current approaches to mantle cell lymphoma: diagnosis ... · mantle cell lymphoma (mcl) is a unique...

512 2017 ASCO EDUCATIONAL BOOK | asco.org/edbook

MCL comprises less than 10% of all cases of non-Hod-gkin lymphoma and has heterogeneous clinical

behavior ranging from indolent to very aggressive. The disease is characterized by the presence of t(11;14) and frequently presents at an advanced stage with a male pre-dominance and median age of 64.1 There is currently no standard of care for patients with newly diagnosed MCL, although many fit patients are considered for intensive, Ara-C–containing, induction therapy followed by autolo-gous stem cell transplantation (ASCT). This approach has resulted in a median time to treatment failure of up to 9 years in studies such as the recently reported MCL Younger study, and similar impressive results have been reported in other studies incorporating Ara-C–containing induction regimens with ASCT.2-5 In addition, currently available novel therapies and those still under investigation have markedly improved outcomes for patients with relapsed disease, re-sulting in prolonged overall survival (OS) for most patients with MCL, including those who cannot undergo ASCT in first remission.6-11 However, despite recent advances, most patients with MCL will ultimately die of their disease, and very few patients are cured outside of an allogeneic stem cell transplant (alloSCT).12 This review summarizes the cur-rently available data regarding identification of indolent compared with aggressive disease, the role of ASCT in first remission, and the appropriate scenarios in which to use maintenance therapies.

DIFFERENTIATING BETWEEN AGGRESSIVE AND LESS AGGRESSIVE MCLRisk Stratification in MCLIdentification of low-risk disease and consideration of a watchful waiting approach. Although most patients with MCL will initiate therapy at the time of diagnosis, a subset of patients with indolent disease can be safely observed (Fig. 1). Martin et al first described a cohort of deferred patients at Cornell, where 31 patients who delayed treatment of at least 3 months could be safely monitored for a median of 12 months (range, 4-128 months) without a negative impact on OS.13 In this series, patients with a good performance status and low International Prognostic Index (IPI) score were more likely to receive deferred therapy.

Similar series have been presented in abstracts from British Columbia (74 patients), Memorial Sloan Kettering Cancer Center (91 patients), and an Emory University–led multicenter cohort (71 patients) describing patients defer-ring therapy for at least 3 months.14-16 In these series, 17% to 29% of patients have pursued deferred therapy with a median time to treatment of 8–35.6 months. Consistent predictors of deferred therapy include good performance status, lack of B-symptoms, and normal lactate dehydro-genase (LDH). Additional pathologic factors including Ki67 less than 30% and lack of blastoid morphology have been associated with deferred therapy in some series. Finally, patients with early-stage disease and those with a leukemic

COHEN, ZAIN, AND KAHL

Current Approaches to Mantle Cell Lymphoma: Diagnosis, Prognosis, and TherapiesJonathon B. Cohen, MD, Jasmine M. Zain, MD, and Brad S. Kahl, MD

OVERVIEW

Mantle cell lymphoma (MCL) is a unique lymphoma subtype, both biologically and clinically. Virtually all cases are char-acterized by a common genetic lesion, t(11;14), resulting in overexpression of cyclin D1. The clinical course is moderately aggressive, and the disease is considered incurable. Considerable biologic and clinical heterogeneity exists, with some patients experiencing a rapidly progressive course, while others have disease that is readily managed. New tools exist for risk stratification and may allow for a more personalized approach in the future. Landmark studies have been completed in recent years and outcomes appear to be improving. Randomized clinical trials have clarified the role of high-dose cy-tarabine (Ara-C) for younger patients and have demonstrated a role for maintenance rituximab therapy. Multiple areas of uncertainty remain, however, and are the focus of ongoing research. This review focuses on (1) strategies to differentiate between aggressive and less aggressive cases, (2) understanding who should receive hematopoietic stem cell transplanta-tion, and (3) the role for maintenance therapy in MCL.

From Emory University, Atlanta, GA; City of Hope, Duarte, CA; Washington University School of Medicine, St. Louis, MO.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Brad S. Kahl, MD, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8056, St. Louis, MO 63110; email: [email protected].

© 2017 American Society of Clinical Oncology

http://asco.org/edbook


asco.org/edbook | 2017 ASCO EDUCATIONAL BOOK 513

CURRENT APPROACHES TO MANTLE CELL LYMPHOMA

presentation (i.e., non-nodal with disease primarily limited to the peripheral blood) are also more likely to be ob-served.17 Interestingly, the MCL IPI (MIPI) has not been as-sociated with selection of deferred therapy in any of the previously reported series, suggesting that this index may not adequately identify the subset of patients with indolent disease who are candidates for this approach. Patients with high-risk MIPI have been safely observed in all previously reported series.

A national cohort analysis from the National Cancer Da-tabase has also evaluated the role of deferred therapy throughout the United States.18 In this series, 492 of 8,029 (6%) patients received deferred therapy with a median time to treatment of 121 days (range, 91–1,152), and de-ferred therapy was associated with an improved OS (haz-ard ratio [HR] 0.79;) in this larger cohort. In a multivariable model, lack of B-symptoms was the strongest variable associated with receipt of deferred therapy, while extran-odal presentation, Hispanic race, and residence outside of the Midwest or Southern regions were also associated with deferred therapy.

In the absence of randomized, prospective studies evalu-ating the role of deferred therapy, it appears that patients without symptoms, with low tumor burden, and without high-risk pathologic features can be safely observed, often for several years. In addition to the clinical and pathologic features mentioned above, SOX11 expression by immuno-histochemistry (IHC) has been evaluated for its potential to identify low-risk, indolent cases. In a review of SOX11

IHC expression from the Nordic group for patients enrolled on the Nordic MCL 2 and 3 protocols, the high-expression group had a 10-year OS of 69% and patients with SOX11HIGH disease had improved OS in a multivariable model.19 A pop-ulation-based series of 173 cases included 160 patients with SOX11 expression by IHC, and the median OS was 3.2 years for patients with SOX11-positive disease compared with 1.5 years for those with SOX11-negative disease.20 How-ever, additional series have suggested that patients with SOX11-negative disease may in fact be predisposed to a leukemic, non-nodal presentation and indolent disease be-havior, and this is reflected in the updated World Health Or-ganization criteria, which identify leukemic, non-nodal MCL as a distinct entity that is SOX11-negative.21 Although its use in the right clinical scenario can provide useful prognostic information, SOX11 expression alone should not be used to identify indolent compared with aggressive disease without considering the clinical situation in a particular patient.Prospective identification of high-risk patients and aggres-sive disease. Early identification of high-risk patients may allow providers to pursue alternative therapies and consider enrollment on clinical trials. Current approaches to identi-fication of high-risk patients include MIPI risk score, Ki67 proliferative index, cytogenetics/fluorescent in situ hybrid-ization, identification of genomic aberrations, and/or evalu-ation of gene expression profiling. Unfortunately, outcomes for patients with identified high-risk features remain poor, even with currently available Ara-C–containing induction, consolidation, and maintenance approaches.22,23

Although patients with low- and intermediate-risk MIPI scores have improved outcomes with currently available therapies, patients with high-risk MIPI scores enrolled in the European MCL Younger and MCL Elderly studies had a median OS of less than 3 years in a pooled analysis, and the median OS for high-risk patients in the MCL Younger cohort alone was only 3.8 years (Table 1).22 The median OS rates for the low- and intermediate-risk subsets were not reached in either study. The impact of MIPI has also been evaluated for the Nordic MCL2 study, in which the low-risk patients have a median OS not reached after 15 years of follow-up, the intermediate-risk patients have a median OS of 11 years, and the high-risk patients have a median OS of 4 years.24 Similar findings have been described by Damon et al with CALGB 59909, in which 67% of patients with high risk MIPI died within the median follow-up of 4.7 years.5

KEY POINTS

• The MIPI integrates four clinical parameters with the Ki-67 proliferation index to identify patients with low- and high-risk disease.

• The best outcomes for younger patients with MCL have been achieved by incorporating high-dose Ara-C into induction therapy, followed by ASCT.

• AlloSCT strategies are most appropriate in the relapsed MCL setting.

• In older patients with MCL, maintenance rituximab has proven benefit after R-CHOP induction therapy, but its role after BR is controversial.

• In younger patients with MCL, maintenance rituximab administered after ASCT improves OS.

FIGURE 1. Predictors of Indolent Versus Aggressive Disease Behavior for Patients With Newly Diagnosed Mantle Cell Lymphoma

Abbreviations: MIPI, Mantle Cell Lymphoma International Prognostic Index; LDH, lactate dehydrogenase.




Ki67 proliferative index and pretreatment cytogenetic as-sessments have been evaluated alone and in combination with MIPI to better define high-risk subgroups. Work by Katzenberger et al and Hsi et al identified Ki67 as a marker of disease activity although the optimal cutoff for high- ver-sus low-risk disease was not described.28,29 In recent years, 30% positivity has been frequently accepted as a cutoff for high- compared with low- Ki67 expression.30,31 Hoster and colleagues have evaluated the role of Ki67 in conjunction with MIPI in patients treated on the MCL Younger and MCL Elderly studies and identified a significantly worse 5-year OS of 41% for patients with Ki67 30% or greater when com-pared with patients with Ki67 less than 30%, whose 5-year OS was 73% to 75%.32 The impact of Ki67 was independent of MIPI risk score, and in a new model (MIPI-c) combining Ki67 and MIPI, patients were divided into four groups rang-ing from low risk (5-year OS: 85%) to high risk (5-year OS: 17%). In this analysis, blastoid growth identified pathologi-cally was not prognostic for OS or progression-free survival (PFS) when Ki67 was included in a multivariable model.

Pretreatment cytogenetics has been used frequently in many hematologic malignancies to aid in risk stratification and therapy selection. In MCL, initial descriptions of out-comes for patients with a complex karyotype suggested in-ferior survival.33,34 A single-center study conducted at The Ohio State University of 80 patients with untreated MCL found that 32 patients (41% of the cohort) had a complex karyotype (defined as ≥ 3 chromosomal abnormalities) identified in involved bone marrow samples.35 Patients with a complex karyotype in this series were more likely to have an elevated leukocyte count, increased LDH, splenomegaly, and be high-risk by MIPI. Two-year OS for the complex karyotype group was 58% compared with 85% for the non-complex group. However, in this analysis, the presence of a complex karyotype was not predictive of OS independent of MIPI and other clinical variables. Sarkozy et al evaluated the role of cytogenetics in a series of 125 patients from France, where nodal tissue, bone marrow, or peripheral blood were used for cytogenetic evaluation.36 Fifty-nine percent of pa-tients had a complex karyotype, and these patients were more likely to have a shortened time to initial therapy and an inferior OS in a multivariable model (HR 2.37); indepen-dent of high-risk MIPI score. This series also evaluated the prognostic impact of specific cytogenetic abnormalities, but none of the identified recurrent abnormalities were inde-pendently associated with OS. A larger cohort of patients

with MCL from five centers evaluated the role of cytoge-netics in untreated MCL and confirmed an association of a complex karyotype with inferior OS (median 4.5 years vs. 11.6 years for noncomplex karyotype;). A multivariable model for OS confirmed that complex karyotype and elevated LDH were independently associated with decreased OS, while MIPI risk group was not.37

Attempts to integrate prognostic markers into more com-prehensive models have been challenging. Hoster and col-leagues have combined Ki67 with MIPI to form the biologic MIPI (MIPI-b) and the MIPI-c.32 However, additional patho-logic features in this series, such as blastoid variant his-tology, were not independently associated with outcome. Staton et al presented the results of a multicenter analysis of 92 patients with untreated MCL who had pretreatment Ki67, MIPI, and cytogenetics reports available for review.23 Within this series, a multivariable model indicated that Ki67 greater than 30% and complex karyotype were both inde-pendently associated with inferior PFS, while MIPI risk score was not. As a result, assessing the relative contribution of each described prognostic marker remains elusive, and many cur-rent projects are limited by modest sample sizes and hetero-geneously treated patient populations. However, a number of currently available prognostic markers reliably identify high-risk patients, many of whom do not respond optimally to currently available therapy, and these patients should be considered for investigational therapies when available.Novel approaches to risk stratification. Currently available approaches to identification of high-risk patients adequately identify patients at risk for early progression, but alternative methods are needed to better understand the biology of high-risk disease and to aid in the development of targeted therapies. Next-generation sequencing and assessment of gene expression offers the potential benefit of more specific identification of risk factors and potential therapeutic tar-gets. Several projects have identified recurrent mutations in MCL, including ATM, CCND1, MLL2, WHSC1, TP53, NOTCH1, and others that occur at a lower frequency.38,39 In two larger series that included 5638 and 2939 patients, there were lim-ited clinical data associated with the presence of the muta-tions. However, additional projects have identified specific mutations or alterations associated with high-risk disease behavior, including NOTCH1,40 CDKN2A,41 and TP53.41

Prior attempts to characterize a proliferative signature in MCL through gene expression profiling have also successfully identified high- versus low-risk patients.42 However, this

TABLE 1. Estimated Survival for Patients With MCL Based on MIPI Risk Group

Study No. of Patients Low Risk Intermediate Risk High Risk

Hoster et al, 200825 409 5-year OS: 60% Median 51 months Median 29 months

Hoster et al, 201422 958 5-year OS: 83% 5-year OS: 63% 5-year OS: 34%

Budde et al, 201126 118 2.5-year OS: 93% 2.5-year OS: 60% 2.5-year OS: 32%

Eskelund et al, 201624 157 Median NR Median 11 years Median 4 years

Chihara et al, 201527 501 5-year OS: 74% 5-year OS: 70% 5-year OS: 35%

Abbreviation: MCL, mantle cell lymphoma; MIPI, Mantle Cell Lymphoma International Prognostic Index; OS, overall survival; NR, not reached.




assay historically required fresh tissue, making its use limited to centers equipped to perform these analyses in real time. As a result, assessment of proliferation by Ki67 has been used as a surrogate. In recent years, investigators with the Lymphoma/Leukemia Molecular Profiling Project have re-liably assessed gene expression using extracted RNA from formalin-fixed, paraffin-embedded archival tissue to identi-fy cell-of-origin in diffuse large B-cell lymphoma.43 Using this same technology, Scott and colleagues developed a 35-gene panel to identify three risk groups of patients with MCL, where high-risk patients have a median OS of 1.1 years and low-risk patients have a median OS of 8.6 years.44 This association remained significant (p < .05) when controlling for Ki67 prolif-erative index as well as MIPI risk score. This assay is prognostic but does not currently guide therapy selection. However, the ability to perform genomic assessments on preserved tissues may provide physicians with better tools to use when counseling patients and selecting therapies in the future.

UNDERSTANDING WHO SHOULD RECEIVE A HEMATOPOIETIC CELL TRANSPLANT FOR MCLPatients requiring therapy are evaluated based on their abil-ity to tolerate a stem cell transplant as most guidelines in-clude an up-front ASCT as part of therapy.45 Besides biologic factors about the disease, the patient must be physiologi-cally fit for high-dose therapy, ASCT, and possible complica-tions associated with the conditioning regimen. Institutional limits to a minimum cardiovascular function, pulmonary re-serve, and renal function are required for this procedure, and physiologic age and comorbidity index are increasingly being used to determine eligibility for transplant.46 The source of stem cells is another important factor in deter-mining eligibility of transplantation. For ASCT, it requires the patient’s bone marrow is healthy enough for mobilization of stem cells, and for alloSCT, there needs to be a suitable donor (i.e., sibling, matched unrelated donor, cord blood, or a haplo-identical donor).

Up-Front Therapies Including ASCTInitial attempts to treat MCL with regimens similar to CHOP (cyclophosphamide, doxorubicin, vincristine, and predni-sone) produced inadequate results with most patients re-lapsing within 2 to 3 years.47,48 Improved responses were noted when rituximab was combined with various chemo-therapy regimens including fludarabine, cyclophosphamide, and rituximab (FCR)49 and CHOP50 without significantly af-fecting time to treatment failure or OS. Following this, mul-tiple aggressive approaches were developed to improve the outcome of younger patients with MCL as listed in Table 2. These studies typically exclude elderly frail patients most in-clude patients with stage II to IV MCL who are considered transplant eligible. ASCT is performed only in patients with chemotherapy-sensitive disease.

One approach pioneered at The University of Texas MD Anderson Cancer Center consisted of alternating cycles of hyperfractionated cyclophosphamide, vincristine, doxo-rubicin, and dexamethasone with high-dose Arc-C and

methotrexate (hyper-CVAD) and produced a response rate of 93% in previously untreated patients.58 Responding pa-tients were taken to ASCT and experienced an impressive 3-year OS of 92% and event-free survival (EFS) of 72%. However, significant toxicity was noted. A phase II study of 97 patients treated with four cycles of rituximab and hy-per-CVAD (R-hyper-CVAD) without ASCT resulted in a 3-year OS of 82%, with 64% of patients still in remission.51 A 15-year follow-up of this patient cohort shows that the median failure-free survival is 4.8 years and median OS is 10 years, with a plateau for FFS at 10 years. Toxicity consisted of myel-odysplastic syndrome/acute myeloid leukemia of 6.2% at 10 years.59 Gruppo Italiano Studio Linfomi and Southwest On-cology Group have evaluated this regimen in a multicenter setting but found the toxicity to be too high even though outcomes were promising.52,53

Major groups in Europe have developed approaches to in-corporate ASCT in up-front therapy. Dexamethasone, cisplatin, and high-dose Ara-C (DHAP) and then R-DHAP was added to CHOP/R-CHOP–based regimens to improve up-front re-sponse rates so that more patients could move to ASCT.3,60 A randomized trial between up-front ASCT after induction compared with interferon (IFN)-alpha confirmed higher re-sponse rates after ASCT and an improved EFS of 39 months compared with 17 months with IFN.54 Effect on OS was not demonstrated with the short follow-up. A dose-intensified Maxi-CHOP regimen with rituximab and high-dose Ara-C fol-lowed by ASCT55 (Nordic 2) has reported the best outcome to date with a median OS of 12.7 and PFS of 8.2 years.55 The European MCL Network (MCL Younger) has shown that the use of high-dose Ara-C in the up-front treatment of MCL with ASCT results in deeper remissions as indicated by negative minimal residual disease (MRD) status by nest-ed polymerase chain reaction as well as increased PFS.2 In this study, 497 patients were randomly assigned to differing induction arms and ASCT where the experimental arm con-tained higher doses of Ara-C (14 mg/m2 compared with 800 mg/m2) as part of DHAP as well as the conditioning regimen of ASCT. Complete responses (CRs) were higher in the Ara-C group (95% vs. 55%), but the objective response rate (ORR) was the same after ASCT in both arms. MRD negativity after induction was higher in the Ara-C group (79% vs. 47%) in the peripheral blood, and this difference was maintained in the bone marrow even after ASCT. At a median follow-up of 6.1 years, time to treatment failure was 9.1 years in the Ara-C group compared with 3.9 years, and OS was 76% at 5 years compared with 69% in the control group. The toxicity of multiagent chemotherapy has prompted investigators to evaluate other regimens that can still incorporate high-dose Ara-C. Armand et al57 evaluated 23 patients with MCL with three cycles of bendamustine plus rituximab (BR) followed by three cycles of high-dose Ara-C and rituximab followed by ASCT. Follow-up is short but the results are promising, as MRD-negative status was reached in 96% of cases after in-duction. Similarly, the LyMa trial is evaluating four cycles of R-DHAP prior to ASCT, reserving R-CHOP therapy only for pa-tients who have a partial response to R-DHAP.56 Upcoming




TABLE 2. Studies of Aggressive Induction Regimens Including ASCT

Treatment Regimen Reference

No. of Patients

Planned Consolidation ASCT

Median Follow-up CR

Median OS

Median DFS TRM Comments

R-CHOP vs. CHOP

Lenz et al, 200550

122 Yes, for younger patients

34% vs. 7% TTF 21 months vs. 14 months; NS

No diff. in OS and PFS

Rituximab improved initial response rates

R-hyper-CVAD with alter-nating MTX/Ara-C 6-8 cycles

Romaguera et al, 200551

97 No 15 years 87 82%; median OS is 4.8 years

64%; median FFS 8.8 years

5 died of toxicity; 4 developed MDS/AML; TRM 8%

EFS was 73% if < age 65

R-hyper-CVAD x 4

Merli et al, 201252

60 Yes, only if PR 46 months 72 Median OS 73% at 5 years

5-year PFS 61%

Only 22% com-

pleted 4 cycles; 3 patients

died; TRM 6.5%

R-hyper-CVAD x 8

Bernstein et al, 201353

49 No 4.8 years 55 6.8 years, 86%

Median PFS 4.8 years; 5.5 years if < age 55

39% did not complete due to toxicity; TRM 2%

Too toxic

CHOP + R x 3 + R-DHAP x 3 (multi-center)

Delarue et al, 20133

60 Yes, in responding patients; TBI-based or BEAM

67 months 96; CR 12% after R-CHOP; 57% after R-DHAP

5 years, 75%

Median EFS 83 months; 5-year OS 75%

1.5%; secondary tumors 18%

Addition of rituximab improved EFS

CHOP or CHOP + R

Dreyling et al, 200554

122 Up-front randomi-zation of IFN- alpha or ASCT; TBI based

After R-CHOP 35%; after ASCT 81%

83% at 3 years vs. 77%

PFS: 39 months for ASCT vs. 17 months for IFN

0 Randomized trial that showed the efficacy of up-front ASCT for MCL

R-Maxi CHOP + HD Ara-C

Geisler et al, 201255

160 ASCT; BEAM/BEAC

6.5 years Median OS 10 years

Median EFS 7.4 years

Late relapses after 5 years

MRD evalua-tion and preemptive rituximab therapy offered to eligible patients

R-CHOP x 6 + DexaBEAM + ASCT (TBI + Ara-C + Mel)

Hermine et al, 20162

497 Yes 6.1 years 95% in Ara-C vs. 55%

5 yr. OS 76% in Ara-C group vs. 69%

TTF 9.1 years in Ara-C group vs. 3.9 years

4% MRD nega-tivity after induction was higher in the Ara-C group 79% vs. 47%; MRD negativ-ity strongest prognostic factor

R-DHAP x 4 +ASCT mainte-nance rituximab vs. obser-vation after transplant

Le Gouill et al, 201656

299 Yes; if CR, ASCT; PR, R-CHOP x 4 ASCT

29.3 months

3 years 83%; no differ-ence in 2 arms

3-year PFS 74%; 2-year EFS 93% in main-tenance arm vs. 81%

Omission of anthracycline; rituximab maintenance improves EFS and OS

Continued




trials are likely to incorporate more targeted agents, such as ibrutinib, in the up-front regimens challenging the para-digms listed above.

There is no consensus on conditioning regimens for ASCT. Earlier studies used total body irradiation (TBI)–based regi-mens and a benefit in MCL was suggested by a retrospective analysis (PFS after 4 years: 71% vs. 0%, p < .0001; OS 89% vs. 60%, p = .07)61 with some indication that it may lead to improve outcomes, but this approach has been associated with an increased incidence of second malignancies and other toxicities, and the field has moved away from it. Sin-gle agents 90Y-ibritumomab-tiuxetan and 131I- tositumumab have shown activity both in up-front therapy of MCL and in relapsed MCL and are an attractive means of delivering radiation to the malignant cells without the toxicity of ra-diation therapy.62,63 Both agents had been safely combined with high-dose chemotherapy as conditioning for ASCT with no increased toxicity.64,65 In the Nordic MCL-3,66 90Y-ibritu-momab-tiuxetan was used in an attempt to overcome the inherent chemotherapy resistance of a suboptimal response to up-front chemoimmunotherapy treated on the MCL-2 regimen. The ORR was 97%, and 4-year OS and PFS was 78% and 71%, respectively, similar to patients in the Nordic MCL-2 group. Use of 90Y-ibritumomab-tiuxetan in patients as consolidation after hyper-CVAD has demonstrated unac-ceptable toxicity with 20% of the patients dying because of second malignancies.67

Predictors of response after ASCT. Despite high response rates, the approaches described above are challenging and there is significant risk of toxicity and second malignancies. In addition, 10% to 30% of patients undergoing aggressive induction never make it to ASCT either because of chemo-therapy resistance or complications such as infections or cardiac events. A careful evaluation of some of the larger series has pointed to a few prognostic factors that can be used to predict outcomes particularly after ASCT, including MIPI/MIPI-b, MRD status, and PET scan response prior to transplant. The Nordic 2 trial demonstrated that the MIPI-b was a prognostic factor with 70% of low intermediate pa-tients alive at 10 years compared with only 23% with a high MIPI-b.55 In the MCL-3 trial, a positive PET before transplant as well as MRD-positive status predicted for a poor out-come.66 Pott et al68 reported on 27 patients post-ASCT who underwent MRD evaluation. Median PFS was 92 months if

MRD-negative compared with 21 months in patients with MRD-positive disease. This was further confirmed in the larger European MCL Network study where 56% of patients achieved MRD after initial chemoimmunotherapy, and this predicted for a prolonged response duration at 2 years: 94% if MRD-negative compared with 71% if MRD-positive. ASCT increased the proportion of MRD from 55% to 72%, and a sustained MRD negativity predicted for improved outcome at 2 years (100% vs. 65% for MRD-positive). Thus, patients with poor prognostic factors, including positive MRD after induction therapy, may benefit from alternative approaches for long-term outcome.

Relapsed SettingASCT in MCL is less effective when offered to patients in the relapsed disease with median PFS of 1 to 2 years. Outcomes of patients undergoing ASCT was better in first complete re-mission when compared with transplants performed later in the disease, even when chemotherapy sensitivity was demonstrated.58,69,70 The use of radio-immunotherapy (RIT) in conditioning regimens may be a way to improve out-comes, and this approach has been reported.64,71 In a non-randomized trial of RIT-containing conditioning regimens compared with conventional regimens for patients with chemoresistant disease from a single institution, the use of RIT was associated with improvements in both PFS and OS following ASCT.

Allogeneic Stem Cell Transplant for MCLIn spite of improved outcomes seen in MCL with the above described approaches, nearly all patients with MCL will re-lapse. The median OS of patients who relapse after ASCT is reported at 19 months,72 though this may change with the approval of newer targeted agents. AlloSCT remains an op-tion for suitable patients and can lead to long-term remis-sions and potential cures. The use of an alloSCT in relapsed lymphoma elicits a graft-versus-lymphoma effect allowing for long-term remissions, albeit at a risk of graft-versus-host disease, infections, and organ dysfunction that can lead to a risk of transplant-related mortality. The use of a reduced intensity-conditioning regimen relies on graft-versus-lym-phoma effect and reduced acute toxicity allowing its use in elderly and frail patients or in patients who have failed an earlier myeloablative ASCT.

TABLE 2. Studies of Aggressive Induction Regimens Including ASCT (Cont'd)

Treatment Regimen Reference

No. of Patients

Planned Consolidation ASCT

Median Follow-up CR

Median OS

Median DFS TRM Comments

R + bendamus-tine x 3 + R-HiDAC

Armand et al, 201657

23 Yes 13 months CR 96% with in-duction; 93% MRD negative

PFS 96% Novel up-front regimen

Abbreviations: ASCT, autologous stem cell transplantation; CR, complete response; OS, overall survival; DFS, disease-free survival; TRM, treatment-related mortality; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; TTF, time to treatment failure; NS, not significant; PFS, progression-free survival; R-Hyper-CVAD, rituximab, cyclophosphamide, vincristine, doxorubicin, and dexa-methasone; MTX, methotrexate; Ara-C, cytarabine; FFS, failure-free survival; MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; EFS, event-free survival; PR, partial response; TBI, total body irra-diation; BEAM, carmustine, etoposide, cytarabine, and melphalan; R-DHAP, rituximab, dexamethasone, cytarabine, and cisplatin; IFN, interferon; HD, high dose; MCL, mantle cell lymphoma; BEAC, carmustine, etoposide, cytarabine, and cyclophosphamide; MRD, minimal residual disease; Dexa, dexamethasone; Mel, melphalan; R-HiDAC, rituximab and high-dose cytarabine.




Early case reports of alloSCT in MCL performed in the 1990s demonstrated long-term remission in patients with chemo-refractory disease.73,74 Several centers have report-ed the outcome of patients with MCL undergoing alloSCT as listed in Table 3 over the past 15 years. There is variability in patient selection, conditioning regimens, and supportive measures. The longest follow-up is 5 years with reported PFS of approximately 30% and OS of up to 50% in some of the newer series. Of note, even patients with refractory dis-ease prior to transplant can achieve long-term remission. Hamadani et al75 reported a 5-year survival of 25% in pa-tients with refractory disease; however, transplant-related mortality was one of the highest in this series. Magnusson et al76 have reported that even patients with PET-positive disease could undergo salvage alloSCT. The 5-year disease- free survival and relapse rates after allogeneic hematopoi-etic cell transplantation were 34% and 25% for all patients and 40% and 33% for residual disease recipients, respec-tively, suggesting that active disease at the time of allograft does not preclude long-term remissions in advanced MCL. EBMT Registry data show that patients who relapsed more than 1 year after ASCT and had a salvage alloSCT had a bet-ter outcome with a 5-year OS of 60%.77 There appears to be no difference between myeloablative and reduced in-tensity-conditioning regimens in terms of outcomes even though there are no studies of direct comparisons. The use of donor lymphocyte infusion to induce remissions in pa-tients with relapsed disease after an alloSCT indicate that there is a graft-versus-lymphoma effect in MCL. The use of RIT with 90Y-ibritumomab tiuxetan as part of reduced inten-sity-conditioning conditioning has been evaluated by Fred Hutchinson Cancer Research Center with no clear advan-tage to its use.

The use of alloSCT has been studied in first remission in comparison with ASCT as reported by Fenske et al,83 and even though the 5-year relapse was lower in the allo-SCT arm (15% vs. 32%, respectively), there was increased transplant-related mortality of 25% at 1 year after the al-loSCT resulting in no difference in the 5-year PFS and OS of both arms. Evens et al used an intensive induction regimen of high-dose Ara-C and randomly assigned young patients to sibling alloSCT or ASCT, but only four patients completed the alloSCT.85 A German group reported on alloSCT in first remission compared with the relapsed setting with no difference between the two arms, thus failing to demon-strate an advantage for an earlier alloSCT.83 In the series from Cruz et al, there were 21 patients who had an alloSCT in first complete remission and showed a 5-year PFS and OS of 80% but with a transplant-related mortality of 19%.80 Hence, at this time, it cannot be recommended that an al-loSCT be performed in first complete remission except in clinical trials.

IS THERE A ROLE FOR MAINTENANCE THERAPY IN MCL?Maintenance therapy with rituximab has been tested in a variety of settings, with most, but not all, studies indicating

clinical benefit. Two randomized clinical trials have demon-strated an OS benefit when maintenance rituximab was used as part of initial management of MCL. Many areas of uncertainty remain, however, including the optimal ritux-imab dose and schedule and the impact of different induc-tion strategies maintenance rituximab efficacy. For example, one study suggested no benefit for maintenance rituximab after a BR induction. This section will review the data around maintenance rituximab in MCL and consider other mainte-nance strategies that may find their way into practice.

Early Studies of Maintenance Rituximab in MCLGiven the significant durable PFS benefit, maintenance rit-uximab has demonstrated in follicular lymphoma, it was natural to speculate that maintenance rituximab might be beneficial in MCL.86,87 MCL was considered an incurable en-tity with a relatively poor prognosis. Response rates to initial therapy were high, but remissions tended to be short lived. Finally, there was a paucity of good options for manage-ment in the relapsed setting. Hence, any strategy that could prolong remission was attractive. The first trial to evaluate maintenance rituximab formally came from the Swiss Group for Clinical Cancer Research.88 Both untreated and previously treated patients were enrolled and assigned to receive four weekly doses of rituximab. Patients without progres-sion were then randomly assigned to receive maintenance rituximab (four more doses over 8 months) or no further therapy. There was no obvious benefit for the maintenance rituximab using this strategy. The following year, the Ger-man Low-Grade Lymphoma Study Group published a study demonstrating a significant (p = .049) response duration benefit for maintenance rituximab in relapsed MCL.89 The first study of maintenance rituximab focusing on the front-line setting came from the Wisconsin Oncology Network, who reported on a single-arm, phase II study evaluating maintenance rituximab for 2 years after a chemoimmuno-therapy induction.90 The 3-year PFS of 50% was substantially better than historical controls using R-CHOP–like induction therapy and strongly suggested a benefit for maintenance rituximab. Patients only achieving a partial remission to the induction did not appear to benefit from maintenance rit-uximab, suggesting a complete remission may be necessary for maintenance rituximab to provide additional benefit. No worrisome safety signals were noted. Long-term follow-up of this cohort revealed that 30% remained progression-free beyond 5 years, again suggesting a potential for long-term benefit after maintenance rituximab.91 A follow-up study by the Wisconsin Oncology Network tested the use of mainte-nance rituximab for 5 years after a chemoimmunotherapy induction.92 The patient population was similar to the pre-vious trial: untreated MCL of any age, requiring therapy. In this follow-up study, the 3-year PFS was 63%, and 50% of patients remained progression-free after 5 years.93 In fact, no relapses beyond 5 years have been observed in this co-hort, again suggesting significant benefit for maintenance rituximab. However, 5 years of maintenance rituximab did appear to translate into more infectious complications,




with only 20% of the group able to complete all 5 years of the planned treatment. The Eastern Cooperative Oncology Group confirmed these promising results in E1405.94 In this trial, after a moderately intensive induction strategy, pa-tients could be assigned to either maintenance rituximab or ASCT at the investigators’ discretion. Despite the fact that the patients assigned to maintenance rituximab were gen-erally older with higher MIPI scores, maintenance rituximab performed as well as ASCT for PFS and OS. However, until 2012, the use of maintenance rituximab remained sporadic as definitive evidence of benefit was lacking.Evidence supporting maintenance rituximab in older pa-tients with MCL. The use of maintenance rituximab in MCL began to gain widespread acceptance with the landmark publication by the European MCL Consortium.95 Patients with MCL age 60 and older were randomly assigned to six cycles of FCR or to eight cycles of R-CHOP. Respond-ing patients underwent a second randomization to receive

maintenance rituximab or IFN-alpha, each given until pro-gression. Treatment until progression was a unique feature as all previous trials of maintenance rituximab in MCL had selected arbitrary stopping points of 8 months, 2 years, or 5 years. Analysis of the trial is complicated because of the use of two different induction strategies and the 2 × 2 factorial design. When combining the two induction arms and comparing maintenance rituximab to IFN-alpha, there was a significant (p < .001) improvement in remission du-ration, favoring maintenance rituximab with a 45% reduc-tion in the risk of progression or death. At 4 years, 58% of the patients in the maintenance rituximab arm were still in remission, compared with 29% of those receiving IFN-alpha. When analyzing the impact of maintenance rituximab ac-cording to induction therapy received, one can see that the induction therapy matters. The remission duration benefit of maintenance rituximab was limited to the pa-tient assigned to R-CHOP and was not apparent in patients

TABLE 3. Series of Allogeneic Stem Cell Transplants in MCL

StudyNo. of Patients Sites Disease Status

Prior ASCT OS PFS

TRM acGVHD chGVHD Comments

Khouri et al, 200378

18 Single center 89% chemo- sensitive

28% 3 years 85.5%

3-year EFS 82%

TRM 11%; chGVHD 36%

DLI induced remission in 1/3 relapses

Maris et al, 200479

33 Single center 42% 2 years 64%

2 years 60%

2 years 24% acGVHD 57% chGVHD 64%

Cruz et al, 201180

21 Multicenter GELTAMO

71% CR, median 2 therapies

14% 5 years 80%

5 years 80%

3 years 19.5% acGVHD 15% chGVHD 78%

OS 43% in patients > age 60 vs. 100% in younger patients

Le Gouill et al, 201281

70 Multicenter 67% 2 years 53%

2 years 50%


Disease status at trans-plant significant for EFS/OS: CR, 62%, 62%; PR, 53%; SD/PD, 11%, 31%

Kruger et al, 201482

33/39 planned

East German Study Group

First consolida-tion

5 years 73%

5 years 67%

TRM 24% acGVHD 15%

Younger patients had better outcome

Fenske et al, 201483

88 CIBMTR 5 years 31%

5 years 24%

1 year 17%

Hamadani et al, 201375

128 RIC; 74 MA

Multicenter CIBMTR

Refractory 3 years 30%

3 years 25%

3 years 47% for both RIC and MA

T-cell depleted trans-plant associated with increased risk of NRM; no difference between MA or RIC

Cook et al, 201084

70 Multicenter 34% 5 years 37%

5 years 14%


DLI induced remission in 15/18 relapsed patients; age and < 2 regimens correlated with OS and PFS

Magnusson et al, 201476

28 5 years 53%

5 years 34%

2 years 15% Allograft had favorable results even if PET+ prior to transplant

Dietrich et al, 201472

80 Multicenter EBMTR

All relapsed after ASCT

2 years 46%

2 years 33%

2 years 30% Remission duration of > 12 months after ASCT was associated with a poor outcome

Abbreviations: MCL, mantle cell lymphoma; ASCT, autologous stem cell transplantation; PFS, progression-free survival; OS, overall survival; TRM, treatment-related mortality; acGVHD, acute cutaneous graft-versus-host disease; chGVHD, chronic graft-versus-host disease; EFS, event-free survival; DLI, donor lymphocyte infusion; CR, complete response; PR, partial response; SD, stable disease; PD, partial disease; CIBMTR, Center for International Blood and Marrow Transplant Research; RIC, reduced intensity conditioning; MA, myeloablative; NRM, nonrelapse mortality; EBMTR, European Bone Marrow Transplantation Registry.




assigned to FCR. There is precedent for such a differential effect following induction. In E1496, a frontline follicular lymphoma trial, patients were randomly assigned to receive to cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy or FC chemotherapy, with patients whose disease did not progress being randomly assigned to main-tenance rituximab for 2 years or observation. A substantial remission duration benefit was observed after CVP chemo-therapy, but no benefit was seen after FC chemotherapy. Why maintenance rituximab would be beneficial after one type of induction therapy and not another is not precisely known. It is possible that the profoundly immunosup-pressive effects of fludarabine-based therapy negate criti-cal effector cell functions necessary for optimal rituximab effectiveness.

The impact of maintenance rituximab on the patients treated with R-CHOP was strong enough to translate into an OS benefit. Based on these striking results, maintenance rituximab gained rapid and widespread adoption in the frontline management of older patients with MCL. An im-portant caveat, however, centers on current induction strat-egies and whether maintenance rituximab confers the same benefit irrespective of the induction. Two small randomized clinical trials have indicated that BR is a superior induction strategy compared with R-CHOP.96,97 As a result, BR as the induction strategy has gained widespread adoption in North America and Europe. Whether maintenance rituximab still confers benefit in patients receiving BR induction was the subject of a recent analysis presented at the 2016 ASCO Annual Meeting.98 The frontline StiL NHL7-2008 study in in-dolent lymphoma was conducted in Germany and Austria and included a subgroup of patients with MCL. These 168 patients were considered ineligible for high-dose therapy and their median age was 71. They received six cycles of BR induction therapy, and patients whose disease responded were randomly assigned to maintenance rituximab for 2 years or to observation. Just 122 patients ultimately were randomly assigned—60 to observation and 62 to mainte-nance. The median PFS was 54.7 months for observation compared with 72.3 months for maintenance, but this dif-ference was not statistically different (HR 0.71; p = .223). These results are not yet published, but the presentation did garner significant attention and has caused many to question whether maintenance rituximab after BR induc-tion is warranted.Evidence supporting maintenance rituximab in younger patients with MCL. In general, outcomes with initial therapy are much better for younger patients with MCL than they are for older patients with MCL. Younger patients typically have lower-risk disease, as measured by the MIPI. They are also more suitable candidates for intensive induction strat-egies, which tend to produce more durable remissions. One would predict it would be more difficult to show benefit from any sort of maintenance strategy in this pop-ulation. The first publication to suggest benefit for mainte-nance rituximab in young patients with MCL who received an intensive frontline treatment came from investigators

at the Fred Hutchinson Cancer Research Center.99 In this retrospective study, the investigators examined a cohort of consecutive patients with MCL that underwent ASCT for MCL and then evaluated outcomes according to whether the patient received maintenance rituximab after ASCT (50 patients) or did not (107 patients). The decision on whether to administer maintenance rituximab was made by the treating physician, and a variety of schedules were used. With a median follow-up of 5 years, maintenance rituximab was associated with an improved PFS (HR 0.44; p = .007) and OS (HR 0.46; p = .03). Grade 4 neutropenia was more common in the maintenance rituximab group (34% vs. 18%, respectively) but this did not translate into increased mortality. Although provocative, this retrospec-tive analysis could not be viewed as definitive as there were some key differences in the two populations. Patients receiving maintenance rituximab were more likely to have received high-dose Ara-C during induction and more likely to be in CR at the time of ASCT. The investigators acknowl-edge that the strategy of maintenance rituximab after ASCT would require confirmation in a prospective randomized controlled trial.

Such confirmation was presented at the 2016 American Society of Hematology Meeting, where the final results of the LyMa trial (NCT00921414) were presented.56 The trial was limited to patients with MCL age 65 and younger, and all patients received induction therapy with four cycles of R-DHAP followed by ASCT using rituximab, carmustine, etoposide, Ara-C, and melphalan (R-BEAM) conditioning. Randomization to maintenance rituximab, consisting of a single dose every 2 months for 3 years or to observation, occurred post-ASCT. The median age was 57, and over half of the patients were low risk by MIPI, which is typical for this patient population. Two hundred ninety-nine patients were enrolled, and 240 patients were randomly selected (120 in each arm). The primary endpoint was EFS with events defined as progression, death, or severe infection after randomization. The final analysis demonstrated that maintenance rituximab after ASCT significantly prolonged EFS (78.9% vs. 61.4%, respectively) at 4 years (HR = 0.46; p = .0016). Maintenance rituximab also prolonged OS at 4 years (88.7% vs. 81.4%, respectively; HR = 0.5; p = .045). There was no difference in the rate of severe infections between maintenance rituximab and observation. Given the OS ad-vantage noted, these results strongly support the use of maintenance rituximab after ASCT in younger patients with MCL. Randomized clinical trials evaluating maintenance rit-uximab are summarized in Table 4.

Other Maintenance Strategies Under InvestigationOngoing studies yet to be analyzed, but which could im-pact the standard of care, are summarized in Table 5. Lena-lidomide has demonstrated single-agent activity in MCL and, for mechanistic reasons, has been combined with rit-uximab in both induction and maintenance strategies, with promising early results.6,100 The U.S. Intergroup trial E1411 (NCT01415752) is focused on older patients with MCL and




is testing 2 years of single-agent rituximab against 2 years of rituximab plus lenalidomide. The primary endpoint is PFS. This trial completed enrollment in September of 2016 (372 patients) and is expected to read out for the primary endpoint in 2019. The Bruton tyrosine kinase inhibitor ibru-tinib has impressive single-agent activity in MCL, and the SHINE trial (NCT01776840) has enrolled 520 older patients with MCL. Following induction therapy with BR or BR plus ibrutinib, patients receive either maintenance rituximab for 2 years or maintenance rituximab for 2 years plus ibru-tinib administered indefinitely. The results of SHINE are expected in 2018 or 2019. Ibrutinib is also being tested in combination with intensive strategies as part of the European MCL Consortium TRIANGLE study (NCT02858258). This three- arm study will compare ASCT alone, ibrutinib mainte-nance alone, and ASCT plus ibrutinib maintenance. Finally, the U.S. Intergroup trial EA4151 will also compare main-tenance rituximab with ASCT plus maintenance rituximab in patients who have achieved an MRD-negative CR to in-duction therapy. This trial is scheduled to begin enrollment in 2017.

CONCLUSIONMaintenance rituximab has been shown to improve OS in both older and younger patients with MCL. However, important questions remain regarding the optimal dose and schedule. Should maintenance be administered for 2 years, 3 years, or indefinitely? In addition, it remains unclear whether the induction strategy impacts the effi-cacy of maintenance. In the trial supporting maintenance rituximab in older patients, the benefit was seen only after R-CHOP induction. However, a small study evaluat-ing maintenance rituximab for 2 years after a bendamus-tine-based induction did not find any benefit. More study of maintenance rituximab after BR induction is warranted so that remaining discrepancies can be resolved. Main-tenance rituximab for 3 years after ASCT in younger pa-tients with MCL was shown to favorably impact OS and represents a new standard of care. Ongoing trials in Europe (TRIANGLE) and in North America (EA4151) will test whether alternative maintenance strategies can replace ASCT or whether such strategies should be an ad-junct to ASCT.

TABLE 4. Randomized Trials of Maintenance Rituximab in MCL

Trial Group No. of Patients Population Induction Regimen Rituximab VersusRituximab Schedule Outcome

SAKK88 104 Untreated or previ-ously treated

Rituximab Observation Single dose every 2 months x 4

No difference

GLSG89 176 Previously treated R-FCM or FCM

Observation 4 weekly doses at 3 and 9 months post-induction

PFS benefit, favor-ing MR

European MCL Network95

316 Older MCL and untreated

R-CHOP or FCR

Interferon-alpha Single dose every 2 months until PD

PFS and OS benefit after R-CHOP, no benefit after FCR

StiL98 122 Older MCL and untreated

BR Observation Single dose every 2 months x 2 years

No difference

LYSA56 240 Younger MCL and untreated

R-DHAP + ASCT

Observation Single dose every 2 months x 3 years

PFS and OS benefit for MR

Abbreviations: MCL, mantle cell lymphoma; SAKK, Swiss Group for Clinical Cancer Research; GLSG, German Low-Grade Lymphoma Study Group; R-FCM, rituximab, fludarabine, cyclophosphamide, and mitoxantrone; PFS, progression-free survival; MR, maintenance rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; FCR, fludarabine, cyclophosphamide, and rituximab; PD, partial disease; OS, overall survival; StiL, Study Group Indolent Lymphomas; BR, bendamustine and rituximab; LYSA, Lymphoma Study Association; R-DHAP, rituximab, dexamethasone, cytarabine, and cisplatin; ASCT, autologous stem cell transplantation.

TABLE 5. Trials in Progress Testing Novel Maintenance Strategies in MCL

Trial Name Population Status No. of Patients Maintenance Question

E1411 (NCT01415752)

Older MCL; frontline regimen

Fully enrolled 372 Rituximab vs. rituximab + lenalidomide

SHINE (NCT01776840)

Older MCL; frontline regimen

Fully enrolled 520 Rituximab vs. rituximab + ibrutinib

TRIANGLE (NCT02858258)

Younger MCL; frontline regimen

Enrollment started 2016 870 ASCT vs. ASCT + ibrutinib vs. ibrutinib

EA4151 (NCT pending)

Younger MCL; frontline regimen

Enrollment to begin 2017 412 Rituximab vs. rituximab + ASCT in MRD negative first remission

Abbreviations: MCL, mantle cell lymphoma; ASCT, autologous stem cell transplantation; MRD, minimal residual disease.




References

1. Swerdlow SH, Campo E, Harris NL, et al (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer; 2008.

2. Hermine O, Hoster E, Walewski J, et al; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016;388:565-575.

3. Delarue R, Haioun C, Ribrag V, et al. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL): a phase II study from the GELA. Blood. 2013;121:48-53.

4. Nastoupil LJ, Shenoy PJ, Ambinder A, et al. Intensive chemotherapy and consolidation with high dose therapy and autologous stem cell transplant in patients with mantle cell lymphoma. Leuk Lymphoma. 2015;56:383-389.

5. Damon LE, Johnson JL, Niedzwiecki D, et al. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009;27:6101-6108.

6. Wang M, Fayad L, Wagner-Bartak N, et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. 2012;13:716-723.

7. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507-516.

8. 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;24:4867-4874.

9. Goy A, Sinha R, Williams ME, et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol. 2013;31:3688-3695.

10. Kahl BS, Spurgeon SE, Furman RR, et al. A phase 1 study of the PI3Kδ inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 2014;123:3398-3405.

11. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma patient demographic and clinical characteristics. J Clin Oncol. 2017;35:826-833.

12. Fenske TS, Hamadani M, Cohen JB, et al. Allogeneic hematopoietic cell transplantation as curative therapy for patients with non-Hodgkin lymphoma: increasingly successful application to older patients. Biol Blood Marrow Transplant. 2016;22:1543-1551.

13. Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009;27:1209-1213.

14. Abrisqueta P, Slack GW, Scott DW, et al. Outcome of observation as initial strategy in patients with mantle cell lymphoma. Blood. 2015;126:2699.

15. Calzada O, Switchenko JM, Maly JJ, et al. Deferred treatment as a viable option for selected patients with mantle cell lymphoma. J Clin Oncol. 2016;34 (suppl; abstr 7567).

16. Kumar A, Ying Z, Alperovich A, et al. Outcome of initial observation in mantle cell lymphoma. Blood. 2016;128:1803.

17. Ambinder AJ, Shenoy PJ, Nastoupil LJ, et al. Using primary site as a predictor of survival in mantle cell lymphoma. Cancer. 2013;119:1570-1577.

18. Cohen JB, Han X, Jemal A, et al. Deferred therapy is associated with improved overall survival in patients with newly diagnosed mantle cell lymphoma. Cancer. 2016;122:2356-2363.

19. Nordström L, Sernbo S, Eden P, et al. SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma--a Nordic Lymphoma Group study. Br J Haematol. 2014;166:98-108.

20. Nygren L, Baumgartner Wennerholm S, Klimkowska M, et al. Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma. Blood. 2012;119:4215-4223.

21. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;128:2375-2390.

22. Hoster E, Klapper W, Hermine O, et al. Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol. 2014;32:1338-1346.

23. Staton AD, Greenwell IB, Switchenko JM, et al. Risk stratification of untreated mantle cell lymphoma patients using MIPI, Ki67 proliferative index and cytogenetics. Blood. 2016;128:1785.

24. Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016;175:410-418.

25. Hoster E, Dreyling M, Klapper W, et al; German Low-Grade Lymphoma Study Group (GLSG); European Mantle Cell Lymphoma Network. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111:558-565.

26. Budde LE, Guthrie KA, Till BG, et al. Mantle cell lymphoma international prognostic index but not pretransplantation induction regimen predicts survival for patients with mantle-cell lymphoma receiving high-dose therapy and autologous stem-cell transplantation. J Clin Oncol. 2011;29:3023-3029.

27. Chihara D, Asano N, Ohmachi K, et al. Prognostic model for mantle cell lymphoma in the rituximab era: a nationwide study in Japan. Br J Haematol. 2015;170:657-668.

28. Hsi ED, Jung S, Lai R, et al. Ki67 and PIM1 expression predict outcome in mantle cell lymphoma treated with high dose therapy, stem cell transplantation and rituximab: a Cancer and Leukemia Group B 59909 correlative science study. Leuk Lymphoma. 2008;49:2081-2090.

29. Katzenberger T, Petzoldt C, Höller S, et al. The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood. 2006;107:3407.

30. Klapper W, Hoster E, Determann O, et al. Ki-67 as a prognostic marker in mantle cell lymphoma — consensus guidelines of the pathology panel of the European MCL Network. J Hematop. 2009;2:103-111.

31. Determann O, Hoster E, Ott G, et al. Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood. 2008;111:2385-2387.




32. Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: results from randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34:1386-1394.

33. Espinet B, Salaverria I, Beà S, et al. Incidence and prognostic impact of secondary cytogenetic aberrations in a series of 145 patients with mantle cell lymphoma. Genes Chromosomes Cancer. 2010;49:439-451.

34. Katzenberger T, Kienle D, Stilgenbauer S, et al. Delineation of distinct tumour profiles in mantle cell lymphoma by detailed cytogenetic, interphase genetic and morphological analysis. Br J Haematol. 2008;142:538-550.

35. Cohen JB, Ruppert AS, Heerema NA, et al. Complex karyotype is associated with aggressive disease and shortened progression-free survival in patients with newly diagnosed mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2015;15:278-285.e1.

36. Sarkozy C, Terré C, Jardin F, et al. Complex karyotype in mantle cell lymphoma is a strong prognostic factor for the time to treatment and overall survival, independent of the MCL international prognostic index. Genes Chromosomes Cancer. 2014;53:106-116.

37. Greenwell B, Staton AD, Lee MJ, et al. Association of complex karyotype with inferior progression-free and overall survival in mantle cell lymphoma. J Clin Oncol. 2016;34 (suppl; abstr 7565).

38. Zhang J, Jima D, Moffitt AB, et al. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood. 2014;123:2988-2996.

39. Beà S, Valdés-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci USA. 2013;110:18250-18255.

40. Kridel R, Meissner B, Rogic S, et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood. 2012;119:1963-1971.

41. Delfau-Larue MH, Klapper W, Berger F, et al; European Mantle Cell Lymphoma Network. High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood. 2015;126:604-611.

42. Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3:185-197.

43. Scott DW, Wright GW, Williams PM, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood. 2014;123:1214-1217.

44. Scott DW, Abrisqueta P, Wright G, et al. Prognostic significance of the proliferation signature in mantle cell lymphoma measured using digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2016;34 (suppl; abstr 7510).

45. Robinson S, Dreger P, Caballero D, et al; European MCL Network and the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation. The EBMT/EMCL consensus project on the role of autologous and allogeneic stem cell transplantation in mantle cell lymphoma. Leukemia. 2015;29:464-473.

46. Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood. 2013;121:2854-2863.

47. Hiddemann W, Unterhalt M, Herrmann R, et al. Mantle-cell lymphomas have more widespread disease and a slower response

to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group. J Clin Oncol. 1998;16:1922-1930.

48. Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27:511-518.

49. 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. Blood. 2004;104:3064-3071.

50. 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;23:1984-1992.

51. 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;23:7013-7023.

52. Merli F, Luminari S, Ilariucci F, et al. Rituximab plus HyperCVAD alternating with high dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma, a multicentre trial from Gruppo Italiano Studio Linfomi. Br J Haematol. 2012;156:346-353.

53. Bernstein SH, Epner E, Unger JM, et al. A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213. Ann Oncol. 2013;24:1587-1593.

54. 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. Blood. 2005;105:2677-2684.

55. Geisler CH, Kolstad A, Laurell A, et al; Nordic Lymphoma Group. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012;158:355-362.

56. Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab maintenance after autologous stem cell transplantation prolongs survival in younger patients with mantle cell lymphoma: final results of the randomized phase 3 LyMa trial of the Lysa/Goelams group. Blood. 2016;128:145.

57. Armand P, Redd R, Bsat J, et al. A phase 2 study of rituximab-bendamustine and rituximab-cytarabine for transplant-eligible patients with mantle cell lymphoma. Br J Haematol. 2016;173:89-95.

58. 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;16:3803-3809.

59. Chihara D, Cheah CY, Westin JR, et al. Rituximab plus hyper-CVAD alternating with MTX/Ara-C in patients with newly diagnosed mantle cell lymphoma: 15-year follow-up of a phase II study from the MD Anderson Cancer Center. Br J Haematol. 2016;172:80-88.




60. Lefrère 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;16:587-593.

61. Milpied N, Gaillard F, Moreau P, et al. High-dose therapy with stem cell transplantation for mantle cell lymphoma: results and prognostic factors, a single center experience. Bone Marrow Transplant. 1998;22:645-650.

62. Wang M, Oki Y, Pro B, et al. Phase II study of yttrium-90-ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27:5213-5218.

63. Smith MR, Li H, Gordon L, et al. Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. J Clin Oncol. 2012;30:3119-3126.

64. Gopal AK, Rajendran JG, Petersdorf SH, et al. High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma. Blood. 2002;99:3158-3162.

65. Krishnan A, Nademanee A, Fung HC, et al. Phase II trial of a transplantation regimen of yttrium-90 ibritumomab tiuxetan and high-dose chemotherapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26:90-95.

66. Kolstad A, Laurell A, Jerkeman M, et al. Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma. Blood. 2014;123:2953-2959.

67. Arranz R, García-Noblejas A, Grande C, et al. First-line treatment with rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine and followed by consolidation with 90Y-ibritumomab-tiuxetan in patients with mantle cell lymphoma. Results of a multicenter, phase 2 pilot trial from the GELTAMO group. Haematologica. 2013;98:1563-1570.

68. Pott C, Schrader C, Gesk S, et al. Quantitative assessment of molecular remission after high-dose therapy with autologous stem cell transplantation predicts long-term remission in mantle cell lymphoma. Blood. 2006;107:2271-2278.

69. Freedman AS, Neuberg D, Gribben JG, et al. High-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation in mantle-cell lymphoma: no evidence for long-term remission. J Clin Oncol. 1998;16:13-18.

70. Vose JM, Bierman PJ, Weisenburger DD, et al. Autologous hematopoietic stem cell transplantation for mantle cell lymphoma. Biol Blood Marrow Transplant. 2000;6:640-645.

71. Cassaday RD, Stevenson PA, Gooley TA, et al. High-dose CD20-targeted radioimmunotherapy-based autologous transplantation improves outcomes for persistent mantle cell lymphoma. Br J Haematol. 2015;171:788-797.

72. Dietrich S, Boumendil A, Finel H, et al. Outcome and prognostic factors in patients with mantle-cell lymphoma relapsing after autologous stem-cell transplantation: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT). Ann Oncol. 2014;25:1053-1058.

73. Corradini P, Ladetto M, Astolfi M, et al. Clinical and molecular remission after allogeneic blood cell transplantation in a patient with mantle-cell lymphoma. Br J Haematol. 1996;94:376-378.

74. Adkins D, Brown R, Goodnough LT, et al. Treatment of resistant mantle cell lymphoma with allogeneic bone marrow transplantation. Bone Marrow Transplant. 1998;21:97-99.

75. Hamadani M, Saber W, Ahn KW, et al. Allogeneic hematopoietic cell transplantation for chemotherapy-unresponsive mantle cell lymphoma: a cohort analysis from the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2013;19:625-631.

76. Magnusson E, Cao Q, Linden MA, et al. Hematopoietic cell transplantation for mantle cell lymphoma: predictive value of pretransplant positron emission tomography/computed tomography and bone marrow evaluations for outcomes. Clin Lymphoma Myeloma Leuk. 2014;14:114-121.

77. Dietrich S, Tielesch B, Rieger M, et al. Patterns and outcome of relapse after autologous stem cell transplantation for mantle cell lymphoma. Cancer. 2011;117:1901-1910.

78. Khouri IF, Lee M-S, Saliba RM, et al. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol. 2003;21:4407-4412.

79. 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;104:3535-3542.

80. Cruz JG, Martino R, Balsalobre P, et al. Long-term results of fludarabine/melphalan as a reduced-intensity conditioning regimen in mantle cell lymphoma: The GELTAMO experience. Ther Adv Hematol. 2011;2:5-10.

81. Le Gouill S, Kröger N, Dhedin N, et al. Reduced-intensity conditioning allogeneic stem cell transplantation for relapsed/refractory mantle cell lymphoma: a multicenter experience. Ann Oncol. 2012;23:2695-2703.

82. Krüger WH, Hirt C, Basara N, et al. Allogeneic stem cell transplantation for mantle cell lymphoma--final report from the prospective trials of the East German Study Group Haematology/Oncology (OSHO). Ann Hematol. 2014;93:1587-1597.

83. Fenske TS, Zhang MJ, Carreras J, et al. Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: analysis of transplantation timing and modality. J Clin Oncol. 2014;32:273-281.

84. Cook G, Smith GM, Kirkland K, et al; Clinical Trials Committee (CTC) of the British Society for Blood and Marrow Transplantation (BSBMT). 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;16:1419-1427.

85. Evens AM, Winter JN, Hou N, et al. A phase II clinical trial of intensive chemotherapy followed by consolidative stem cell transplant: long-term follow-up in newly diagnosed mantle cell lymphoma. Br J Haematol. 2008;140:385-393.

86. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009;27:1607-1614.

87. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding




to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377:42-51.

88. Ghielmini M, Schmitz S-FH, Cogliatti S, et al; Swiss Group for Clinical Cancer Research. Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol. 2005;23:705-711.

89. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular. Blood. 2006;108:4003-4008.

90. Kahl BS, Longo WL, Eickhoff JC, et al; Wisconsin Oncology Network. Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network. Ann Oncol. 2006;17:1418-1423.

91. Kenkre VP, Long WL, Eickhoff JC, et al. Maintenance rituximab following induction chemo-immunotherapy for mantle cell lymphoma: long-term follow-up of a pilot study from the Wisconsin Oncology Network. Leuk Lymphoma. 2011;52:1675-1680.

92. Chang JE, Peterson C, Choi S, et al. VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study. Br J Haematol. 2011;155:190-197.

93. Chang JE, Peterson C, Carmichael LL, et al. Durable remissions with the VcR-CVAD regimen for mantle cell lymphoma (MCL), regardless of age: long-term follow-up of a Wisconsin Oncology Network (WON) study. Blood. 2016;128:149.

94. Chang JE, Li H, Smith MR, et al. Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group Study (E1405). Blood. 2014;123:1665-1673.

95. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367:520-531.

96. Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381:1203-1210.

97. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123:2944-2952.

98. Rummel MJ, Knauf W, Goerner M, et al. Two years rituximab maintenance vs. observation after first-line treatment with bendamustine plus rituximab (B-R) in patients with mantle cell lymphoma: First results of a prospective, randomized, multicenter phase II study (a subgroup study of the StiL NHL7-2008 MAINTAIN trail). J Clin Oncol. 2016;34 (suppl; abstr 7503).

99. Graf SA, Stevenson PA, Holmberg LA, et al. Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma. Ann Oncol. 2015;26:2323-2328.

100. Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373:1835-1844.


current approaches to mantle cell lymphoma: diagnosis ... · mantle cell lymphoma (mcl) is a unique...

Documents