Mantle-cell lymphoma in the elderly: is it time to CHOP and change?

Mantle cell lymphoma (MCL) is rightly regarded by hemato-oncologists as having the worst features of both high and low grade disease: an aggressive clinical course, but with a natural history of resistant and relapsing disease rendering it incurable with standard therapy. There is evidence that the bleak prognosis once associated with MCL is perhaps improving, with median survival increasing to a recently reported 4–5 years [1], as a result of better combination chemotherapies and supportive care. However, it is known that the majority of patients presenting with MCL are elderly (median age 65 years), and the optimal management of this group of patients is not established.

Significant advances have been made in the management of younger patients with MCL. The addition of high-dose cytarabine in particular to combination immunochemotherapy in younger adults has resulted in striking improvements in outcome. The European MCL Network study, MCL Younger, comparing R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to R-CHOP alternating with R-DHAP (rituximab, dexamethasone, cytarabine [Ara-C], cisplatin) as induction regimens prior to autologous stem cell transplant (ASCT), demonstrated a higher overall response rate (ORR) (94% vs. 90%) and a higher complete response (CR) rate (39% vs. 26%) for the Ara-C containing arm, which translated into a longer time to treatment failure (not reached vs. 49 months) [2]. Similarly promising results are beginning to emerge from the ongoing GOELAMS (Groupe Ouest Est d’Etude des Leucémies et Autres Maladies du Sang) and GELA (Groupe d’Etude des Lymphomes de l’Adulte) LyMa study [3]. Such dose-intense approaches, first pioneered with the R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) regimen [4], that incorporate rituximab and high-dose cytarabine at induction to obtain a CR and consolidating with ASCT, are now recognized as the standard of care in those patients fit enough to tolerate it [2].

However, over the age of 65, or where significant comorbidities exist, the toxicity of such therapy generally renders such an approach impossible [4]. For these patients, there is no recognized gold-standard therapy, and the physician has a range of chemotherapy options from which to choose.

Historically, older patients with MCL have been treated with combination chemotherapy regimens such as CVP (cyclophosphamide, vincristine, prednisone) [5] and CHOP [6]. These regimens gave overall response rates of 60–70%, but with short progression-free survivals (14–21 months). Despite the fact that these regimens underpin much of the current treatment of MCL, the published studies are limited in their applicability to older adults, with median ages of approximately 60 in the studies described, and with many of the studies excluding older adults. The addition of the CD20 monoclonal antibody rituximab to chemotherapy improves response rates, and, in spite of marked heterogeneity between the studies, a meta-analysis was able to demonstrate improved survival versus chemotherapy alone [7]. R-CHOP is now an accepted treatment of MCL, and is a comparator arm in multicenter studies. Purine analogs have also demonstrated efficacy in MCL, particularly when used with cytotoxics such as cyclophosphamide [8], with high ORRs in untreated patients, and progression-free survival (PFS) comparable to the R-CHOP-like regimens. However, poorer outcomes were seen when elderly patients were given R-FC (rituximab, fludarabine, cylophosphamide) compared with R-CHOP [9].

In their article in this issue of the journal, Räty and colleagues [10], on behalf of the Finnish Lymphoma Group, offer an alternative approach, using prolonged cyclical chemotherapy in elderly patients with this disease. The study, which commenced in 2004, examined the outcome in 60 patients with MCL treated with chemotherapy based on CHOP, with the addition of rituximab, cytarabine and fludarabine to the regimen. In part, this study examines whether the benefits seen with cytarabine in younger patients can be translated to older adults. The protocol employed alternating cycles of treatment (R-CHOP for cycles 1, 3 and 5, R-Ara-C for cycles 2 and 4, R-fludarabine-Ara-C for cycles 6–8, and CHOP for cycles 9–10). In patients with a demonstrated response after induction (cycle 5), the treatment was followed by 2 years of maintenance rituximab.

The dose of cytarabine used in this study at 4 g/m² per cycle is significantly lower than the 12 g/m² used in high-dose regimens in younger adults, and the addition of fludarabine will further potentiate the action of cytarabine through accumulation of the active form of the drug [11].

The median age in this study was 74 (range 65–83), and patients with up to and including World Health Organization (WHO) performance status 3 were included. The study was conducted across multiple sites, and 87% of patients had some form of comorbidity. As such this represents a “real world” study, reflected by a permissive approach to dose reduction by the treating physician where necessary. In spite of the pragmatic approach taken, the results obtained are very encouraging. An ORR of 95% was obtained, with 87% of patients attaining a CR, the majority of whom were minimal residual disease (MRD) negative by flow cytometry. Progression-free survival was 70% at 4 years. It was noted that 13 patients did not complete the planned therapy. However, and perhaps surprisingly, severe infections were rare, and the treatment was well tolerated. Seventy-three percent of patients were able to complete the entire treatment course including the rituximab maintenance. A multivariate analysis of outcome determined that high Mantle Cell Lymphoma International Prognostic Index (MIPI), biological markers of disease and a high performance status (WHO ≥ 2) were predictive of poor outcome. Importantly, age in itself was not predictive of outcome, with no difference in patients ≤ 75 or ≥ 75.

One caution should be highlighted. Although no patient has suffered death or severe infection as a result, nearly half the patients experienced grade 4 neutropenia during rituximab maintenance. As other studies using maintenance rituximab in MCL mature, further data on this may become available. In spite of this caveat, the article by Räty et al. is important. It challenges our expectations of treatment of MCL in this age group. Although not randomized, it suggests that prolonged, multi-agent chemotherapy including rituximab, cytarabine and fludarabine is feasible, and outcomes appear good compared with standard approaches.

So, is this study an extension of the experience in younger patients with this disease, where the incorporation of cytarabine significantly improves outcomes over anthracycline based therapy? This is a small non-randomized trial, but the results are impressive, and would suggest this to be the case. As such, are so many cycles of therapy necessary, and could the same outcome be achieved without the additional cycles of R-CHOP? “CHOP free” regimens are now being investigated in younger patients, and maybe it is time we tested this hypothesis in more elderly patients where the use of anthracyclines can be difficult. The dose of cytarabine is not established in this disease, and lower dose schedules should be explored, perhaps extending its use still further with a sliding scale based on age.

Cytarabine appears to be a key drug in MCL. It is important that its use extends to the majority of our patients, and as such we need to design appropriate randomized trials to explore this further.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.