For patients with relapsed or refractory lymphoma such as diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL), high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) has been established as the standard. However, in those patients in whom HDCT/ASCT is precluded because of advanced age, other co-morbidities, and/or poor performance status, long-term survival rates following salvage therapy have been generally poor.
Conventional standard salvage regimens including R-ICE, R-DHAP, R-ESHAP, and R-GDP are potentially more toxic in older patients with relapsed/refractory lymphoma. While some patients may derive benefit from salvage therapy alone (without proceeding to HDCT/ASCT), it is necessary to balance the toxicity of further combination chemotherapy with the usually modest gain in progression-free survival (PFS) and overall survival (OS). Accordingly, there is a need to identify chemotherapy regimens that are both effective and tolerable in this cohort of patients who would not be considered eligible for HDCT and ASCT. There is a distinct paucity of such regimens.
GemOX (+/- rituximab) has been shown in a number of studies to be an active regimen, that is well-tolerated, particularly for patients greater than 65/70 years with relapsed DLBCL, HL, mantle cell and follicular lymphoma who are not suitable for HDCT/ASCT. Gemcitabine offers advantages over its parent compound, cytarabine, in terms of delivery of highly effective intracellular concentrations. Gemcitabine has demonstrated single-agent efficacy in relapsed or refractory aggressive lymphoma, including mantle cell lymphoma (MCL).r In addition, the platinum derivative oxaliplatin has similar efficacy to cisplatin, with improved renal safety and reduced induction of chemo-resistance.
The favourable safety profile of oxaliplatin makes this agent potentially suitable for elderly patients with co-morbidities. The mechanistic synergy and non-overlapping toxicity profiles of rituximab, gemcitabine and oxaliplatin (R-GemOX) indicate that combination regimens containing these three agents may offer advantages over conventional regimens in terms of efficacy, safety and tolerability.
Each component of the R-GemOX regimen may contribute to its efficacy; indeed, the results of this study support a synergistic or supra-additive action for rituximab when combined with gemcitabine and oxaliplatin. This observation is consistent with results from previous studies in lymphoma and other cancers. Response rates of 20% to 25% have been reported for single-agent gemcitabine in relapsed or refractory aggressive lymphoma (including MCL).r
Gemcitabine and oxaliplatin display supra-additive effects in human colon cancer cell lines, and the feasibility and safety of this combination has been shown in various solid tumours and in patients with lymphoma.
The schedule of R-GemOx is usually every 2 weeks. However, in the study by Lopez et alr, after the first cycle, most patients required treatment delays resulting in treatment being administered every 3 weeks. Since this study reported 33% grade IV neutropenia, it was felt that administering R-GemOX every 2 weeks would require growth factor support.
In multiple prospective and retrospective studies rrrrrrr R-GemOX is effective, and safe amongst older patients with relapsed/refractory lymphomas and who are not generally considered sufficiently fit for HDCT and ASCT. There are limited published retrospective data in the use of R-GemOX as salvage pre-ASCT.
A search of the literature found moderate evidence to support the use of R-GemOX in the treatment of non-Hodgkin Lymphoma. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the study by El Gnaoui et al.
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
El Gnaoui et al. 2007r |
Yes |
No |
Gemcitabine and oxaliplatin administered on day 2 |
|
Lopez et al. 2008r |
Yes |
Yes |
- |
|
Mounier et al. 2013r |
Yes |
No |
Rituximab was given on day 1 and gemcitabine and oxaliplatin administered on day 2 |
Case series |
N/A |
N/A |
N/A |
- |
Observational studies
|
Dhanapal et al. 2017r |
Yes |
Yes |
- |
Franch-Sarto et al. 2018r |
Yes |
Yes |
- |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
V 3.2024 |
Yes |
No |
3 to 6 cycles recommended |
BCCA |
N/A |
N/A |
N/A |
- |
CCO |
N/A |
N/A |
N/A |
- |
Efficacy
A brief summary of the three key trials of R-GemOX in relapsed/refractory aggressive NHL are shown in the table below.
|
Lopez et alr |
El Gnaoui et alr |
Mounier et alr |
Number |
32 |
46 |
49 |
Age (years) |
69 |
64 (43-78) |
69 (41-77) |
Overall response rate (ORR) |
43% |
83% |
61% |
PFS (med) |
6 months |
43% (at 2 years) |
6 months |
OS (med) |
9.1 months |
66% (at 2 years) |
12 months |
Amongst a total of more than 120 patients in the above 3 studies results are reasonably consistent and demonstrate favourable response rates, as well as median PFS and OS.
Retrospective studiesrr demonstrate less favourable response rates than the original studies (ORR 44%; complete response (CR) 30%), likely reflecting relapse after primary therapy with rituximab-based chemotherapy and poorer outcomes in patients not enrolled in clinical trials, however, toxicities remain comparable.
Toxicity
The GemOX (+/- R) regimen has a favourable toxicity profile.
No nephrotoxicity has been seen and haematological toxicity has been manageable with the help of growth factor support, primarily to maintain a 14-day rather than a 21-day schedule.
Oxaliplatin-associated neurotoxicity occurred in only 9% of cycles in the study by El Gnaouir with no grade 3 or 4 events but was grade 3 or 4 in 7% of patients (all reversible) in the study by Lopez et al.r In retrospective studies rates of febrile neutropenia are 14-22%.rr
In conclusion, the GemOX (+/- Rituximab) regimen shows promising activity with an acceptable toxicity profile and may be a favourable treatment option for patients with relapsed/refractory lymphoma who are not eligible for HDCT and ASCT.