Are we improving the survival of patients with mantle cell lymphoma: if so, what is the explanation?

Mantle cell lymphoma (MCL) became a separate entity in the Revised European-American Lymphoma (REAL) classification in 1994 [1], based on its distinct molecular features [hallmark t(11;14)] and immunophenotype but also its distinct clinical course, with poorer outcome among “indolent lymphomas.” Such challenges led to exploring early on novel approaches that have translated into an improvement of patient outcome in the last two decades. In this issue of Leukemia and Lymphoma, Abrahamsson et al. report on the improvement of MCL survival from the Swedish registry [2], corroborating previous observation from other groups in Europe [3]. Overall, the median overall survival (OS) in patients with MCL has shifted from 2–3 years in the late 1970s to 4–5 years in the mid-1990s. As expected, multiple factors can be invoked to explain progress in MCL outcome, from better supportive care measures to the use of dose-intensive strategies, which have clearly led to very long progression-free intervals, and the development of promising novel therapies for a disease that commonly shows chemoresistance in the relapse setting.

MCL induction therapy was for years essentially standard chemotherapy from chlorambucil to cyclophosphamide, vincristine and prednisone (COP) and mostly cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), which became the “default” standard. However, the median progression-free survival (PFS) was still very disappointing, in the range of 16–18 months [3]. The addition of rituximab clearly increased the overall response rate (ORR), complete response (CR) rate and time to treatment failure (TTF), but had no significant impact on PFS or OS compared to CHOP alone [4,5].

Based on these poor results, the natural shift was to use high-dose therapy (HDT) and autologous stem cell transplant (ASCT) as consolidation in first remission. The initial favorable results of smaller phase II trials were confirmed by one large German trial in which patients responding to CHOP chemotherapy were randomized between maintenance interferon (IFN) and HDT-ASCT [6]. In that study there was a significant difference, with longer response duration in the HDT-ASCT consolidation arm (no difference in OS likely due to cross-over design). Meanwhile, studies from the Groupe d’Etude des Lymphomes de l’Adulte (GELA) suggested that the use of cytarabine would be beneficial in MCL (dexamethasone, AraC and cisplatin [DHAP] after CHOP clearly improved the ORR and CR rate), which led to a promising regimen alternating CHOP and DHAP [7] (improved later by the addition of ritxumab as well) [8]. The importance of AraC was also suggested by the MCL2 trial from the Nordic group, with impressive PFS in excess of 5 years and very few relapses [9]. In this trial a built-in rituximab (R) maintenance (based on conversion to positive – not considered a failure – real-time quantitative polymerase chain reaction [RQ-PCR], tracking t(11;14) translocation or CDR3 clonotypic sequences) might have contributed to the observed long disease-free intervals, as some late relapses after 6 years are now reported. A commendable European Union (EU) effort with a large randomized trial in younger patients compared R-CHOP/R-DHAP induction with high-dose AraC consolidation and ASCT versus R-CHOP followed by HDT-ASCT (both arms using a chemotherapy/total body irradiation conditioning regimen). A preliminary report confirmed the superiority of the high-dose AraC arm in MCL frontline therapy [10], with longer TTF (the primary endpoint) over the R-CHOP induction arm. Though more follow-up is needed to see the impact on OS, the quality of response seen in the high-dose AraC arm with much earlier and deeper CR will likely translate into longer duration of first complete remission, a critical factor for durable long-term clinical benefit. The Nordic regimen (R-maxi-CHOP alternating with high-dose cytarabine) is not very different from R-HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone), another dose-intensive regimen frequently used in younger patients with MCL aged less than 65 years. The initial experience of M. D. Anderson with the classic R-HyperCVAD (alternating with methotrexate and high-dose AraC) was recently updated [11], with 52% of patients aged <65 years still in remission at 10 years with a median follow-up of 8 years. While the debate on dose-intensive (DI) therapies versus HDT-ASCT in MCL is still ongoing, a retrospective analysis in the National Comprehensive Cancer Network (NCCN) series [12] showed significantly superior PFS for both DI therapy and HDT-ASCT over the R-CHOP regimen, similar to our experience [13]. Although the impact of such strategies on OS is still debated, they have dramatically extended PFS over conventional therapies, and patients with MCL can nowadays enjoy prolonged remissions, though unfortunately over time a large number of patients still relapse.

In the relapse setting, conventional chemotherapy or even HDT-ASCT offers limited benefit [14], as commonly a patient’s disease develops chemoresistance. A subset of patients can be brought to non-myeloablative allogeneic SCT with varying results, depending on the series, but undeniably a subgroup of patients can enjoy very long disease-free survival and might potentially be cured [14,15]. Hopefully, newly developed transplant modalities (e.g. donor T helper cell type 2 [TH2] amplification) [16] will reduce complications, especially chronic graft-versus-host disease (which occurs in more than half of patients), which is certainly a limiting factor in that population.

Meanwhile a number of novel therapies have emerged in the field of relapsed/refractory MCL, including proteasome inhibitors (bortezomib: first agent approved in MCL), immunomodulatory drugs (IMiDs: lenalidomide) and mammalian target of rapamycin inhibitors (mTORi: temsirolimus), while other agents more recently entering the clinic appear very promising as well, such as phosphoinositide 3-kinase (PI3K) inhibitors (CAL-101) and Bruton’s tyrosine kinase inhibitors (BTKi: PCI-32765).

Such new biologicals or small molecules have shown single-agent activity in relapsed/refractory MCL with in some cases prolonged responses [17], offering a bridge to allogeneic transplant, though the main focus at this point is the integration of such new compounds in the management of MCL, i.e. with chemo-immunotherapy regimens. In the frontline setting these novel agents are currently tested either in combination (with R-CHOP or with a bendamustine backbone, for example) or even with DI therapy or HDT-ASCT as again combination or sequential therapy, including consolidation post-induction as well as maintenance strategies post-induction [18]. These ongoing studies will help develop strategies to build on the long PFS intervals seen with DI therapies and/or ASCT and reduce the risk of relapse in patients with MCL, which hopefully will continue to improve their outcome.

Although recent series suggest that the use of DI therapy/HDT-ASCT is feasible in some patients older than 65 [19], the median age at diagnosis in MCL is the early to mid-60s. As in younger patients, ongoing studies are looking at the integration of new biologicals in combination, consolidation or maintenance schedules, with promising preliminary results.

If the landscape of MCL has clearly evolved, some controversy remains regarding patient management and the benefit of aggressive therapies [20], though some of these “discrepancies” among series might reflect differences among treatments and patient characteristics. Recent efforts to develop clinical prognostic models in MCL have led to the MCL International Prognostic Index or MIPI [21], which still needs prospective validation. Biological stratification, focused initially on the proliferation signature (with Ki-67 or MIB-1 as surrogate marker), might not be as useful yet in the clinic. A growing perception of the complexity and heterogeneity of MCL is emerging as a consequence of considerable progress in the understanding of MCL biology over the last decade [22]. The identification of predominant pathways might help stratify patients with MCL and guide us in the future management of MCL, especially regarding the choice among novel agents or their combinations.

Overall an intense effort in a relatively rare subtype of lymphoma has led to significant improvement in the outcome of patients with MCL. The high-quality CR rate and prolonged response duration with PFS in excess of 5 years seen in the frontline setting [23,24], as well as the avenue of novel therapies, constitute a very promising foundation to continue to transform the prognosis of patients with MCL. As the number of options continues to increase, a sustained effort should be encouraged for enrollment of patients with MCL in clinical trials to keep moving forward in this venture.

Potential conflict of interest:

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