Yttrium-90 Ibritumomab Tiuxetan (Zevalin) for Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Not Appropriate for Autologous Stem Cell Transplantation: Results of an Open-Label Phase II Trial.

Presently, there is no standard second-line regimen for patients (pts) with diffuse large B-cell lymphoma (DLBCL) who cannot undergo stem cell transplantation. Since yttrium-90 (⁹⁰Y) ibritumomab tiuxetan (Zevalin) is highly active in pts with follicular lymphoma, we wished to establish whether it is also effective in pts with relapsed DLBCL. We therefore conducted a prospective, single-arm, open-label, non-randomized, multicenter phase II trial to evaluate the efficacy and safety of ⁹⁰Y ibritumomab tiuxetan in elderly pts with histologically confirmed first relapsed or primary refractory DLBCL not appropriate for autologous stem cell transplantation. Pts were divided into 2 groups: those previously treated with chemotherapy alone [Group A, n=76], and those previously treated with chemotherapy and rituximab [Group B, n=28]. Pts in Group A were further divided into 3 strata: pts with primary refractory disease (stratum 1, n= 33), pts relapsing within a year from presentation (stratum 2, n=10), and those relapsing more than 1 year from presentation (stratum 3, n=33). All pts were to receive a single dose of ⁹⁰Y ibritumomab tiuxetan 14.8 MBq/kg (0.4 mCi/kg) up to a maximum dose of 1184 MBq (32 mCi). The primary endpoint was overall response (ORR) assessed by using IWNHL criteria at Weeks 6, 12, and 24. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). 104 pts were included. Three pts progressed after the first rituximab dose and in 1 patient the ¹¹¹In labeling procedure failed; 103 pts were evaluable for efficacy and 104 for safety. An ORR of 44% was observed in the entire study population. In Group A, the ORR was 52% in stratum 1, 40% in stratum 2, 58% in stratum 3. In Group B, where 37% of pts were refractory to CHOP-rituximab, the ORR was 19%. The median PFS was 5.9, 2.3, and 6.2 months in strata 1, 2, 3 of Group A, respectively; the median PFS for Group B was 1.6 months. Median OS in Group A was 22.4 months in stratum 3 and has not yet been reached at a maximum follow-up time of 32 months in strata 1&2. Median OS was 4.5 months for Group B. Adverse events (AEs) with the exception of hematologic AEs were generally mild or moderate (CTC grade 1 and 2). There were 4 deaths due to SAEs. Three pts died of suspected cerebral hemorrhage, preceded by CTC grade 4 thrombocytopenias; another died of bleeding from a duodenal ulcer 280 days after the start of study medication, but this AE was determined not to be related to the study drug. The incidence of severe infection is low with 7% of pts hospitalized for infection during the study. In conclusion, ⁹⁰Y ibritumomab tiuxetan has useful activity in the treatment of relapsed/refractory DLBCL, with no unexpected toxicities observed. The results of this study support a further evaluation of ⁹⁰Y ibritumomab tiuxetan in combination with chemotherapy or immuno-chemotherapy earlier in the time course of DLBCL.