Abstract

Background

Despite therapeutic approach that combines rituximab-containing chemotherapy, followed or not by autologous stem cell transplantation (auto-SCT), mantle cell lymphoma (MCL) patients experience relapses. Reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) at time of relapse may represent an attractive strategy.

Patients and methods

We report a multicenter retrospective analysis. Seventy MCL patients underwent RIC-allo-SCT in 12 centers.

Results

Median age at transplantation was 56 years and median time from diagnosis to transplantation was 44 months. The median number of previous therapies was 2 (range, 1–5) including autologous transplantation in 47 cases. At time of transplantation, 35 patients were in complete remission, 20 were in partial response and 15 in stable disease or progressive disease. The median follow-up for living patients was 24 months. The 2-year event-free survival (EFS) and overall survival (OS) rates were 50% and 53%, respectively. The 1- and 2-year transplant-related mortality rates were 22% and 32%, respectively. The statistical analysis demonstrated that disease status at transplantation was the only parameter influencing EFS and OS.

Conclusions

These results suggest that RIC-allo-SCT may be an effective therapy in MCL patients with a chemo-sensitive disease at time of transplantation, irrespective of the number of lines of prior therapy. Studies are warranted to investigate the best type of RIC regimen.

introduction

Mantle cell lymphoma (MCL) accounts for ∼5% of non-Hodgkin's lymphomas (NHLs) and was identified as a particular aggressive NHL entity in the early 1990s [1–4]. Given the aggressive natural history of MCL, intensive chemotherapy procedures with or without myeloablative chemotherapy followed by autologous stem cell transplantation (auto-SCT) has been evaluated both in prospective and retrospective studies. Indeed, Dreyling et al. [5] demonstrated that upfront combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) followed by auto-SCT can allow for longer disease control duration as compared with CHOP plus interferon-alpha (IFN-α) maintenance therapy. In the latter study, the complete remission (CR) rate was 81% after auto-SCT as compared with 37% after CHOP plus IFN-α. In addition, the Nordic group showed that high-dose CHOP alternating with high-dose cytarabine combined to rituximab and followed by auto-SCT can yield superior results if compared with conventional chemotherapy without auto-SCT [6]. Thus far, the benefit of auto-SCT in MCL has been confirmed by several reports [7–12]. The hyper-CVAD regimen (with or without rituximab) with or without autologous stem cell support has been also evaluated in untreated MCL patients and could achieve CR rate > 90% and 3-year overall survival (OS) rate ∼82% [13]. In addition to high dose therapy, the use of rituximab upfront or at time of relapse has also improved response rates in MCL and OS [14]. Lenz et al. [15] showed that CR rates with R-CHOP was superior to CHOP alone upfront. At time of first relapse, addition of rituximab to the fludarabine, cyclophosphamide and mitoxantrone (FCM) regimen was also shown to be superior to FCM alone [16]. While in the auto-SCT setting, Tam et al. [17] confirmed that addition of rituximab upfront led to a longer disease control duration. Furthermore, a meta-analysis demonstrated that rituximab plus chemotherapy was superior to chemotherapy alone in MCL [14]. The use of rituximab as a preemptive treatment of relapse after auto-SCT has also been explorer [18]. More recently, a phase III trial conducted by the European MCL network showed that a rituximab maintenance followed R-CHOP improved OS [19].

However, despite better understanding of MCL pathophysiology and improved OS [20, 21], MCL remains an incurable disease and most patients will experience relapse. Results of salvage chemotherapies are probably insufficient to provide long-term disease control. In addition, because median age at time of diagnosis is 65–68 years, most patients are not eligible for conventional myeloablative allogeneic SCT. Therefore, reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) may represent an attractive strategy. Several reports showed the feasibility of RIC-allo-SCT in aggressive lymphoma [22–28]. Some studies underlined the efficacy of RIC-allo-SCT and demonstrated the potential efficacy of graft versus lymphoma effect whereas others reported disappointing results. However, only few studies addressed the issue of RIC-allo-SCT in the setting of MCL [17, 27, 29]. Thus, the place of RIC-allo-SCT in MCL remains questionable [30]. The present retrospective report analyzed the outcome of 70 heavily pretreated MCL patients who underwent salvage RIC-allo-SCT.

patients and methods

study design

This was a retrospective study carried out in 12 allo-SCT centers [University of Hamburg, Germany (n = 14); University of Nantes, France (n = 10); La Pitié-Salpétrière Hospital, Paris, France (n = 8); Chaim Sheba Medical Center, Israel (n = 8); University Hospital of Bordeaux (n = 7); University Hospital of Lille, France (n = 6); University Hospital of Montpellier, France (n = 6); University Hospital of Grenoble, France (n = 4); University Hospital of Clermont-Ferrand, France (n = 3); Necker Hospital, Paris, France (n = 2); University Hospital of Angers, France (n = 1) and Hôtel-Dieu Hospital, Paris (n = 1)], which examined the outcome of 70 consecutive MCL patients who received salvage RIC-allo-SCT in each individual center. The diagnosis of MCL was made by the local pathologist experts according to standard international recommendations at time of diagnosis. Informed consent from patients and donors was obtained according to institutional guidelines in accordance with the Declaration of Helsinki. Investigators were requested to report on MCL adult patients aged ≥18 years who underwent RIC-allo-SCT as salvage treatment. Indication for RIC-allo-SCT depended on each center's policy.

study definitions and statistical analysis

Clinical outcomes that were collected included demographic, disease and transplantation characteristics, graft versus host disease (GVHD) status, time to relapse and survival. Characteristics considered were recipient age, sex, disease remission status at time of RIC-allo-SCT, type of donor and RIC-allo-SCT characteristics (GVHD prophylaxis and stem cell source). An HLA-matched was defined by an identical A/B identity at the serologic level and DRB1 plus DQB1 identities at the molecular level.

CR was defined as the disappearance of all clinical, biological and radiological disorders related to lymphoma. Partial response (PR) was defined as a > 50% reduction of tumor burden. Progressive disease was defined by > 25% increase of tumor mass. Other cases were defined as stable disease (SD) [31]. Standard criteria were used for GVHD assessment [32]. Incidences of transplant-related mortality (TRM) and acute and chronic GVHD were calculated. Probabilities of OS and event-free survival (EFS) were calculated using the Kaplan–Meier estimate. The log-rank test was used for univariate comparisons. All potential prognostic factors of the univariate analysis (P value ≤ 5%) were included in the multivariate analyses, using Cox proportional hazards. Cox proportional hazard models without any covariate adjustment were fit to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Cumulative incidence was calculated for TRM. All P values were two-sided; significance was set at the level of 5%. No adjustment was made for multiple comparisons. Statistical analyses were carried out using R software version 2.8.1.

results

patients and transplant characteristics

Patients and transplant characteristics are summarized in Table 1. A total of 70 MCL patients were included. Patients underwent RIC-allo-SCT from June 1999 to October 2008. All patients in this series presented with a refractory or relapsed MCL. The median number of previous lines of therapies was 2 (range, 1–5) including auto-SCT in 47 cases (a chemotherapy regimen followed by an auto-SCT is counted as one line). Prior chemotherapy regimens contained anthracyclines in 65 cases (94%), cytarabine in 59 cases (85.5%) and rituximab in 48 cases (69%). Eight patients (11%) received bortezomib. Median time from diagnosis to RIC-allo-SCT was 44 (range, 6–120 months). At time of transplantation, 55 patients were in CR or PR (of whom 35 patients in CR). HLA-identical sibling donors were used in 53% of cases. Various RIC regimen (n = 16) were used. Briefly, 66 patients received a fludarabine-containing regimen (94%). Twenty-six patients received busulfan plus fludarabine. Twelve patients received low-dose total body irradiation (TBI) and fludarabine. Five patients received fludarabine and cyclophospamide. Fifteen patients received fludarabine and melphalan including six patients who also received rituximab. In total, 15 patients received low-dose TBI (2 Gy), 25 (36%) received busulfan, 18 (26%) received melphalan and 11 (16%) received cyclophosphamide. Anti-thymoglobulin (ATG) was used as part of the RIC regimen in 43 cases (62%).

Table 1.

Patients and transplant characteristics

Characteristics n = 70 (%) 
Median age at transplantation 56 (range 33–67.5) 
Relapse after auto-SCT 47 (67) 
RIC-allo-SCT before 2004 36 (51) 
Times between diagnosis and RIC-allo-SCT (months) 44 (range, 6–120) 
Disease status at transplantation  
 CR 35 (50) 
 PR 20 (29) 
 SD/progressive 15 (21) 
 Donor related 37 (53) 
 HLA matched 56 (80) 
Sex patient/donor (missing = 2)  
 M/M 35 (51) 
 M/F 14 (21) 
 F/M 15 (22) 
 F/F 4 (6) 
CMV serostatus patient/donor (missing = 3)  
 P/P 17 (25.5) 
 P/N 9 (13.5) 
 N/P 27 (40) 
 N/N 14 (21) 
Stem cells source  
 PBSC 65 (93) 
 BM 4 (6) 
 PBSC + BM 1 (1) 
Conditioning regimens  
 Busulfan/fludarabine 24 (36) 
 TBI/fludarabine 12 (17) 
 Fludarabin/cyclophosphamide 5 (7) 
 Fludarabine/melphalan 9 (13) 
 Fludarabine/melphalan/rituximab 6 (8) 
 Others 12 (17) 
ATG-containing 43 (62) 
GVHD prophylaxis (missing = 1)  
 CsA–MTX 35 (51) 
 CsA–MMF 29 (42) 
 CsA alone 5 (7) 
Characteristics n = 70 (%) 
Median age at transplantation 56 (range 33–67.5) 
Relapse after auto-SCT 47 (67) 
RIC-allo-SCT before 2004 36 (51) 
Times between diagnosis and RIC-allo-SCT (months) 44 (range, 6–120) 
Disease status at transplantation  
 CR 35 (50) 
 PR 20 (29) 
 SD/progressive 15 (21) 
 Donor related 37 (53) 
 HLA matched 56 (80) 
Sex patient/donor (missing = 2)  
 M/M 35 (51) 
 M/F 14 (21) 
 F/M 15 (22) 
 F/F 4 (6) 
CMV serostatus patient/donor (missing = 3)  
 P/P 17 (25.5) 
 P/N 9 (13.5) 
 N/P 27 (40) 
 N/N 14 (21) 
Stem cells source  
 PBSC 65 (93) 
 BM 4 (6) 
 PBSC + BM 1 (1) 
Conditioning regimens  
 Busulfan/fludarabine 24 (36) 
 TBI/fludarabine 12 (17) 
 Fludarabin/cyclophosphamide 5 (7) 
 Fludarabine/melphalan 9 (13) 
 Fludarabine/melphalan/rituximab 6 (8) 
 Others 12 (17) 
ATG-containing 43 (62) 
GVHD prophylaxis (missing = 1)  
 CsA–MTX 35 (51) 
 CsA–MMF 29 (42) 
 CsA alone 5 (7) 

auto-SCT, autologous stem cell transplantation; RIC-allo-SCT, reduced-intensity conditioning allogeneic stem cell transplantation; CR, complete remission; PR, partial remission; SD, stable disease; M, male; F, female; CMV, cytomegalovirus; P, positive; N, negative; PBSC, peripheral blood stem cell; BM, bone marrow; TBI, total body irradiation; ATG, anti-thymoglobulin; GVHD, graft versus host disease; CsA, cyclosporine; MTX, methotrexate; MMF, mycophenolate.

outcome

In this series, eight patients (11%) failed to engraft. Veno-occlusive disease (VOD) was reported in five cases including two patients with a previous history of auto-SCT. Among the five VOD patients, four have received a melphalan-containing regimen and four have received at least four lines of therapy before RIC-allo-SCT. Grade 3–4 acute GVHD was observed in 18 patients and 12 patients experienced extensive chronic GVHD. With a median follow-up of 24 (range, 1–103 months), 33 patients have died, of whom 21 were of TRM. The 1- and 2-year TRM rates were 22% (95% CI, 11–31%) and 32% (95% CI, 19–43%), respectively (Figure 1A). Disease status after RIC-allo-SCT could not be assessed in 12 patients because of early death. In the 58 assessable patients, 52 and 3 achieved CR and PR, respectively. The three remaining patients had SD or progressed after transplantation. The median EFS and OS were 18 and 27 months, respectively (Figure 1B and C). At 2 years, the EFS and OS rates were 50% (95% CI, 39–55%) and 53% (95% CI, 42–68%), respectively.

Figure 1.

(A) Cumulative incidences of post-allo-SCT transplant-related mortality (TRM); (B) overall survival for all patietns; (C) event-free survival for all patients.

Figure 1.

(A) Cumulative incidences of post-allo-SCT transplant-related mortality (TRM); (B) overall survival for all patietns; (C) event-free survival for all patients.

statistical analyses for survival and TRM

The results of the statistical analysis are presented in Table 2. The number of lines of previous treatments before RIC-allo-SCT had no impact on OS, EFS or TRM. No differences were observed between patients receiving a graft from an HLA-identical sibling or from an unrelated donor. However, there was a trend toward and increased incidence of grade 3–4 acute GVHD when using an unrelated donor (P = 0.087, RR 0.12–1.16). Statistical analysis found no correlation between cGVHD and patient's outcome. A similar result was obtained for the subgroup of living patients after D100 (n = 58). OS and EFS were also not modified according to time of transplantation (period 1999–2003 versus 2004–2008). Among parameters evaluated for EFS, OS and TRM, only disease status at time of RIC-allo-SCT reached statistical significance in univariate analysis (Figure 2). Indeed, the 2-year EFS rates for CR, PR and SD/progressive patients were 62.5% (95% CI, 47–83%), 53% (95% CI, 35–80%) and 11% (95% CI, 19–66%), respectively. The 2-year OS rates for CR, PR and SD/progressive patients were 62% (95% CI, 46–83%), 53% (95% CI, 34–81%) and 31% (95% CI, 13–73%), respectively. In univariate analysis, there was a trend for longer OS when patient did not receive ATG as part of the conditioning regimen (P = 0.11, Figure 3).

Table 2.

Statistical analysis

 OS
 
EFS
 
TRM
 
 Univariate HR (95% CI) Univariate HR (95% CI) Univariate HR (95% CI) 
Patient gender NS  NS  NS  
Age at transplantation NS  NS  NS  
Number of lines of chemotherapy before RIC-allo-SCT ( ≤ 2 versus > 2) NS  NS  NS  
Types of chemotherapy regimen prior RIC-allo-SCT NS  NS  NS  
Times between diagnosis and RIC-allo-SCT NS  NS  NS  
Disease status at allo-SCT (CR/PR versus other) 0.0023 3.3 (1.53–7.04) 0.00032 3.97 (1.87–8.42) 0.028 3.03 (1.13–8.16) 
Source of stem cells (BM versus PBSC) NS  NS  NS  
Donor related versus unrelated NS  NS  NS  
HLA mismatched versus matched NS  NS  NS  
Sex donor/patient (M/F versus other) NS  NS  NS  
CMV serostatus donor/patient NS  NS  NS  
Use of TBI NS  NS  NS  
Use of fludarabine NS  NS  NS  
Use of ATG 0.115 1.77 (0.87–3.61) NS  NS  
Conditioning regimens NS  NS  NS  
GVHD prophylaxis NS  NS  NS  
 OS
 
EFS
 
TRM
 
 Univariate HR (95% CI) Univariate HR (95% CI) Univariate HR (95% CI) 
Patient gender NS  NS  NS  
Age at transplantation NS  NS  NS  
Number of lines of chemotherapy before RIC-allo-SCT ( ≤ 2 versus > 2) NS  NS  NS  
Types of chemotherapy regimen prior RIC-allo-SCT NS  NS  NS  
Times between diagnosis and RIC-allo-SCT NS  NS  NS  
Disease status at allo-SCT (CR/PR versus other) 0.0023 3.3 (1.53–7.04) 0.00032 3.97 (1.87–8.42) 0.028 3.03 (1.13–8.16) 
Source of stem cells (BM versus PBSC) NS  NS  NS  
Donor related versus unrelated NS  NS  NS  
HLA mismatched versus matched NS  NS  NS  
Sex donor/patient (M/F versus other) NS  NS  NS  
CMV serostatus donor/patient NS  NS  NS  
Use of TBI NS  NS  NS  
Use of fludarabine NS  NS  NS  
Use of ATG 0.115 1.77 (0.87–3.61) NS  NS  
Conditioning regimens NS  NS  NS  
GVHD prophylaxis NS  NS  NS  

OS, overall survival; EFS, event-free survival; TRM, transplant-related mortality; HR, hazard ratio; CI, confidence interval; RIC-allo-SCT, reduced-intensity conditioning allogeneic stem cell transplantation; CR, complete remission; PR, partial remission; BM, bone marrow; PBSC, peripheral blood stem cell; M, male; F, female; CMV, cytomegalovirus; TBI, total body irradiation; ATG, anti-thymoglobulin; GVHD, graft versus host disease and NS, not significant. Only results with a P value < 0.2 are listed.

Figure 2.

(A) Overall Survival after transplantation according to disease status prior RIC-allo-SCT. (B) Event-free survival after transplantation according to disease status prior RIC-allo-SCT. (C) Cumulative incidences of post-allo-SCT transplant-related mortality according to disease status prior RIC-allo-SCT. ( … ..), patients in stable/progressive disease; (----), patients in partial response and ( __ ) patients in complete response.

Figure 2.

(A) Overall Survival after transplantation according to disease status prior RIC-allo-SCT. (B) Event-free survival after transplantation according to disease status prior RIC-allo-SCT. (C) Cumulative incidences of post-allo-SCT transplant-related mortality according to disease status prior RIC-allo-SCT. ( … ..), patients in stable/progressive disease; (----), patients in partial response and ( __ ) patients in complete response.

Figure 3.

(A) Overall survival according to the use of anti-thymoglobulin (ATG). (B) Event-free survival according to the use of ATG ( __ ), patients who did not received ATG and (----) patients who received ATG.

Figure 3.

(A) Overall survival according to the use of anti-thymoglobulin (ATG). (B) Event-free survival according to the use of ATG ( __ ), patients who did not received ATG and (----) patients who received ATG.

discussion

Long-term survival in patients with relapsed/refractory MCL remains poor, even after optimal salvage chemotherapy. Such poor outcome is the result of a higher rate of disease progression even after high-dose chemotherapy and auto-SCT. Selection of chemoresistant malignant clones after multiple chemotherapy regimens may explain relapse. Therefore, there is room for improvement in the management of patients with relapsed/refractory MCL.

The current report assessed the outcome of 70 MCL patients who underwent RIC-allo-SCT as salvage therapy. Only few reports addressed the issue of RIC-allo-SCT in the specific setting of relapsed MCL. In this series, the 2-year EFS and OS rates were 50% and 53%, respectively. No plateau phase achieved at any time point after transplantation can question the existence of a graft versus MCL effect (GV–MCL). However, there are other findings in the present report that support the existence of a GV–MCL effect and potential curative action of RIC-allo-SCT in refractory/relapsed. First, we observe a trend showing that the use of ATG increases the risk of relapse. One explanation is that ATG eradicates T cells and, thus abrogates the GV–MCL [33, 34]. The use of ATG can also explain why < 30% of our patients experienced cGVHD as compared with 50–60% in other reports [17, 27]. Interestingly, we observe a trend of a plateau phase in the group of patients who did not received ATG (see Figure 3A and B). A longer follow-up is necessary before to confirm this trend. Second, it is interesting to notice that the outcome after RIC-allo is not related to the number of previous lines of chemotherapy. This suggests that the immune mediated allogeneic GV–MCL effect imparted by RIC-allo-SCT may provide an alternative non-cross-resistant mechanism that can eradicate chemo-resistant residual MCL cells. Indeed, the 3-year EFS for the 47 patients who relapsed after autologous is 48.7% (95% CI, 33.5–71%). The favorable impact of RIC-allo has also been reported by other groups. Recently, Tam et al. updated the M. D. Anderson's experience using RIC-allo-SCT for MCL with a long-term follow-up [17, 29]. This study confirmed previous reports from the same group showing that the number of lines of prior therapy was a major determinant for EFS only if patients had received more than five lines of prior therapies, a situation which was not encountered in our series. The latter highlights the potential for selection bias in single-center series and underscores the need for multicenter comparative trials in order to define the optimal salvage treatment strategy in MCL. In the M. D. Anderson's experience, the 6-year PFS rate was 46%, with a plateau phase achieved after 3 years and no relapse beyond 63 months of follow-up. Interestingly, most of the patients reported by the M. D. Anderson group received an RIC regimen containing fludarabine, cyclophosphamide and rituximab, raising the question of the role of rituximab as part of the RIC regimen for long-term disease control as already shown in follicular lymphoma [35]. In the Seattle's experience in relapsed/refractory MCL patients, using fludarabine and low-dose TBI (2 Gy), the 2-year OS and disease-free survival rates were 65% and 60%, respectively. As shown in our analysis, disease status at time of transplantation was also highly predictive for outcome in the Seattle series [36]. Taken together, disease status at time of transplantation is likely the major determinant for outcome in the setting of RIC-allo-SCT for MCL. The type of RIC regimen may also be one major parameter. Despite a relatively high number of patients, the multicenter nature of our analysis might explain some of the discrepancies observed between our results and those of the M. D. Anderson and the Seattle groups. An inherent difficulty in interpreting the disparate results between individual reports lies with the heterogeneity of the studies (single-center versus multicenter and cooperative group versus registry studies), the heterogeneity of the patients studied, the variation in the RIC procedure itself (e.g. the conditioning regimen and GVHD prophylaxis) and the duration of follow-up. Indeed, we failed to collect some items about patient's characteristic at time of diagnosis (like morphological variant, bulky disease, Mantle International Prognostic Index score … ) that could have potentially influenced patient's outcome. There is an almost universal consensus, however, that disease status at time of allo-SCT is a major determinant of response to RIC-allo-SCT, with chemorefractory patients experiencing significantly inferior survival rates because of poor disease control and an increased TRM. This is illustrated by the study from Robinson et al. reporting multicenter data from the EBMT in 22 MCL cases, and showing a 1-year TRM rate of 46% [28]. In the initial EBMT report, all patients relapsed within 2 years followed transplantation. The update of the EBMT study included 180 MCL patients, the 5-year PFS was 25% and 1-year TRM was 32% [37]. The British experience has also recently been published [27]. The study included 70 patients. The PFS at 5 years was only 37% with 18 patients who died because of MCL. Though, the results of the current study and those of other large studies support the ongoing exploration of RIC-allo-SCT in the treatment of patients with relapsed MCL. However, the continuous incidence of disease relapse after RIC-allo-SCT remains an issue and the TRM remains too high. Several options may enhance these results. One option would be to avoid the use of ATG which not only reduces GVHD but also abrogates the graft-versus-lymphoma effect. The use of alemtuzumab in the conditioning regimen causes also deep depletion of T cells that reduces the GV–MCL, and thus increases risk of relapse [38, 39]. This finding in MCL and NHLs is in accordance with other reports that addressed the question of RIC-allo-SCT in chronic lymphocytic leukemia [40, 41]. An other option would be the administration of prophylactic donor lymphocytes infusions (DLIs) as it has been showed that DLIs can eradicate residual MCL cells [42]. Minimal residual disease (MRD) monitoring after allo-SCT could thus be very useful to decide of a preemptive relapse treatment by DLIs. In addition, results of MRD monitoring carried out at key time points during the course of the treatment may also be of great interest to select high-risk of relapse patients for whom a conventional chemotherapy treatment will not be sufficient to eradicate the disease. The European MCL network showed that CR patients who do not reach MRD negativity at the molecular level after auto-SCT are highly exposed to relapse. Therefore, MRD + patients at least at end of treatment could be good candidates for alternative therapeutic options including RIC-allo-SCT [43]. Rituximab in the conditioning regimen or its use early after RIC-allo-SCT may represent another attractive modality toward decreasing the incidence of disease relapse with little, if any, toxicity. Interestingly, the European MCL network reported a phase III prospective study that demonstrated the advantage for OS of a rituximab maintenance followed R-CHOP [19]. Bortezomib or lenalidomide which have demonstrated efficacy as single agent in relapsed/refractory MCL may also be an attractive option for a post RIC-allo-SCT strategy [44–46]. Indeed, the ultimate objective of RIC-allo-SCT is the achievement of long-term disease control without undue TRM. The issue of tolerability of a treatment strategy such as RIC-allo-SCT is of major importance in a disease setting in which the median age at diagnosis is usually older than 60 years, and patients being heavily pretreated, including those who had failed previous auto-SCT.

In all, we conclude that data from this study provides further insight into the feasibility and efficacy of RIC-allo-SCT in MCL. The described results can lay the groundwork for prospective trials aiming to determine the exact role of RIC-allo-SCT in MCL. Moreover, these results are expected to be further improved with strategies aiming to enhance the immune effect without enhancing GVHD. A risk-adapted strategy combining with close minimal residual disease monitoring may also help selecting those MCL patients who will most benefit from RIC-allo-SCT.

disclosure

The authors have declared no conflict of interest.

acknowledgements

SLG and MM would like to thank the ‘Région Pays de Loire’, the Institut National du Cancer (INCa), the ‘Association pour la Recherche sur le Cancer (ARC)’, the ‘Fondation de France’, the ‘Fondation contre la Leucémie’, the ‘Agence de Biomédecine’, the ‘Association Cent pour Sang la Vie’ and the ‘Association Laurette Fuguain’ for their generous and continuous support for our clinical and basic research work. We thank the nursing staff for providing excellent care for the patients.

references

1
Andersen
NS
Jensen
MK
de Nully Brown
P
, et al.  . 
Danish population-based analysis of 105 mantle cell lymphoma patients: incidences, clinical features, response, survival and prognostic factors
Eur J Cancer
 , 
2002
, vol. 
38
 (pg. 
401
-
408
)
2
Banks
PM
Chan
J
Cleary
ML
, et al.  . 
Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data
Am J Surg Pathol
 , 
1992
, vol. 
16
 (pg. 
637
-
640
)
3
Zhou
Y
Wang
H
Fang
W
, et al.  . 
Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004
Cancer
 , 
2008
, vol. 
113
 (pg. 
791
-
798
)
4
Raffeld
M
Jaffe
ES
bcl-1, t(11;14), and mantle cell-derived lymphomas
Blood
 , 
1991
, vol. 
78
 (pg. 
259
-
263
)
5
Dreyling
M
Lenz
G
Hoster
E
, et al.  . 
Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network
Blood
 , 
2005
, vol. 
105
 (pg. 
2677
-
2684
)
6
Geisler
CH
Kolstad
A
Laurell
A
, et al.  . 
Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group
Blood
 , 
2008
, vol. 
112
 (pg. 
2687
-
2693
)
7
de Guibert
S
Jaccard
A
Bernard
M
, et al.  . 
Rituximab and DHAP followed by intensive therapy with autologous stem-cell transplantation as first-line therapy for mantle cell lymphoma
Haematologica
 , 
2006
, vol. 
91
 (pg. 
425
-
426
)
8
Gianni
AM
Magni
M
Martelli
M
, et al.  . 
Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen)
Blood
 , 
2003
, vol. 
102
 (pg. 
749
-
755
)
9
Khouri
IF
Romaguera
J
Kantarjian
H
, et al.  . 
Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma
J Clin Oncol
 , 
1998
, vol. 
16
 (pg. 
3803
-
3809
)
10
Lefrere
F
Delmer
A
Levy
V
, et al.  . 
Sequential chemotherapy regimens followed by high-dose therapy with stem cell transplantation in mantle cell lymphoma: an update of a prospective study
Haematologica
 , 
2004
, vol. 
89
 (pg. 
1275
-
1276
)
11
Lefrere
F
Delmer
A
Suzan
F
, et al.  . 
Sequential chemotherapy by CHOP and DHAP regimens followed by high-dose therapy with stem cell transplantation induces a high rate of complete response and improves event-free survival in mantle cell lymphoma: a prospective study
Leukemia
 , 
2002
, vol. 
16
 (pg. 
587
-
593
)
12
Vigouroux
S
Gaillard
F
Moreau
P
, et al.  . 
High-dose therapy with autologous stem cell transplantation in first response in mantle cell lymphoma
Haematologica
 , 
2005
, vol. 
90
 (pg. 
1580
-
1582
)
13
Romaguera
JE
Fayad
L
Rodriguez
MA
, et al.  . 
High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine
J Clin Oncol
 , 
2005
, vol. 
23
 (pg. 
7013
-
7023
)
14
Schulz
H
Bohlius
JF
Trelle
S
, et al.  . 
Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis
J Natl Cancer Inst
 , 
2007
, vol. 
99
 (pg. 
706
-
714
)
15
Lenz
G
Dreyling
M
Hoster
E
, et al.  . 
Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG)
J Clin Oncol
 , 
2005
, vol. 
23
 (pg. 
1984
-
1992
)
16
Forstpointner
R
Dreyling
M
Repp
R
, et al.  . 
The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group
Blood
 , 
2004
, vol. 
104
 (pg. 
3064
-
3071
)
17
Tam
CS
Bassett
R
Ledesma
C
, et al.  . 
Mature results of the MD Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma
Blood
 , 
2009
, vol. 
113
 
18
(pg. 
4144
-
4152
)
18
Andersen
NS
Pedersen
LB
Laurell
A
, et al.  . 
Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma
J Clin Oncol
 , 
2009
, vol. 
27
 (pg. 
4365
-
4370
)
19
Klui-Nelemans
J
Hoster
E
Hermine
O
, et al.  . 
R-CHOP versus R-FC followed by maintenance with rituximab or IFN: first results of a randomized trial for elderly patients with mantle cell lymphoma
Ann Oncol
 , 
2011
 
22(S4); iv186
20
Jares
P
Colomer
D
Campo
E
Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics
Nat Rev Cancer
 , 
2007
, vol. 
7
 (pg. 
750
-
762
)
21
Herrmann
A
Hoster
E
Zwingers
T
, et al.  . 
Improvement of overall survival in advanced stage mantle cell lymphoma
J Clin Oncol
 , 
2009
, vol. 
27
 (pg. 
511
-
518
)
22
Branson
K
Chopra
R
Kottaridis
PD
, et al.  . 
Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies
J Clin Oncol
 , 
2002
, vol. 
20
 (pg. 
4022
-
4031
)
23
Corradini
P
Dodero
A
Farina
L
, et al.  . 
Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome
Leukemia
 , 
2007
, vol. 
21
 (pg. 
2316
-
2323
)
24
Escalon
MP
Champlin
RE
Saliba
RM
, et al.  . 
Nonmyeloablative allogeneic hematopoietic transplantation: a promising salvage therapy for patients with non-Hodgkin's lymphoma whose disease has failed a prior autologous transplantation
J Clin Oncol
 , 
2004
, vol. 
22
 (pg. 
2419
-
2423
)
25
Rezvani
AR
Storer
B
Maris
M
, et al.  . 
Nonmyeloablative allogeneic hematopoietic cell transplantation in relapsed, refractory, and transformed indolent non-Hodgkin's lymphoma
J Clin Oncol
 , 
2008
, vol. 
26
 (pg. 
211
-
217
)
26
Thomson
KJ
Morris
EC
Bloor
A
, et al.  . 
Favorable long-term survival after reduced-intensity allogeneic transplantation for multiple-relapse aggressive non-Hodgkin's lymphoma
J Clin Oncol
 , 
2009
, vol. 
27
 (pg. 
426
-
432
)
27
Cook
G
Smith
GM
Kirkland
K
, et al.  . 
Outcome following Reduced-Intensity Allogeneic Stem Cell Transplantation (RIC AlloSCT) for relapsed and refractory mantle cell lymphoma (MCL): a study of the British society for blood and marrow transplantation
Biol Blood Marrow Transplant
 , 
2010
, vol. 
16
 (pg. 
1419
-
1427
)
28
Robinson
SP
Goldstone
AH
Mackinnon
S
, et al.  . 
Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation
Blood
 , 
2002
, vol. 
100
 (pg. 
4310
-
4316
)
29
Khouri
IF
Lee
MS
Saliba
RM
, et al.  . 
Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma
J Clin Oncol
 , 
2003
, vol. 
21
 (pg. 
4407
-
4412
)
30
Le Gouill
S
Mohty
M
Guillaume
T
, et al.  . 
Allogeneic stem cell transplantation in mantle cell lymphoma: where are we now and which way should we go?
Semin Hematol
 , vol. 
48
 (pg. 
227
-
239
)
31
Cheson
BD
Pfistner
B
Juweid
ME
, et al.  . 
Revised response criteria for malignant lymphoma
J Clin Oncol
 , 
2007
, vol. 
25
 (pg. 
579
-
586
)
32
Przepiorka
D
Weisdorf
D
Martin
P
, et al.  . 
1994 Consensus Conference on Acute GVHD Grading
Bone Marrow Transplant
 , 
1995
, vol. 
15
 (pg. 
825
-
828
)
33
Finke
J
Bethge
WA
Schmoor
C
, et al.  . 
Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial
Lancet Oncol
 , 
2009
, vol. 
10
 (pg. 
855
-
864
)
34
Mohty
M
Labopin
M
Balere
ML
, et al.  . 
Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire
Leukemia
 , 
2010
, vol. 
24
 (pg. 
1867
-
1874
)
35
Khouri
IF
McLaughlin
P
Saliba
RM
, et al.  . 
Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab
Blood
 , 
2008
, vol. 
111
 (pg. 
5530
-
5536
)
36
Maris
MB
Sandmaier
BM
Storer
BE
, et al.  . 
Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma
Blood
 , 
2004
, vol. 
104
 (pg. 
3535
-
3542
)
37
Robinson
SP
Taghipour
G
Canals
C
, et al.  . 
Reduced-intensity conditioning and allogeneic stem cell transplantation in mantle cell lymphoma: update from the lymphoma working party of the EBMT
EBMT meeting Hamburg. Germany March 19–22,
 , 
2006
38
Morris
E
Thomson
K
Craddock
C
, et al.  . 
Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma
Blood
 , 
2004
, vol. 
104
 (pg. 
3865
-
3871
)
39
Perez-Simon
JA
Kottaridis
PD
Martino
R
, et al.  . 
Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders
Blood
 , 
2002
, vol. 
100
 (pg. 
3121
-
3127
)
40
Dreger
P
Dohner
H
Ritgen
M
, et al.  . 
Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial
Blood
 , vol. 
116
 (pg. 
2438
-
2447
)
41
Michallet
M
Sobh
M
Milligan
D
, et al.  . 
The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry
Leukemia
 , 
2010
, vol. 
24
 (pg. 
1725
-
1731
)
42
Sohn
SK
Baek
JH
Kim
DH
, et al.  . 
Successful allogeneic stem-cell transplantation with prophylactic stepwise G-CSF primed-DLIs for relapse after autologous transplantation in mantle cell lymphoma: a case report and literature review on the evidence of GVL effects in MCL
Am J Hematol
 , 
2000
, vol. 
65
 (pg. 
75
-
80
)
43
Hermine
O
Hoster
E
Walewski
J
, et al.  . 
Alternating courses of 3x cHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen and autolgous stem cell transplantation (ASCT) is superior to 6 courses CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: results of the MCL younger trial of the European mantle cell lymphoma network
Blood
 , 
2010
 
Abstract 110
44
Fisher
RI
Bernstein
SH
Kahl
BS
, et al.  . 
Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma
J Clin Oncol
 , 
2006
, vol. 
24
 (pg. 
4867
-
4874
)
45
Goy
A
Younes
A
McLaughlin
P
, et al.  . 
Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma
J Clin Oncol
 , 
2005
, vol. 
23
 (pg. 
667
-
675
)
46
Wiernik
PH
Lossos
IS
Tuscano
JM
, et al.  . 
Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma
J Clin Oncol
 , 
2008
, vol. 
26
 (pg. 
4952
-
4957
)