Rituximab-Pecc Induction Followed By 90y-Ibritumomab Tiuxetan Consolidation in Relapsed or Refractory DLBCL Patients Who Are Not Eligible for or Have Failed ASCT: Results from a Phase II HOVON Study
Authors: Lugtenburg Pieternella J , Zijlstra Josée M , Doorduijn Jeanette K , Böhmer Lara H , van Marwijk Kooy Marinus , Hoogendoorn Mels , Berenschot Henriette W , Beeker Aart , Valster Fransje , Schouten Harry C. , Luten Marleen , Hofwegen Henk , Chitu Dana A , Brouwer Rolf E , van Imhoff Gustaaf W 
Published: October 2019

Abstract
Background: Patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for autologous stem cell transplantation (ASCT) have a poor prognosis. Treatment with salvage chemotherapy has generally been disappointing. In many centers in the Netherlands the oral PECC regimen is used for such patients. 90Y-ibritumomab tiuxetan (Zevalin®, Spectrum Pharmaceuticals) radioimmunotherapy (RIT) is clinically active as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating salvage therapy with Rituximab (R)-PECC, in responsive patients followed by 90Y-ibritumomab tiuxetan consolidation.
Methods: Adult patients with refractory/relapsed DLBCL, more than one year after or not eligible for ASCT, were treated with R-PECC (Prednisone 40 mg/m2 po D1-5; Etoposide 100 mg/m2 po D1-5; Chlorambucil 8 mg/m2 po D1-5; Lomustine 80 mg/m2 po D1 and Rituximab 375 mg/m2 iv D1) q 28 days for 4 cycles. Complete (CR) or partial responders (PR) received consolidation with a single dose 90Y-ibritumomab tiuxetan (15 MBq/kg, 0.4 mCi/kg). Response was evaluated according to the revised Cheson criteria (2007).
Results: Between November 2008 and February 2012 62 patients were enrolled. Median age was 70 years (range, 45-82). Secondary IPI score was high-intermediate or high in 42% patients. All patients had received CHOP at first-line, 12 without rituximab. Prior therapies consisted of (R)-CHOP (65%), R-CHOP and R-DHAP/VIM (24%) or R-CHOP and R-DHAP/VIM plus ASCT (11%). Fourteen patients (23%) were refractory to the last prior therapy. After 4 cycles of R-PECC the overall response rate (ORR) was 31/62 (50%), with 14 of 62 (23%) patients achieving a CR and 17 of 62 (27%) achieving a PR, 13 of 62 (21%) patients had progressive disease. ORR of relapsed patients was significantly higher than that of patients refractory to their last prior treatment (63% vs 7%, p=0.0001). 29 of 31 responsive patients received consolidation with RIT. The remaining two patients with PR did not proceed to RIT because of one toxic death and one misinterpretation of the response. The ORR after the end of the entire treatment was 29% (23% CR, 6% PR), RIT consolidation improved the overall best response (from PR to CR) in 5 of the 17 PR pts after the R-PECC only regimen. The median follow-up time of patients still alive is 48 months (range, 0-67 months). The median response duration in the patients that received R-PECC only was 9 months (range 3-63 months). The median response duration in the patients that received RIT consolidation was 20 months (range 0-59 months). The failure free survival at 1 yr from start of RIT consolidation was 52% (95% CI=[33%,68%]) and the overall survival 62% (95% CI=[42%,77%]). There was one treatment related death, due to sepsis and pneumonia after the first R-PECC cycle. The R-PECC regimen was well tolerated by most patients. The most common grade 3 or 4 adverse events during R-PECC treatment were hematological toxicity (27%), infection (19%) and malaise (11%). Adverse events after RIT were primarily hematologic. Grade 3 to 4 trombocytopenia and neutropenia occurred in 8 patients (28%) and 5 patients (17%), respectively. Eight patients received platelet transfusions and 6 patients red blood cell transfusions.
Conclusions: The R-PECC regimen shows good clinical activity in relapsed DLBCL patients. Its activity in refractory patients is low. This largely oral regimen provides patients not eligible for high-dose salvage treatment with a convenient treatment schedule with an acceptable safety profile. Consolidation with RIT was well tolerated and resulted in long response durations in half of the patients.

Disclosures
Lugtenburg: Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Roche: Consultancy; Celgene: Consultancy. Off Label Use: 90Ytrium-ibritumomab tiuxetan for diffuse large B-cell lymphoma. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Doorduijn:Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Hoogendoorn:Gilead: Consultancy; Novartis: Consultancy.