Upfront Consolidation Combining Yttrium-90 Ibritumomab Tiuxetan and High Dose Therapy with Stem-Cell Transplantation in Poor Risk Patients with Diffuse Large B-Cell Lymphoma

High dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is considered as a relevant option for upfront consolidation in patients with poor risk aggressive lymphomas (Fitoussi, hematologica 2011; 96(8):1136-1143). Adding Y⁹⁰-Ibritumomab Tiuxetan to BEAM regimen would improve outcomes in relapse or refractory lymphomas. We evaluated the safety and efficacy of standard-dose Y⁹⁰-Ibritumomab Tiuxetan combined with high-dose BEAM after first line induction treatment in patients under 65 years of age with poor prognosis diffuse large B-cell lymphoma (DLBCL). (clinicaltrials.gov: NCT00689169).

Pathologically proven CD20+ DLBCL patients, 18–65 years of age, with IPI ≥ 2, in CR, CRu or PR according to the IWG 1999 criteria after rituximab-containing induction therapy were included. Patients received Rituximab 250 mg/m² on d-21, Rituximab 250 mg/m² followed by Y⁹⁰-Ibritumomab Tiuxetan 0.4mCi/kg on d-14, BEAM started on d-7 followed by ASCT. FDG-PET scans evaluated using Juweid criteria were performed before transplant in all patients, but were not decisional. Patients were analyzed by immunochemistry for CD10, BCL6, MUM1 and BCL2 expression. End of treatment assessment was done at day 100 (D100). The primary end point was event-free survival (EFS) at 2 years.

Seventy five consecutive patients were enrolled from August 2007 to December 2008. Median age was 49 years (19–64) with 7 pts (9%) older than 60 years. The IPI score was 2 in 28 pts (37%) and >2 in 47 pts (63%), bulky disease ≥ 10 cm in 29 pts (39%) and mediastinal involvement in 20 pts (26%). Thirty six patients received 4 (14 pts) or 6 (22 pts) cycles of R-CHOP and 39 had 4 cycles of R-ACVBP as induction treatment. After induction, 63 patients (84%) were in CR or CRu and 12 (16%) were in PR, 21 pts (28%) presented with positive PET. Four pts progressed before they completed the treatment including 2 with positive PET. Median follow-up was 34 months for the 71 patients eligible for analysis. Median time to reach a neutrophil count > 500/μL and platelet count > 20 000/μL was 11 days. Neutropenic fever (100%) and mucositis (78%) occurred in most patients. Other adverse events (AE) were usually mild to moderate in severity. Twenty three AE were reported as serious, mostly infection (n=9). One of them was fatal due to septic shock. The 2-yr EFS and overall survival (OS) was 79% (95% CI: 67–88%) and 83% (95% CI: 70–88%) respectively. Fourteen pts relapsed including 9 before D100. The Overall Response Rate (CR+CRu+PR) was 83%, 59 patients (81%) achieved a CR/CRu, 2 pts were in PR. The 2-year DFS was 91% (95% CI: 80% – 96%). There were no differences in OS (p=0.9) and EFS (p=0.8) between patients in CR/Cru or in PR. Positive PET imaging before transplant did not predict treatment failure. Nineteen pts with positive PET after induction were consolidated with Y⁹⁰-Ibritumomab Tiuxetan and BEAM, one died of sepsis, 18 achieved a CR/CRu and 3 relapsed at 9, 14 and 20 month. Mediastinal involvement, non-GCB phenotype and high BCL2 expression did not affect outcome. IPI score (2 v >2) and bulky disease at diagnosis appeared to be prognosis factors for OS: 96% v 75% (p = 0.02) and 91% v 70% (p=0.02) respectively, but not for EFS: 2 years EFS 89% v 73% (p = 0.09) and 84% v 70% (p=0.1) respectively.

Adding Y⁹⁰ Ibritumomab Tiuxetan to BEAM is safe without an increase in transplant-related toxicity. First line consolidation with Y⁹⁰ Ibritumomab Tiuxetan and HDT induced high rates of EFS and OS in poor prognosis patients with DLBCL irrespectively of PET status after induction treatment and warrants randomized study.

Gisselbrecht:roche: Consultancy, Research Funding; baxter: Research Funding.