For patients with relapsed or refractory lymphoma (eg. diffuse large B-cell, Hodgkin) HDCT and 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 and overall survival. Accordingly, there is a need to identify chemotherapy regimens which 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, which is well-tolerated, particularly for patients greater than 65/70 years with relapsed DLBCL, HL, mantle 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 GemOx is usually every 2 weeks. However, in the study by Lopez et alr, after the first cycles, most patients suffered treatment delays to the degree that in most cases they were administered every 3 weeks. Since there was a 33% grade IV neutropenia in that study, it was felt that in order to administer R-GemOX every 2 weeks, it will require the administration of growth factors.
In at least five studiesrrrrr (R-)GemOx has been shown to be effective, and safe among older patients with relapsed/refractory lymphomas and who are not generally considered sufficiently fit for HDCT and ASCT.
A search of the literature found limited 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. 2007 |
Yes |
No |
Gemcitabine and Oxaliplatin administered on day 2 |
|
Lopez et al. 2008 |
Yes |
Yes |
- |
|
Mounier et al. 2013 |
Yes |
No |
Rituximab was given on day 1 and Gemcitabine and Oxaliplatin administered on day 2 |
Case series |
N/A |
No |
N/A |
- |
Observational studies |
N/A |
N/A |
N/A |
- |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
V 2.2015 |
Yes |
N/A |
- |
BCCA |
N/A |
N/A |
N/A |
- |
CCO |
N/A |
N/A |
N/A |
- |
Efficacy
A brief summary of a few of 3 of the key trials of R-GemOx 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) |
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 |
Among 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 progression-free and overall survival.
Toxicity
The GemOx (+/- R) regimen has a very favourable toxicity profile.
No nephrotoxicity has been seen, and haematological toxicity has been manageable with the help of growth factor support, primarily in order to maintain a 14-day rather than a 21-day schedule.
Studies showed that there are few serious infections and few deaths unrelated to progression. 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 Other toxicities occur in a minority of patients .
In conclusion, the GemOx (+/- R) 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.