Is Early Hematopoietic Stem-Cell Transplantation Necessary in Mantle-Cell Lymphoma?

The unifying concept defining mantle-cell lymphoma (MCL) as a t(11;14)-containing lymphoma driven by cyclin D1 dates to the early 1990s. With median survival of 3 to 5 years, MCL was then considered aggressive. Now, however, with overall survival (OS) in the range of 7 years, even without novel agents, and the lack of a plateau in survival, it is reasonable to consider MCL as a low-grade lymphoma. Accepting this concept removes the sense of urgency to begin aggressive therapy that often accompanies this diagnosis. It also affects interpretation of appropriate clinical trial end points. Although curative therapy is our ultimate goal, at present the goal of therapy, including high-dose chemotherapy with autologous hematopoietic stem-cell transplantation (HDC/aHCT), is prolongation of OS. In the absence of data indicating that this is achievable, studies often use progressionfree survival (PFS) as a surrogate end point that is not yet validated as a predictor of long-term outcome. Selecting optimal treatment approaches for MCL is often as much art as science, and there is no single correct approach. An evolving general approach is to offer intensive regimens, now usually including HDC/aHCT, to young, fit patients, whereas older, less fit patients receive less intensive therapy, such as bendamustine-rituximab. However, an OS benefit for HDC/aHCT has not been convincingly demonstrated, and novel agents such as the BTK inhibitor ibrutinib are changing the field. The large Center for International Blood and Marrow Transplant Research (CIBMTR) database of treatment outcomes for HCT in MCL, reported in the article by Fenske et al that accompanies this editorial, provides important historical data that support the use of HDC/aHCT and reduced-intensity conditioning allogeneic stem-cell transplantation (RIC-alloHCT) in the subset of patients with chemotherapy-sensitive MCL, and provides lessons regarding the role and timing of autologous and RIC-alloHCT. Analysis of this large cohort with mature follow-up confirms good outcomes for chemotherapysensitive patients undergoing HCT early in their course and the expected balance of better disease control, possibly curative, but with higher toxicity, for RIC-alloSCT. Patients in this database were selected as having chemotherapy-sensitive disease and proceeding to HCT. Because the data cutoff was 2007, definition of complete remission (CR) likely varied with time and may not have been uniform, and most patients were treated before newer effective agents were available. Few patients received rituximab after HCT. Use of multivariable analysis from time of diagnosis as a better outcome indicator than the commonly reported time from HCT is helpful and should be adopted in other settings. Although it is common, as in the study by Fenske at al, to analyze autologous and allogeneic HCT outcomes together, it is important to bear in mind the quite different theoretical mechanisms of benefit for these two procedures which, although obvious, are often obscured by our semantics of referring to both as transplantation. HDC/aHCT supports higher doses of myelosuppressive chemotherapy, and has not been curative in MCL or other indolent lymphomas; RIC-alloHCT is an immunologic attack that may be curative, but at a cost of significant shortand long-term toxicities. Lack of demonstrable benefit in OS for RIC-alloHCT is an important finding. I agree with the placement of RIC-alloHCT in the authors’ algorithm and will not discuss RIC-alloHCT further. Once we accept that HDC/aHCT is not curative in MCL and that OS is improving with other therapies, it is worth stepping back to consider the goals of therapy in MCL. Fenske et al conclude that so-called early HCT provides excellent outcomes and improves OS compared with so-called late HCT; however, the latter finding may reflect a biologic selection, and the outcomes may in fact be similar to non-HCT approaches. In prognostically favorable groups, such as MCL with a low MCL International Prognostic Index (MIPI) score or low proliferative rates by gene expression or Ki67, OS is already quite long. Patient selection of a younger population with low MIPI scores for HDC/aHCT may make results seem favorable. The important question of whether intensive therapies overcome poor prognostic features, which would support the authors’ algorithm recommending that all patients in first or second complete remission (CR1 or CR2) undergo HCT, remains unknown. In fact, analysis of patients with high MIPI scores in two studies showed poor outcomes despite HDC/aHCT. The National Comprehensive Cancer Network data showed similar outcomes with intensive therapy with or without HCT. The Nordic Lymphoma Group demonstrated marked improvement with inclusion of rituximab and high-dose cytarabine; HCT was already included in their historical control data. The only randomized comparison of HDC/aHCT and non-HCT consolidation with interferon failed to show a survival benefit, and antedated use of rituximab and high-dose cytarabine. In the CIBMTR data, OS is not much longer than PFS, raising concern about efficacy of subsequent therapy after HDC/aHCT. Treatment strategies using non-HDC/ aHCT consolidation or maintenance can provide comparable OS; for example, in unselected patients, the estimated 5-year OS rate is 73% with radioimmunotherapy, the 3-year OS rate is 91% with rituximab, and in patients older than age 60 years who respond to rituximab plus cyclophosphamide, doxorubicin, vincristine, and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 4 FEBRUARY 1 2014