A Multi-Center Prospective Randomized Study Comparing Ibritumomab Tiuxetan (Zevalin) and High-Dose BEAM Chemotherapy (Z-BEAM) Vs. BEAM Alone as the Conditioning Regimen Prior to Autologous Stem-Cell Transplantation In Patients with Aggressive Lymphoma; Possible Advantage for Z-BEAM In Low-Risk Patients

High-dose chemotherapy and autologous stem-cell transplantation (autoSCT) is the standard therapy for patients (pts) with refractory/recurrent aggressive lymphoma, who are chemo-sensitive to second-line therapy. However, a significant subset of pts still fail autoSCT, due to recurrent disease. Moreover, there is evidence to suggest, that it is even more difficult to rescue pts who were given rituximab as part of their initial therapy, which is currently the standard of care. A few phase II studies combined ibritumomab tiuxetan (Zevalin) in the conditioning regimen attempting at augmenting the anti-lymphoma effect of the regimen without increasing toxicity. As a general role these studies showed the feasibility and safety of this approach and suggested a possible advantage. The current study is a multi-center, prospective randomized study comparing the outcomes after standard high-dose BEAM chemotherapy with or without Zevalin, administered at a fixed does of 0.4 mCi/kg, 7 days prior to the start of conditioning, in pts with aggressive lymphoma. Pts were stratified according to disease risk. Pts were scored as high risk for relapse if they had an initial remission of less than 12 months, or if they had a high IPI score (≥3) at relapse. Pts who had none of these criteria were scored as low-risk disease. The study included 43 pts, median age 55 years (range, 23–67), 27 men, 16 women. Thirty-four pts had diffuse large B-cell lymphoma which was either refractory to first-line therapy (n=6) or recurrent (n=28). Nine pts had transformed follicular lymphoma, in first (n=2) or second remission (n=7). All pts responded to second-line therapy, however 16 pts had positive PET-CT prior to autoSCT. Twenty-six pts were scored as high-risk and 17 as low-risk disease. In all, 22 pts were randomized to Z-BEAM and 21 to BEAM alone. Patient (pt) and disease characteristics were well matched in the 2 groups. Accrual to the study was much slower than expected from historical autoSCT rates in the participating institutions as in the rituximab era, the number of relapses of aggressive lymphoma is reduced, while a significant subset of pts are chemo-refractory at relapse. All pts engrafted after SCT in a median of 10 days and 13 days for neutophil and platelet recovery, respectively, with no difference between the 2 regimens. The early toxicity profile was also not different between the regimens. There was one non-relapse related death in the entire group. This was a pt given Z-BEAM, who died 7 months after autoSCT from JC-virus encephalitis. So far, no secondary malignancies or myelodysplasia occurred in any pt. With a median follow-up of 18 months (range, 1–39), 16 pts relapsed. The estimated 2-year progression-free survival (PFS) rate is 44% (95%CI, 24–64%). The 2-yr PFS for high- and low-risk disease was 31% and 61%, respectively (p=0.04). Multivariable analysis identified advanced age (≥55 years) and high-risk disease as poor prognostic factors for PFS, with hazard ratios of 5.7 (p=0.006) and 3.5 (p=0.04), respectively. Positive PET-CT prior to autoSCT was not found to be of poor prognosis in this data set. Conditioning with Z-BEAM had a protective effect with borderline statistical significance, hazard ratio 0.4 (p=0.08). It seems that the advantage of Z-BEAM was more pronounced in low-risk disease, where 2-yr PFS after Z-BEAM and BEAM alone was 89% and 44%, respectively (p=NS). In pts with high-risk disease the 2-yr PFS was 49% and 33%, respectively (p=NS). Similarly in young pts 2-yr PFS was 100% and 40% after Z-BEAM and BEAM alone, respectively (p=0.08). So far, due to limited pt number and follow-up, the subset analysis could not reach statistical significance. Interestingly, 5 of 10 events in the BEAM group occurred beyond 1 year from autoSCT, compared with only 1 of the 7 events in the Z-BEAM group. This also suggests that the addition of Zevalin may be more effective in pts with a better prognosis, and less effective in poor risk pts who are destined to relapse early. In conclusion, the inclusion of Zevalin in the high-dose chemotherapy regimen given prior to autoSCT is feasible and with no added toxicity. It is possible that this approach may have an advantage in reducing post autoSCT relapse rate and may improve outcome, especially in younger pts and pts with low-risk disease. Larger studies with a longer follow-up are needed to confirm these initial observations. These studies may focus on younger pts with good prognostic characteristics.

No relevant conflicts of interest to declare.