Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone: until what age?

The advent of rituximab, a decade ago, has dramatically changed the course of diffuse large B-cell lymphoma (DLBCL). The association of the antibody with chemotherapy in elderly patients was the first demonstration of an increase in survival [1]. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) has become a standard, but it also appears that the known limitations of chemotherapy in older or frailer patients persist in the era of immunochemotherapy. Rituximab in combination with reduced-intensity anthracycline-based regimens has been proposed in fit patients, and represents the current standard strategy for frontline treatment in this population [2]. However, there is a wide field of investigation into the adaptation of treatment to patient age, individual condition and specific characteristics of the tumor.

In this issue, Merli et al. [3] describe the results of the AZINTER3 trial conducted by the Intergruppo Italiano Linfomi. This prospective randomized study compared the standard R-CHOP with an attenuated “R-miniCEOP” regimen (rituximab, epirubicin, cyclophosphamide, vinblastine and prednisone) in patients with DLBCL aged more than 65 years. Although no differences could be shown between the immunotherapy regimens in terms of remission rate and survival, this article delivers important messages.

One-third of the patients registered to the trial were considered unable to receive the randomized regimen. Patients were selected according to a dedicated comprehensive geriatric assessment (CGA) including a functional status scale (activities of daily living; ADL) and a co-morbidity score (Cumulative Illness Rating Scale for Geriatrics [CIRS-G] and Balducci scoring system). This trial and recent publications have underlined the pertinence of detecting a frail phenotype in the geriatric context. The IADL (instrumental activities of daily living) scale, measuring the abilities of the patient in terms of daily activities, autonomy and dependence, was associated in a univariate analysis with an unfavorable outcome in DLBCL treated by R-miniCHOP, and appeared more relevant than the performance status [2,4]. The Charlson index has also recently been considered as a prognostic factor independent of the International Prognostic Index (IPI) in patients older than 65 years [5]. A simplified method of CGA, proposed by Tucci and colleagues, appeared to be more effective than clinical judgment in identifying elderly patients with DLBCL who could benefit from aggressive therapy [6]. More specifically, risk factors of chemotherapy toxicity and especially hematological toxicities can be predicted by a CGA, but its relevance in lymphoma remains to be evaluated [7]. It would be very interesting to know the characteristics of the “unfit” patients in the current trial in comparison to the randomized population, as well as the treatment they received and the outcome of this cohort. Frail patients with significant cardiac dysfunction or relapsing following anthracycline-based regimens warrant alternative treatments. Recently, lenalinomide in combination with rituximab has shown promising results in patients older than 65 years, with a high percentage of patients achieving a continuous complete response (CR) after maintenance therapy [8]. Bendamustine in combination with rituximab has been also evaluated in a phase II study, including unfit patients with a median age of 85 years, giving an overall response rate of 69% [9].

Interestingly, despite the fact that patients were uniformly selected and displayed a favourable CGA, age (above 72 years) still remained a prognostic factor in the current trial, suggesting that other factors, independent of “frailty” status, may be associated with aging and poor outcome. As an example, elderly patients with DLBCL are more common in the activated B-cell like/non-germinal center B-cell like (ABC/non-GCB) subgroup as compared to younger patients [10]. Three independent series demonstrated a clearly skewed distribution of the two main molecular subtypes during aging, with an increase of the ABC subtype of 7–13% per decade after age 50 years [10–12]. Whether this molecular subclassification remains clinically relevant in a geriatric setting is unknown. Nutritional parameters may also play a crucial role in a geriatric setting. Albuminemia was the only prognostic factor retained in a multivariate analysis in the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trial involving patients over 80 years uniformly treated by R-miniCHOP [2]. Results of the trial from Merli et al. show a trend toward favoring standard R-CHOP in the younger subgroup and R-miniCEOP in the older subgroup. However, conclusions regarding R-miniCEOP should take into account the fact that the number of patients over 80 years in the randomized population was probably low, and that the two regimens appear to exhibit similar side effects. Attenuated immunotherapy regimens now represent a platform for introducing new monoclonal antibodies and small molecules in the frontline treatment of older, fit, patients with DLBCL.

To tailor individual treatment in elderly patients remains an issue, and several efficient tools including biomarkers and geriatric scales are now available for physicians. Their incorporation into the design of upcoming clinical trials, as proposed here by the Italian intergroup, will probably improve the outcome of elderly patients with DLBCL.

Potential conflict of interest:

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