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Open questions in the management of mantle cell lymphoma
Cancer Treatment Reviews, 6, 39, pages 602 - 609
Mantle cell lymphoma (MCL) is one of the lymphomas with the worse prognosis (median survival 3–5 years) as it has an aggressive evolution and at the same time is incurable. Biologically it is characterized by the t(11;14)(q13;q32) translocation leading to overexpression of cyclin D1. This review focuses on a number of controversial issues in the management of this disease, as how to stage patients with a disease which often has extranodal localizations, how to recognize the small subgroup of cases with an indolent course, which treatment is suggested for the young and fit or for the elderly, the role of CNS prophylaxis, rituximab maintenance and radiotherapy, the indications to allogeneic transplantation and the place of new active anti-lymphoma drugs.
Keywords: Mantle cell lymphoma, First line therapy, Conventional therapy, Intensive therapy.
Mantle cell lymphoma (MCL) derives from pre-germinal centre B-cells of the follicle mantle zone, marginal zone or peripheral blood memory B-cells and accounts for approximately 3–10% of non-Hodgkin’s lymphomas (NHLs).1 and 2 It predominantly occurs in advanced aged white men, and commonly presents with extensive lymphadenopathy and extra-nodal involvement, especially bone marrow, gastrointestinal tract, liver, spleen or Waldeyer’s ring. MCL is one of the lymphomas with the worse prognosis, carrying the unfavorable characteristics of both indolent (incurable) and aggressive lymphomas (rapidly growing). Despite the existence of an indolent subgroup (10–15% of MCL patients) who survive more than 10 years, most cases follow a relatively rapid disease progression, short response to treatment, inevitable relapses, and continuously declining survival curve with a median survival of only 3–5 years.3, 4, and 5 MCL are morphologically divided into classical variants (including nodular, diffuse, mantle zone and rarely follicular growth pattern), aggressive variants (blastoid and pleomorphic) and the very indolent variant “in situ” MCL. The t(11;14)(q13;q32) translocation leading to overexpression of cyclin D1 (an important cell cycle regulator of G1/S phase) is the most important but not exclusive genetic characteristic of most MCL. Cyclin D2 or D3 is overexpressed in cyclin D1-negative MCL with similar morphologic, pathologic, clinical and molecular features of typical MCL.6 and 7
The clinical management of patients presenting with MCL has been the subject of a number of recent reviews.8, 9, 10, and 11 In this paper, we address some issues which are still controversial and subject of frequent debate.
Which are the necessary staging examinations?
Essential staging procedures include physical examination, history enquiring for B symptoms, complete blood count (CBC), bone marrow biopsy ± aspirate, and computed tomography (CT) scan of the chest, abdomen and pelvis. Optional further examinations are 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET)-CT, GI-endoscopy and cerebrospinal fluid (CSF) examination.
The role of PET/CT is established in the staging and response assessment of diffuse large B-cell and Hodgkin lymphoma, while its role in other lymphomas is still debated. PET/CT is not included for MCL in the consensus recommendations for staging or surveillance based on scarce data and especially limited therapeutic consequences. 12 In MCL, extranodal sites are involved in up to 90% of patients, these being mainly bone marrow, gastrointestinal tract and liver. The involvement of these organs may be difficult to be differentiated on PET/CT from physiologic or reactive uptake ( Fig. 1 ).
MCL patients have bone marrow and peripheral blood involvement at diagnosis in approximately 80% and 35% of cases, respectively, 13 while CSF is not routinely examined. The available data suggest that CNS involvement is rare in asymptomatic MCL patients at diagnosis and more than 50% of symptomatic patients have no morphologic or immunophenotypic evidence of CSF involvement despite multiple lumbar punctures. 14 For these reasons, CSF examination and CNS prophylaxis is not considered mandatory in MCL patients.
The estimation of GI tract involvement at presentation is variable 15 depending if one considers only symptomatic cases (25%) or histological examination of endoscopically obtained tissue (88% in the lower GI tract and 43% in the upper GI tract). 8 GI tract endoscopy examination is suggested for clinical stage I–II patients, in order to confirm the early stage and better define the indication to localized treatment, or in cases of “in situ” MCL to exclude the possible coexistence of overt MCL. GI tract endoscopy examination is also necessary to document complete response in patients included into clinical trials. 4
How to recognize good-risk patients?
The survival of MCL patients varies from the median 18 months of the blastoid and plemorphic variants to the 5–12 years without therapy of the indolent non-nodal leukemic subset. 8 To discriminate these heterogeneous patients, prognostic factors specific for MCL have been investigated, looking at clinical characteristics and biological properties.
The international prognostic index (IPI) originally developed for DLBCL and the follicular lymphoma IPI (FLIPI) originally developed for FL fail to recognize a low-risk group in MCL. 16 A prognostic index specific for MCL (MIPI) and its simplified version (sMIPI) were developed based on four clinical variables (age, performance status, white blood cell count and lactate dehydrogenase [LDH] level). 16 The MIPI can discriminate MCL in three groups with a median survival of approximately 3, 5 or 7 years.
Gene expression profiling could be a molecular predictor of survival. MCL patients can be stratified into four prognostic groups according to a survival predictor score generated by 20 proliferation-related genes. 17 A PCR-based five-gene model was also proposed to predict survival on fresh-frozen or formalin-fixed, paraffin-embedded MCL samples. 18 Based on a genome-wide microRNA profiling platform of high-throughput quantitative real-time PCR (qRT-PCR), MCL cases could also be separated into three clusters with different biologic and clinical characteristics. 19 Although GEP warrants further validation and is currently not available for routine clinical application, it allows a better understanding of genomic alterations and may in the future lead the way to better patient-tailored and risk-adapted treatment options.
Recently, an indolent subset of MCL was identified by non-nodal presentation, hypermutated immunoglobulin variable-region heavy chain (IgVH), absence of genomic complexity, and no need of treatment for years. The SOX11, an antigen highly expressed in 90–95% of MCL, but rarely in other B-cell lymphomas, is used for the diagnosis of cyclin D1-negative MCL. 20 Recently it was proposed as a useful marker to recognize the indolent subset but its prognostic role is still controversial: in one study SOX11-negative MCL patients presenting as nodal disease had inferior OS (median OS 494 vs. 1488 days, P = 0.0498) while in another study, SOX-11 negative non-nodal MCL had superior OS (5-year OS 78% vs. 36%, P = 0.001) compared with SOX11-positive MCL patients.21 and 22 Hence, the role of SOX11 in predicting MCL prognosis remains apparently controversial, and it should not be used in the routine clinical settings before prospective validation has taken place.
Which is the optimal first line therapy for young and fit patients?
There is no generally accepted standard treatment for MCL, but the majority of studies suggest that the best treatment is one including an anthracycline-containing chemotherapy, rituximab and high-dose cytarabine (HD-AraC) followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR). Deferred initial treatment is acceptable in selected asymptomatic MCL patients ( Fig. 2 ). 23
In untreated MCL patients, CHOP or R-CHOP-like chemotherapy obtains an overall remission rate (ORR) of 75–96% but relatively low complete remissions (CR) (7–48%) with short remission duration (14–21 months) ( Table 1 ).24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, and 35 More intensive therapies including high dose chemotherapy regimens were therefore explored and showed higher activity ( Table 2 ).36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and 52 These regimens should be carried out in centers with extensive experience in treating patients with leukemia, as they cause important cytopenias requiring specialized treatment. As an example, when the Hyper-CVAD/MA + rituximab regimen was applied at the MD Anderson Cancer Center it obtained excellent results (median TTF 5.9 years, and median OS not reached in 10-year follow up) 53 ; however, these could not be replicated in multicenter trials as the one from the Gruppo Italiano Studio Linfomi (GISL) 41 or from the Southwest Oncology Group (SWOG) 0213 study. 39 In the randomized phase III trial of the European MCL Network, R-CHOP alternating with R-DHAP followed by ASCT significantly improved ORR, CRR and TTF with a good tolerance compared with R-CHOP followed by ASCT supported myeloablative radio-chemotherapy without Ara-C.
|Study phase||Induction||N||Response rate (ORR/CRR,%)||Median PFS||Median OS||Reference (year)|
|II||COP||35||60 (40)||20 months||45% (2-year)||Teodorovic et al. (1995) 24|
|II||COP||46||83 (18)||–||–||Unterhalt et al. (1996) 25|
|II||R-CHOP||40||96 (48)||16.6 months||–||Howard et al. (2002) 26|
|II||VcR-CVAD||30||90 (77)||73% (18 months)||97% (18 months)||Chang JE et al. (2008) 27|
|II||R-CHOP + Bortezomib||36||91 (72)||44% (2 years); 23 months||86% (2-year)||Ruan J et al. (2011) 28|
|II||R-CHOP followed by 90Y-ibritumomab||56||82 (55)||34.2 months (median TTF)||NR (median OS); 73% (5-year)||Smith et al. (2012) 29|
|III||CHOP vs. COP||26 vs. 37||88 (38) vs. 84 (22)||7 vs 10 months||60% vs 65% (2-year)||Meusers et al. (1989) 30|
|III||CHOP vs MCP||46 vs. 40||87 (15) vs. 73 (20)||21 vs 15 months, 46% vs 30% (2 years), 20% vs 9% (5 years)||61 vs 48 months, 85% vs 82% (2 years), 57% vs 31% (5-year)||Nickenig et al. (2006) 31|
|III||R-MCP vs MCP||44 vs. 46||71 (32) vs. 63 (15)||PFS: 20 vs 18 months; EFS: 18 vs 13 months||56 vs 50 months||Herold et al. (2008) 32|
|III||R-CHOP vs R-Bendamustine||48 vs. 45 (MCL)||95 (35) vs. 89 (32)||22 vs 33 months||–||Rummel et al. (2009) 33|
|III||R-CHOP×8 vs R-FC×6 followed by rituximab vs IFN maintenance||560 (first randomization) 310 (second randomization)||R-CHOP vs. R-FC: 87% (50%) vs. 78% (52%)||Rituximab vs. IFN: 57% vs. 26% (4-year RD)||R-CHOP vs. R-FC: 64 vs. 40 months; In R-CHOP subgroup, rituximab vs. IFN: 87% vs. 57% (4-year)||Kluin-Nelemans et al. (2011, 2012)34 and 35|
CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), COP (cyclophosphamide, vincristine, and prednisone), CR (complete response), EFS (event free survival), FCM (fladarabine, cyclophosphamide, mitoxantrone), FFS (failure free survival), IFN (interferon), MCP (mitoxantrone, chlormabucil, prednisolone), NR (not reached), OS (overall survival), PFS (progression free survival), PR (partial response), R (rituximab), RD (remission duration), TTF (time to treatment failure).
|Study phase||Induction||Consolidation||N||Response rate (OR/CR,%)||Median PFS||Median OS||Reference (year)|
|II||Hyper-CVAD/MA||High dose CY, TBI,autologous or allogeneic blood or marrow stem-cell transplantation||45 (25 untreated)||93.5 (38)||72% (3-year EFS, 25 untreated pts)||92% (3-year, 25 untreated pts)||Khouri et al. (1998) 36|
|II||Hyper-CVAD/MA||–||25 (age ⩾65)||92 (68)||15 months (median FFS)||–||Romaguera et al. (2000) 37|
|II||R-Hyper-CVAD/R-MA||–||97||97 (87)||64% (3-year FFS), 43% (8-year FFS),||82% (3-year), 56% (8-year)||Romaguera et al. (2005) 38|
|II||R-Hyper-CVAD/R-MA||–||49||88 (58)||89% (1-year PFS), 63% (2-year PFS)||91% (1-year), 76% (2-year)||Epner et al. (2007) 39|
|II||R-Hyper-CVAD/R-MA||–||32||53 (50)||75% (2-year FFS)||93% (2-year)||Merli et al. (2008) 40|
|II||R-HCVAD-AM||–||63||83 (72)||61% (5-year PFS)||73% (5-year)||Merli et al. (2012) 41|
|II||R-DHAP||ASCT||24||96 (92)||65% (3-year EFS)||69% (3-year)||de Guibert et al. (2006) 42|
|II||CHOP×4 + DHAP×2||CHOP: TBI, high dose CY, VP-16 followed by APBSCT; DHAP: TBI,high dose Ara-C, melphalan (TAM8) followed by APBSCT||28||CHOP: 57% (2%) DHAP: 92% (84%)||51 months (median EFS)||81 months||Lefrère et al. (2002) 43|
|II||CHOP + HD-Ara-C||HD-R-Cy-TBI followed by ASCT||34||88 (24)||83% (4 years)||87% (4-year)||Dreger et al. (2007) 44|
|II||R-CHOP×3 + HD-Ara-C×1||BEAM followed by ASCT||87||70 (64)||36% (4-year FFS)||66% (4-year FFS)||van ‘t Veer et al. (2009) 45|
|II||CHOP×2 + R-CHOP×1 + R-DHAP×3||TAM6 or BEAM followed by ASCT||60||(R)-CHOP: 93 (12); R-DHAP: 95 (61)||83 months (median EFS)||NR (median OS); 75% (5-year)||Delarue et al. (2008) 46|
|II||(R)-maxi-CHOP×3/(R)- HD-Ara-C × 3||BEAM or BEAC followed by R-in vivo purged ASCT||160||96 (54)||56% (6-year EFS), 66% (6-year PFS), 43% (projected 10-year EFS), 7.4 years (median EFS)||70% (6-year), 58% (projected 10-year)||Geisler et al. (2012) 47|
|III||R-CHOP vs. CHOP||Dexa-BEAM, TBI, high dose CY followed by ASCT vs. IFN maintenance||62/63 vs. 60||94 (34)/92 (33) vs. 75 (7)/75 (8)||PFS: 20 vs. 19 months,TTF: 28 vs. 14 months||76% vs. 76% (2-year), 59% vs. 46% (5-year)||Lenz et al. (2005) 48 Hoster et al. (2008) 49|
|III||CHOP/CHOP-like||Dexa-BEAM, TBI, high dose CY followed by ASCT vs. IFN maintenance||75 vs. 69||–||RD: 3.7 vs. 1.6 years; TTF: 2.6 vs. 1.4 years||7.5 vs. 5.3 years||Dreyling et al. (2008) 50|
|III||R-CHOP × 6 vs. R-CHOP × 3/R-DHAP × 3||R-CHOP: DexaBEAM, high dose CY, TBI followed by ASCT; R-CHOP/R-DHAP: TBI,high dose Ara-C, melphalan (TAM8) followed by ASCT||497||After induction: 90 (26) vs. 94 (39) after ASCT: 97 (63) vs. 97 (65)||TTF: 49 months vs. NR; RD after ASCT: 48 months vs. NR||79% vs. 80% (3-year)||Dreyling et al. (2008) 51 , Hermine et al. (2010) 52|
APBSCT (autologous peripheral blood stem cell transplantation), ASCT (autologous stem cell transplantation), BEAC (BCNU, etoposide, cytarabine, and cyclophosphamide), BEAM (BCNU, etoposide, cytarabine, and melphalan), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CR (complete response), DHAP (dexamethasone, high dose of cytarabine, and cisplatin), EFS (event free survival), FCM (fladarabine, cyclophosphamide, mitoxantrone), FFS (failure free survival), HyperCVAD/MA (fractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone; alternated with high-dose methotrexate and cytarabine), IFN (interferon), NR (not reached), OS (overall survival), PFS (progression free survival), PR (partial response), R (rituximab), RD (remission duration), TBI (total-body irradiation), TTF (time to treatment failure).
Rituximab is only moderately effective as monotherapy in MCL (approximately 30% RR). 54 Nevertheless, in addition to chemotherapy rituximab significantly improved ORR and PFS. 48 A meta-analysis of three randomized controlled trials suggested an OS advantage for the addition of rituximab to chemotherapy compared with chemotherapy alone in patients with untreated or relapsed mantle cell lymphoma, although the important heterogeneity among the trials make this conclusion less solid. 55 The NCCN Non-Hodgkin’s Lymphoma Outcomes Database analysis also showed a PFS benefit of rituximab maintenance in untreated young and fit patients. 56
The prospective randomized phase III clinical trial of Europe MCL Network (n = 144) showed that ASCT produced superior response duration (median 3.7 vs. 1.6 years) and median OS (7.5 vs. 5.3 years) compared with interferon maintenance after CHOP/CHOP-like or R-CHOP. A subgroup analysis with a relative short follow-up time (12 months) showed ASCT to only benefit the CHOP induction group, but not the R-CHOP group. 57 The Nordic Lymphoma Group study MCL2 including increased dose CHOP, rituximab, HD-AraC and ASCT obtained a median EFS of 7.4 years and more than 10 years of median OS and response duration. However, late relapses occurred and the survival curve does not display a plateau. 47 A recent analysis of 167 young patients with MCL in the NCCN Non-Hodgkin’s Lymphoma Outcomes Database showed comparable PFS for patients treated with R-HyperCVAD/R-MA, R-HyperCVAD/R-MA followed by HDT/ASCT, and R-CHOP followed by HDT/ASCT, comparable OS for patients treated with R-HyperCVAD/R-MA and R-CHOP followed by HDT/ASCT, and inferior PFS and OS for patients treated with R-CHOP alone. 56
It has been demonstrated that a non-detectable minimal residual disease (MRD) after HD/ASCT (by PCR analysis of clonal IGH gene rearrangement) is associated with longer median PFS (92 vs. 21 months) and OS (median OS not reached vs. 44 months). 58
Which is the optimal treatment for elderly or unfit patients?
Some of the treatments whichnot yet been evaluated in the first-line improved the outcome for the young and fit (as HD-AraC or ASCT) are not applicable to the elderly or unfit, who are the majority of MCL patients. A wild range of options, including R-CHOP, milder immune-chemotherapy or single agents, are never the less available as induction therapy for palliative care. Closely monitoring asymptomatic and low-risk (indolent) patients is also a possibility which can spare or delay the toxicity of treatment. 23
R-CHOP, which obtains an ORR >90%, CRR 30–40%, with a median PFS of 16–29 months) is considered an acceptable frontline therapy for MCL in elderly patients. The addition of rituximab to a purine analogue-based regimen (FCM) produced improved response rate and survival of relapsed and refractory FL and MCL patients in a prospective randomized phase III trial of the German Low-Grade Lymphoma Study Group (GLSG), 59 but R-FC was inferior (mainly because of increased toxicity) to R-CHOP as frontline induction therapy in the prospective randomized phase III MCL elderly trial of the European Mantle Cell Lymphoma Network. 60
Bendamustine alone or in combination with other chemotherapeutic agents have potent activity in MCL. A randomized phase III trial comparing BOP (bendamustine, vincristine and prednisone) and COP (cyclophosphamide, bendamustine, vincristine and prednisone) in untreated patients with advanced indolent non-Hodgkin’s lymphoma and MCL, showed a higher 5-year event-free, progression-free and overall survival for BOP. 61 In the subgroup of 93 patients with MCL of a large randomized phase III trial conducted by the German Study Group on Indolent Lymphomas (StiL) in untreated elderly patients (median age 70 years) with indolent NHL and MCL, bendamustine–rituximab (BR) extended progression-free survival by nearly 1 year with better tolerance compared with R-CHOP. 33 R-bendamustine seems therefore to be a valid alternative to R-CHOP in elderly patients with MCL.
Is CNS prophylaxis mandatory?
CNS involvement is extremely rare at diagnosis, but at the time of relapse the incidence of CNS involvement in MCL patients is 4–22%. In five retrospective studies,14, 62, 63, 64, and 65 CNS relapse occurred after a median time of 12–51 months from diagnosis. Median survival from the time of CNS involvement was 2–9 months. Blastoid variant, high MIPI score, high ki67 and high LDH serum level are predictors of CNS involvement.62, 63, 64, 65, and 66
It is controversial whether prophylaxis can really prevent CNS relapse. CNS infiltration is usually a late event and part of a systemic relapse, and systemic progression of MCL is the cause of death in almost all cases. 62 Gill et al. observed an incidence of four cases of CNS relapse in 52 patients who never received CNS prophylaxis 63 while none of the 10 patients who received CNS prophylaxis developed CNS relapse. Despite the limited data, many oncologists prefer to administer CNS-directed therapy (systemic or intrathecal) at least in younger patients.
High-dose methotrexate (HD-MTX), the most active CNS-penetrating agent, is the backbone of systemic prophylaxis and treatment in primary or secondary CNS lymphoma. However, in a series of MCL patients, the incidence of CNS infiltration observed in patients receiving high dose MTX-containing regimens was the same as that detected in the remaining patients. 62 It is unclear whether HD-MTX exercises a prophylactic effect in patients with MCL. Due to the lack of comparative data, it is even more difficult to evaluate the CNS-prophylactic effect of HD-Ara-C and HD-MTX-containing regimens given to young and fit MCL patients, as in the HyperCVAD/MA regimen. A recent large retrospective survey of the European MCL network showed that most CNS relapses occurred within 2 years, suggesting that CNS prophylaxis may have a role in patients with high-risk features. 66
Should MCL patients receive rituximab maintenance?
The use of rituximab for eradicating MRD in MCL has shown to be successful in two trials after autologous transplantation,67 and 68 so that the idea of administering this drug after remission could be of interest.
In the single-agent rituximab maintenance study of the Swiss Group for Clinical Cancer Research (SAKK), a prolonged rituximab schedule doubled the EFS of MCL patients (12 vs. 6 months) compared to rituximab induction only, but the difference did not reach statistical significance. 54 A subsequent phase III rituximab maintenance trial in relapsed follicular lymphoma (FL) and MCL was performed by the German Low Grade Lymphoma Study Group (GLSG). After induction chemotherapy with either FCM or R-FCM, patients were randomized to rituximab maintenance or observation. In MCL, ORR was superior in R-FCM arm (58% vs. 48%) and a marginal statistically significant improvement in response duration was found in 47 patients who received rituximab maintenance after initial R-FCM therapy. 69
The large prospective randomized European Mantle Cell Lymphoma Network Elderly Trial involved 560 patients.34, 35, and 70 A first randomization comparing two induction chemotherapies showed that R-CHOP is superior to R-FC, while a second randomization showed that rituximab maintenance significantly improved both remission duration (57% vs. 26%) and OS (77% vs. 62%) at 4 years for patients responding to R-CHOP but not after R-FC. R-CHOP induction followed by bimonthly rituximab maintenance until relapse achieved the best PFS and OS, and is now seen by many as the new standard treatment for elderly patients with MCL. 35
Have radiotherapy or radio-immunotherapy a role in treating MCL?
Ionising radiations are used to treat MCL in the form of local radiotherapy, radio-immunotherapy and as total body irradiation (TBI) to prepare for autologous stem cell transplantation.
There are no randomized trials available including a sufficient number of early stage MCL patients. A retrospective analysis of 26 cases with stage IA or IIA without bulky disease, patients having received radiation therapy alone or in combination with chemotherapy had a longer 5-year PFS (68% vs. 11%) and OS (71% vs. 25%) compared to cases treated without irradiation. 71 In addition, mantle cell lymphoma is highly radiosensitive as radiation induced 100% ORR (CR 64%), lasting local response (median response duration 9 months) and minimal systemic toxicity in a series of 21 consecutive early and advanced staged MCL patients. 72 Despite the lack of high-level evidence, it is reasonable to consider radiation therapy as part of treatment in early stage and certain advanced staged MCL patients.
There are few studies using RIT as first line therapy in MCL. Previously untreated MCL patients (n = 14) were enrolled in a phase II trial of a multimodal dose-dense therapy followed by 131I-tositumomab (Bexxar) consolidation. The overall response rate (ORR) was 100% with a complete response rate (CR) of 86%. The median progression-free survival is 36.5 months with 11/14 (79%) MCL patients being alive and in continued CR. The median overall survival has not been reached. 73 Other RIT-containing regimens, such as 131I-tositumomab (Bexxar) followed by CHOP, FCM followed by 90Y-ibritumomab tiuxetan (Zevalin), and R-CHOP followed by Zevalin produced also high complete response rates and meaningful PFS/OS in untreated patients with MCL. The incorporation of radio-immuno-conjugates into conditioning regimens prior to ASCT has not yet been evaluated in the first-line treatment setting. 74 Incorporation of RIT as induction therapy, consolidation therapy after remission induction, or as part of marrow ablative regimens is being further explored in MCL.
The role of radiotherapy as a component of the conditioning regimen prior to autologous stem cell transplantation is still not defined. A small (n = 18) retrospective study suggested that TBI may improve the EFS after ASCT in MCL. 75 In contrast, another retrospective analysis (n = 73) in a single institution found no difference in the 1- and 3-years EFS and OS rates between TBI/cyclophosphamide (or melphalan) and BEAM as the conditioning regimen. 76 In a multicentre study with a median follow-up of 3.9 years using data of the European Blood and bone Marrow Transplant (EBMT) registry and Autologous Blood and Marrow Transplant Registry (ABMTR) between 1983 and 1998, no benefit was found on RR, PFS and OS for TBI-conditioned MCL patients (43% of 181 patients). 77 A study of the chronologically subsequent cohort (n = 418), always from the EBMT registry (period 2000–2007) showed in contrast that TBI was associated with a significant reduction in the incidence of relapse and a trend to a better DFS in patients transplanted in first partial response, while TBI could probably be avoided in patients transplanted in CR. 78
Should any patient with MCL be allo-transplanted?
Patients who are young and fit enough for it are consolidated with ASCT in first remission in the majority of centers. At relapse they are therefore candidates for allo-transplant.
Considering the median age (65–68 years) of MCL patients, reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) at time of relapse may represent an attractive strategy. A retrospective analysis of 70 refractory or relapsed MCL patients in 12 centers suggested that RIC-allo-SCT could be effective in MCL patients with a chemosensitive disease at time of transplantation, obtaining a 2-year EFS, OS and transplant-related mortality rates of 50%, 53%, and 32%, respectively. 79 The mature results of 17 years of transplantation experience in patients with MCL at MD Anderson Cancer Center retrospectively compared autologous SCT in first remission (AUTO1, n = 50), autologous SCT for relapsed or refractory MCL (AUTO2, n = 36), and non-myeloablative allogeneic SCT for relapsed or refractory MCL (NST, n = 35). The 6-year actuarial PFS of AUTO1, AUTO2 and NST were 39%, 10% and 46%, respectively, while the 6-year actuarial OS were 61%, 35% and 53%, respectively. These results suggest that autologous transplantation in first remission gives better results than in second line and, as well as NST in relapsed or refractory disease, can result in long-term disease-free survival in selected patients. 80
Consolidation with allo-SCT after first response is the only potential curative option for patients with MCL. However, the much higher toxicity and mortality following allo-SCT limited the experience on allo-SCT in first remission. The possible graft vs. lymphoma (GVL) advantage and a lower relapse rate must be balanced with graft vs. host disease (GVHD) and transplant-related mortality (TRM). Based on data of the BMT registry at Johns Hopkins Oncology Center from 1980 to 2003, an estimated 3-year EFS was equally 70% both in autologous (n = 26) and allogeneic (n = 10) BMT in first remission. 81
New drugs for treating MCL
Following the registration in the US and Europe of the proteasome inhibitor bortezomib for the treatment of relapsing MCL, 82 the combination of this compound with the R-CHOP regimen was evaluated and appeared safe and somehow active (with ORR of 81% and 2 year PFS of 44%). 28 VcR-CVAD (bortezomib combining rituximab, cyclophosphamide, doxorubicin, vincristine and dexamethasone), 27 and RiPAD + C (bortezomib in combination with rituximab, doxorubicin as a continuous infusion, dexamethasone and chlorambucil) 83 also showed activity in recent phase II trials as first line therapy of MCL. Moreover, studies addressing the addition of Bortezomib to either the EPOCH-R (NCT0114738) or the R-HyperCVAD (NCT00477412) regimen, as well as to other chemotherapeutic combinations are currently recruiting patients.
Many other new compounds have shown promising activity. Several new antibodies are currently under clinical evaluation in MCL, including second and third-generation anti-CD20 antibodies, antibodies targeting B-cell antigens other than CD20 (such as CD22, CD40 and CD80), radionuclide-conjugated anti-CD20 antibodies, toxin-conjugated antibodies, to mention just a few. Compared with type-I (rituximab-like), type-II (tositumomab-like) anti-CD20 antibodies possess stronger antibody-dependent cytotoxicity and stronger direct effects on B-cells. Obinutuzumab (GA-101) is a third-generation humanised and glycoengineered CD20 IgG1 type-II antibody with enhanced binding ability to FcγRIIIa and increased antibody-dependent cytotoxicity. 84 The immunotoxin denileukin diftitox (a conjugate of interleukin-2 with the diphtheria toxin) has been approved by the US FDA for the treatment of cutaneous T-cell lymphoma. In a phase II trial, denileukin diftitox was also effective in relapsed or refractory B-cell NHLs (including MCL) and was well-tolerated. 85 Inotuzumab ozogamicin (CMC-544), a CD22 mAb conjugated with the potent chemotherapy agent calicheamicin, resulted in significant single agent activity in both indolent and aggressive NHL, including MCL.
Small molecules with promising activity in MCL include the proteasome inhibitor Carfilzomib, the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, the histone deacetylase inhibitor vorinostat (SAHA), the Cdk inhibitor flavopiridol, the PKC-β inhibitor enzastaurin, the PI3K δ inhibitor CAL-101 and the Bruton tyrosine kinase (BTK) inhibitor PCI-32765 (Ibrutinib). Incorporation of these agents in combination regimens (either with other targeted agents or with chemotherapy) in the first line therapy of MCL is an active and challenging area of clinical research. An example is represented by the before mentioned bortezomib-based regimens,27, 28, and 83 which showed activity in recent phase II trials, but other combinations (based on lenalidomide, bendamustine and other compounds) are also under scrutiny.
Lenalidomide and thalidomide are immune modulatory drugs (IMiDs) with multiple mechanisms of action including modulation of immune response and microenvironment effect. IMiDs have the potential to interfere with indolent and aggressive NHL growth and survival. In phase II trials, lenalidomide monotherapy resulted in ORR of 42–53%, CR/CRu of 17–21%, with median PFS lasting from 5.6 months to more than 2 years in refractory or relapsed patients.86, 87, 88, 89, and 90
Conflicts of interest
I hereby certify that both myself and Dr Emanuele Zucca received honoraries for medical advice and as speakers and for research support from the following companies:Roche, Cellgene, Jansen.
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a Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
b State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
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