line chemotherapy are not generally accepted as ASCT candidates.26 Z-BEAM may be able to partially overcome the poor prognosis of chemorefractoriness.21, 27 When the secondary IPI was retrospectively applied to patients included in the PARMA study, it could distinguish patients with different survival probabilities.28 Hamlin et al applied the secondary age-adjusted IPI to 150 patients treated for relapsed/refractory aggressive lymphoma.29 Among the patients with chemosensitive disease (ASCT candidates), 4-year PFS was 69%, 46%, and 25% for patients with low, intermediate, and high secondary IPI, respectively. Several studies have shown that positive fluorodeoxyglucose (FDG)-PET before ASCT is associated with a poor outcome. Derenzini et al showed a 3-year PFS of 87% and 35% in patients with negative and positive FDG-PET scans before ASCT.30 These observations were recently confirmed in a meta-analysis.31 Schot et al combined FDG-PET with the clinical risk scores. Both were independent predicting factors, and the combined score separated patients into 4 groups with PFS of 5% to 100%.32 Relapse within 12 months from diagnosis has been shown in the PARMA trial as a very poor prognostic factor.33 Similarly, the CORAL study identified early relapse, secondary IPI >1, and prior rituximab therapy as poor prognostic factors in relapsed lymphoma.5 Three major risk factors were identified in the current study. Advanced age was a dominant poor prognostic factor. Disease risk defined as relapse within 12 months of diagnosis and/or secondary IPI >2 was another significant risk factor. These 2 known risk factors were combined to reduce the number of subsets in this limited patient group. Positive PET-CT was a third factor. The effect of prior rituximab could not be analyzed, as all but 1 patient had rituximab with frontline therapy. These risk factors were combined, similarly to the approach of Schot et al, showing a wide separation in prognosis. Patients with none of these factors had an excellent outcome, whereas patients with all 3 factors had a dismal outcome regardless of the regimen used. The intermediate group with 1 or 2 risk factors had a PFS of 48%. In this group, Z-BEAM was shown to have an advantage over BEAM alone, with 2-year PFS of 69% and 29%, respectively (P = .07) and 2-year OS of 100% and 63%, respectively (P = .008). It is possible that higher than standard doses of the radioconjugate will benefit higher-risk patients, but this has not yet been tested. The current observations must be considered with caution, as they are based on small patient subsets. We cannot rule out that subtle differences in the risk profile between the groups that were not statistically significant because of patient numbers contributed to the difference in survival. However, these observations can serve as hypothesis generating for further studies. Results of any future clinical study should be interpreted in light of these prognostic factors.
The major limitation of this study is the low patient number, resulting from early closure of the study because of low accrual. Rituximab in frontline chemotherapy leads to selection of a poor-risk population at relapse that is becoming a major challenge. Other studies have shown a lower response rate at relapse for patients with prior rituximab therapy. The study was designed to compare 2 conditioning regimens; therefore, patients were randomized only after documented response to second-line therapy. We do not have data on response rate before randomization, but based on the above discussion, we can expect that improved outcome after first-line therapy and low response rate after relapse led to the low accrual. It seems that even for responding patients, results are currently inferior to those of patients in the prerituximab era, as PFS in the control group was only 37%. This emphasizes the need for better regimens. Larger, international studies with longer follow-up will be needed to confirm these observations before the new Z-BEAM regimen can be accepted as a standard of care for ASCT in the era of rituximab-containing front-line and second-line chemotherapy.