In the LY.12 trial, response rates were similar in patients treated with GDP and DHAP (45.1% v 44.1%, p=0.005), meeting the prespecified criteria for non-inferiority. The rates of autologous stem cell transplantation (52% versus 49%) and stem cell mobilisation (88% versus 82%, p=0.14) were similar. After a median follow up of 53 months, there was no difference in 4-year OS (39% in each arm, HR 1.03) or 4-year EFS (26% in each arm, HR 0.99).
Progression-free survival and Overall Survivalr
Fig 2. (A) Progression-free survival for patients randomly assigned to gemcitabine, dexamethasone, and cisplatin (GDP; gold line) or dexamethasone, cytarabine, and cisplatin (DHAP; blue dashed line). (B) Overall survival for patients randomly assigned to GDP (gold line) or DHAP (blue dashed line). HR, hazard ratio.
© Journal of Clinical Oncology 2014
Subgroup analysis of LY.12 demonstrated similar outcomes for patients with transformed follicular lymphoma compared with DLCBL (ORR 47% v 45%, 4y OS 39% v 41%, and 4y EFS 27% v 27%).r Outcomes were also similar for patients aged <60 and >60 years (4y OS 40% v 36%, 4y EFS 28% v 20%) with comparable toxicity rates.r
Quality of life (QoL) assessment by FACT-Total score favoured GDP, with more patients reporting an improved QoL and less patients reporting a worse QoL after 2 cycles of therapy. Fewer patients treated with GDP required hospitalisation for treatment of adverse events or other illnesses (18% v 30%, p<0.001).
Several prospective and retrospective single arm studies have also reported the efficacy of GDP+/-R as follows:
- 51 patients from 9 Canadian centres with relapsed/refractory aggressive B cell lymphoma received GDP in this phase II prospective trial. The ORR was 49% (CR 16%, PR 33%).r
- A retrospective review of 152 RR DLBCL patients treated in Canada between 2002 and 2010 with GDP +/-R reported an ORR of 49%, CR 16%, transplantation rate of 52%, 2y OS 28% and 2y progression free survival (PFS) 21%. Only 20% of patients with RR DLBCL received R-GDP (patients with rituximab-refractory disease, i.e. relapse within 6 months of prior therapy, were excluded), of whom 47% had received prior rituximab. The response rate specific to the R-GDP cohort was not reported.r
- A retrospective review of 50 RR DLBCL patients treated in China between 2005 and 2010 with R-GDP reported an ORR of 72%, CR 56%, 2y OS 70% and 2y PFS 48%. Responses were higher in relapsed compared with refractory patients (48% v 24%). The response rate in the 18 patients who had received prior rituximab was lower than rituximab-naïve patients, though the difference was not statistically significant (75% v 100%, p=0.3).r
Rituximab is routinely incorporated into salvage regimens for aggressive B-cell lymphomas. The addition of rituximab to salvage therapy improves PFS in rituximab-naïve patients,r but there is no randomised evidence to support the addition of rituximab to salvage chemotherapy for aggressive B-cell lymphoma refractory to or relapsing after a prior rituximab-containing regimen. However, rituximab was included as a protocol amendment in the phase III LY.12 study and has become a standard addition to salvage regimens. Evidence to support this approach includes:
- A subset analysis of the 414 aggressive B-cell lymphoma patients in the LY.12 study who had received prior R-CHOP revealed a higher response rate in patients receiving R-salvage (n= 318, including both R-GDP or R-DHAP) than salvage alone (n=96, GDP or DHAP alone) of 46% versus 25% (CR 16% v 4%) and higher transplant rates (52% v 31%), with no difference in OS or PFS. Where patients who relapse within 1 year of primary therapy were excluded, the inclusion of rituximab at salvage significantly improved OS with a trend towards improved PFS.r
- Of the 396 patients with RR aggressive B-NHL treated on the CORAL study with R-DHAP v R-ICE, prior rituximab exposure did not affect EFS in patients relapsing more than 12 months after a rituximab containing first line regimen. However, in patients with early relapse (<12 months) after first line therapy, previous rituximab exposure predicted a poor outcome compared with rituximab naïve patients.r
This data supports the addition of rituximab to GDP for patients with relapsed disease; the role of rituximab in patients with rituximab-refractory disease is less clear, though rituximab is commonly used and is available on the PBS for this indication.
Note that R-GDP has not been formally compared with other salvage regimens (eg R-ICE, R-ESHAP) in a phase III setting and thus there is no clear evidence of superiority of one regimen over another. Outcomes of R-DHAP and R-ICE were essentially equivalent in the large phase III CORAL trial, although patients with germinal centre B-cell (GCB) subtype DLBCL had an improved PFS with R-DHAP versus R-ICE.rr