Abstract
Background: Salvage chemoimmunotherapy, followed by high-dose therapy and autologous stem cell transplantation (ASCT) for responding patients, is standard treatment for fit patients with diffuse large B-cell lymphoma (DLBCL) failing first line rituximab-CHOP treatment. Response to salvage treatment is critical for a durable progression free survival (PFS) following ASCT. The 3-year event free survival (EFS) for patients treated with rituximab (R) in first-line regimens who received salvage chemotherapy in combination with R was only 21% (ref-1). The anti-CD20 monoclonal antibody ofatumumab (O) has shown efficacy in R resistant lymphoma cell lines and in patients with relapsed or refractory intermediate grade lymphoma when combined with chemotherapy (ref-2). In this randomised phase III study we compared the efficacy of O versus R in combination with DHAP (cisplatin, cytarabine, dexamethasone), aiming to improve PFS following salvage treatment and ASCT (NCT01014208).
Methods: CD20+ DLBCL patients, aged ≥18y, in first relapse or not responding (<CR) to first-line R-CHOP-like treatment, with FDG-PET positive measurable disease, were randomised 1:1 between 3 cycles of R-DHAP or O-DHAP. Randomisation was stratified for risk factors: relapse >1y vs ≤1y (including PR, SD or PD) and secondary age adjusted IPI (sAAIPI) 0-1 vs 2-3. Either O 1000 mg or R 375 mg/m2was administered for a total of 4 infusions on days 1 and 8 of cycle 1, and day 1 of cycles 2 and 3 of DHAP. DHAP was dosed as published (ref 1). Peripheral blood stem cells (PBSC) were harvested during cycle 2 or 3. Responding patients (PR+CR) after 2 cycles received the third cycle followed by high-dose therapy and ASCT. Response after 2 cycles was determined by CT scans, and response after 3 cycles and 3 months after ASCT was determined by combined CT+FDG-PET scans according to RRCML criteria by an independent review. Patients with SD after cycle 2 or progressive disease did not proceed to ASCT. The primary endpoint was PFS, defined as time from randomisation to SD after cycle 2, PD or death, whichever came first. EFS included new therapy as an event in addition to the definitions for PFS.
Results: Between March 2010 and December 2013, 447 patients were randomised: 222 O-DHAP, 225 R-DHAP. Two patients in the R-DHAP arm were excluded from the ITT-population in accordance with the protocol because they did not receive any study treatment. The database cut-off date was Feb 28, 2014. Patient characteristics were evenly distributed between study arms: median age 57y (range, 18-83); 39% ≥60y; male 61%; Caucasian 72%; LDH >ULN 49%; ECOG PS >1 8%; stage III/IV 63%; sAAIPI 2-3 40%; and response to first line therapy: CR >1y 29%, CR ≤1y 11%, PR 36%, SD 8%, PD 16%. PFS, EFS and OS were not significantly different in the O-arm vs R-arm: PFS-2y 21% vs 26% (HR 1.14, 95% CI 0.90-1.45, p=0.27); EFS-2y 14% vs 17% (HR 1.12, p=0.27); OS-2y 41% vs 36% (HR 0.86, p=0.25). sAAIPI and response duration after first-line treatment were risk factors significantly associated with PFS and OS. In all, 102 (46%) patients in the O-arm and 113 (51%) in the R-arm died, 79% due to disease progression. Response to salvage was not significantly different between the study arms; ORR: O-arm 38% (CR 15%) vs R-arm 42% (CR 22%). ASCT on protocol was completed by 74 (33%) patients in the O-arm and 81 (36%) in the R-arm. Off protocol SCT was completed by 37 (17%) patients in the O-arm and 26 (12%) in the R-arm. No major differences in clinically relevant toxicity were observed between the arms. Rash (22% vs 9%) and raised serum creatinine (24% vs 16%) were increased in the O-arm. Time to neutrophil (ANC >0.5x109/L and increasing) and platelet (PLT >10x109/L and increasing) recovery after each cycle of DHAP therapy, and PBSC harvest, did not differ between the arms. Time to engraftment (PLT ≥20x109/L and 3 consecutive days of ANC ≥0.5x109/L, prior to day 42) after ASCT was shorter in the R-arm vs the O-arm (HR 0.62, p=0.05).
Conclusion: In this large international study no difference in efficacy was found between ofatumumab and rituximab in combination with DHAP as salvage treatment for refractory or relapsed DLBCL. Improved treatment for patients failing first line R-CHOP treatment is urgently needed.
Ref 1: Gisselbrecht, J Clin Oncol; 2010:28:4184
Ref 2: Matasar, Blood; 2013 122: 499
Off Label Use: Ofatumumab is an anti-CD20 monoclonal antibody. Ofatumumab is not indicated in DLBCL. Matasar:Genentech, Merck: Membership on an entity's Board of Directors or advisory committees. Radford:Millennium, Seattle Genetics, Cell Medica: Consultancy, Equity Ownership, Honoraria, Research Funding, Speakers Bureau, Wife is a GSK/AZ Share Holder Other. Ardeshna:Roche, Gilead, Millenium: Consultancy, Honoraria, Speakers Bureau. Kim:Novartis, Takeda, Celgene: Research Funding. Hong:Fudan University Shanghai Cancer Center: Employment. Davies:Hoffman LaRoche, GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ogura:GlaxoSmithKline Jansen Pharma Takeda, Eisai, Symbio, Zenyakuu, Pfizer, Chugai, Celgene, Astra Zeneca, Mundi, Sorasia, GSK, Takeda: Honoraria, Research Funding. Fennessy:GlaxoSmithKline: Employment, Equity Ownership. Liao:GlaxoSmithKline: Employment, Equity Ownership. Lisby:Genmab: Employment. Lin:GlaxoSmithKline: Employment, Equity Ownership. Hagenbeek:Milennium, Genmab: Membership on an entity's Board of Directors or advisory committees.
Author notes
Asterisk with author names denotes non-ASH members.
