Advanced age remains the most important predictor for outcome in DLBCL as defined by the IPI.19,20
The poorer outcomes observed in adults over the age of 60 years may be related to several factors, including inherently more chemotherapy-resistant disease and/or the inability to tolerate multiagent chemotherapy because of other comorbidities. Multiple previous studies in older populations with DLBCL have shown inferior outcomes in terms of rates of complete remission and long-term survival when decreased doses of chemotherapy drugs were administered to these populations in order to improve tolerability and minimize drug toxicity.21–25
Rituximab has resulted in improved rates of remission and survival in all patients with DLBCL, and R-CHOP chemotherapy has been demonstrated to be the standard of care in 3 separate trials comparing CHOP with R-CHOP in the elderly population.2–6
Rituximab has multiple in vivo mechanisms including complement-mediated lysis, antibody-dependent cytotoxicity, and induction of apoptosis. The primary mechanism by which rituximab exerts its anti-lymphoma effect remains undefined.17,26
GM-CSF has been observed in vitro to possibly potentiate rituximab activity by upregulation of CD20 expression on tumor cells and by stimulation of immune effector cells. Interferon α, IL-2, IL-4, IL-6, G-CSF, and GM-CSF have all been shown to enhance CD20 expression to variable degrees and also enhance rituximab binding to tumor cells.13,14,27
GM-CSF exposure was also observed to enhance rituximab-induced apoptosis of B-cell lymphoma cells.15–17
Previous phase II experience with GM-CSF plus rituximab in rituximab-naive patients with relapsed follicular NHL suggested objective response rates that were higher than those predicted with rituximab alone.28,29
Based on these data, we hypothesized that GM-CSF administered in combination with R-CHOP would potentiate the activity of rituximab while facilitating the maintenance of dose intensity.
The outcomes in the current study compare favorably to those reported in the US intergroup and the GELA (Groupe d’Etude des Lymphomes de l’Adulte) trials, which tested R-CHOP chemotherapy in similar patient populations.2–5
With comparable follow-up, the GELA reported 5-year PFS and OS of 54% and 58%, compared with 68% and 70% observed in our trial. Comparison with the US intergroup experience is less straightforward, as those investigators used failure-free survival (which is defined differently than PFS). However, the US intergroup reported 3-year OS of 67%, compared with our 3-year OS of 84%.
Based on our experience, further investigation of GM-CSF combined with standard chemotherapy is warranted. Additional experience with GM-CSF raises questions as to whether GM-CSF could be administered in a more optimal dosing schedule to further improve efficacy. For example, in the recent report by Cartron et al suggesting improved activity of GM-CSF plus rituximab compared with rituximab alone in relapsed follicular lymphoma, GM-CSF was administered on days 1–8 and rituximab on day 5 of each 21-day cycle.12
It is possible that the efficacy from the combination of GM-CSF with rituximab is best achieved by “priming” of the immune response for several days before exposure of lymphoma cells to rituximab. The toxicity from the GM-CSF was not trivial, with 6 patients (16%) discontinuing as a result of toxicity that was clearly GM-CSF related and 2 additional patients discontinuing because of thrombotic events that may have been related. Previous studies have suggested an increased risk of thrombosis with GM-CSF usage.29,30
Our clinical experience clearly demonstrates the ongoing challenges with chemotherapy toxicity in older populations, as 39% of enrolled patients were unable to complete the protocol therapy, mainly because of chemotherapy toxicity (21%) with subsequent inability to receive additional chemotherapy off-protocol. These issues with tolerability may be reflective of the enrolled population, with 29% of patients having high-risk disease by IPI criteria. By comparison, in the RICOVER-60 and GELA trials, < 20% of older adult DLBCL patients treated with R-CHOP chemotherapy had high-risk disease by IPI criteria, and both studies reported > 90% dose intensity for all cycles of chemotherapy.4–6
In contrast, the US intergroup included 28% IPI high-risk patients, and 20% of patients were unable to complete more than 5 cycles of induction chemotherapy.2,3
Despite the fact that 9 out of 39 patients could not complete the planned R-CHOP chemotherapy, the outcome of our cohort was surprisingly good. We observed just 11 lymphoma relapses and 8 deaths from lymphoma, despite the advanced age and unfavorable IPI risk distribution. The vast majority of patients completing 6–8 cycles of R-CHOP chemotherapy were cured. This suggests that the relatively poor outcomes observed in older patients with DLBCL are more likely because of patients’ inability to tolerate curative therapy rather than affliction with a biologically more chemotherapy-resistant disease.