Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
2014; Elsevier BV; Volume: 25; Linguagem: Inglês
10.1093/annonc/mdu264
ISSN1569-8041
AutoresM. Dreyling, Carsten Geisler, Olivier Hermine, Hanneke C. Kluin‐Nelemans, Steven Le Gouill, Simon Rule, Ofer Shpilberg, Jan Walewski, Marco Ladetto,
Tópico(s)Chronic Lymphocytic Leukemia Research
ResumoMantle cell lymphoma (MCL) is a less frequent subtype of lymphoid malignancies and represents 6%–9% of malignant lymphoma in Western Europe. The annual incidence of this disease has increased during recent decades to 1–2/100 000 recently. MCL is more common in males than in women with a 3 : 1 ratio. Diagnosis should be based on a surgical specimen, preferably a lymph node biopsy. Core biopsies should only be carried out in patients without easily accessible lymph nodes (e.g. retroperitoneal bulk), keeping in mind the heterogeneity of MCL. In the rare cases with leukaemic manifestation only, a bone marrow biopsy may be sufficient if additional diagnostic measures are applied [immunohistochemistry, detection of t(11;14)(q13;q32)]. Fine-needle aspirations are inappropriate for a reliable evaluation of additional risk factors (cytology, cell proliferation). The histological report should give the diagnosis according to the World Health Organization (WHO) classification and Ki-67 as the most established histomorphological risk factor [1.Swerdlow S.H. Campo E. Harris N.L. et al.WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.in: 4th edition. IARC Press, Lyon, France2008: 233-237Google Scholar] [I, A]. Most tumours have a classic morphology of small-medium sized cells with irregular nuclei. However, the malignant lymphocytes may present with a spectrum of morphological variants, including small round (resembling chronic lymphocytic leukaemia), marginal zone-like, pleomorphic and blastoid cells. As only the minority of these cases are correctly diagnosed based on classical histology only, review by an expert haematopathologist is advised. Specifically, additional immunohistochemistry for detection of the pathognomonic cyclin D1 overexpression is mandatory. In the rare cyclin D1-negative cases, detection of Sox-11 may help to establish the diagnosis [2.Fu K. Weisenburger D.D. Greiner T.C. et al.Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling.Blood. 2005; 106: 4315-4321Crossref PubMed Scopus (285) Google Scholar]. Extended gene expression profiling suggests a more favourable clinical course in cases with low cell proliferation; however, this technique is not yet applicable in clinical routine practice. If possible, additional biopsy material should be stored freshly frozen to allow additional molecular (currently still investigational) analyses. Since treatment may differ depending on the stage of the disease, initial staging should be thorough, particularly in the rare cases with non-bulky stages I and II (Table 1). Initial work-up should include a computed tomography (CT) scan of the neck, thorax, abdomen and pelvis, and a bone marrow aspirate and biopsy (Table 2). Positron emission tomography-CT (PET-CT) scan is not mandatory, but may be recommended and is especially useful in the rare limited stages I/II, before localised radiotherapy [IV, C]. Gastrointestinal endoscopy is also recommended in these rare cases to detect asymptomatic involvement. Of note, when analysed, the majority of MCL patients will have gastrointestinal involvement.Table 1Ann Arbor classificationStageArea of involvementI (IE)One lymph node region or extralymphatic site (IE)II (IIE)Two or more lymph node regions or at least one lymph node region plus a single localised extralymphatic site(IIE) on the same side of the diaphragmIII (IIIE, IIIS)Lymph node regions or lymphoid structures (e.g. thymus, Waldeyer's ring) on both sides of the diaphragm with optional localised extranodal site (IIIE) or spleen (IIIS)IVDiffuse or disseminated extralymphatic organ involvementA, no symptoms; B, unexplained fever of >38°C, drenching night sweats; or loss of >10% body weight within 6 months. Open table in a new tab Table 2Diagnostic work-upHistoryB symptomsPhysical examinationWaldeyer's ring, peripheral lymph nodes, liver, spleenLaboratory work-upBlood and differential count in leukaemic cases: FACS (CD5/CD20+, CD23/CD200), FISH for t(11;14) recommendedLDH, uric acid, liver and renal function electrophoresis (optional: immune fixation)SerologyHepatitis B, C and HIV serologyImagingChest X-rayAbdominal ultrasoundCT neck, chest, abdomen, pelvisMRT only in selected locations (CNS)Optional: PETBone marrowHistology (cyclin D1 immunohistochemistry)CytologyRecommended: FACS, FISH for t(11;14)Optional: PCR for IgH rearrangementToxicityElectrocardiogram, cardiac ultrasound (before anthracyclines, ASCT)Pulmonary function (before ASCT)Creatinine clearanceOptional: reproductive counselling in young patientsFACS, fluorescence-activated cell sorting; FISH, fluorescence in situ hybridisation; LDH, lactate dehydrogenase; HIV, human immunodeficiency virus; CT, computed tomography; MRT, magnetic resonance tomography; CNS, central nervous system; PET, positron emission tomography; PCR, polymerase chain reaction; ASCT, autologous stem-cell transplantation. Open table in a new tab A, no symptoms; B, unexplained fever of >38°C, drenching night sweats; or loss of >10% body weight within 6 months. FACS, fluorescence-activated cell sorting; FISH, fluorescence in situ hybridisation; LDH, lactate dehydrogenase; HIV, human immunodeficiency virus; CT, computed tomography; MRT, magnetic resonance tomography; CNS, central nervous system; PET, positron emission tomography; PCR, polymerase chain reaction; ASCT, autologous stem-cell transplantation. Central nervous system involvement is rare in asymptomatic patients at diagnosis, but a lumbar puncture may be considered in high-risk cases [at least two of the following risk factors: blastoid variant, elevated lactate dehydrogenase (LDH), impaired performance status] or neurological symptoms [3.Cheah C.Y. George A. Giné E. European Mantle Cell Lymphoma Network et al.Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network.Ann Oncol. 2013; 24: 2119-2123Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. A full blood count, blood chemistry including LDH and uric acid as well as screening tests for human immunodeficiency virus (HIV) and hepatitis B and C are required. Staging is carried out according to the Ann Arbor classification system (Table 1), with mention of bulky disease >5 cm when appropriate. For prognostic purposes, a 'Mantle cell lymphoma International Prognostic Index' (Table 3; web-based calculator: www.european-mcl.net/de/clinical_mipi.php) has been established [I, A] [4.Hoster E. Dreyling M. Klapper W. et al.A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma.Blood. 2008; 111: 558-565Crossref PubMed Scopus (686) Google Scholar].Table 3Simplified MIPI risk factorPointsAge (years)ECOGLDH (ULN)WBC (109/l)0<500–1<0.67 70–≥1.50≥15.000For each prognostic factor, 0–3 points were given to each patient and points were summed up to a maximum of 11. Patients with 0–3 points in summary were classified as low risk, patients with 4–5 points as intermediate risk and patients with 6–11 points as high risk. ECOG performance status was weighted with 2 points if patients were unable to work or bedridden (ECOG 2–4). LDH was weighted according to the ratio to the ULN. Thus, for an ULN of 240 U/l, the limits were 180, 240 and 360 U/l.MIPI, mantle cell lymphoma international prognostic index; ECOG, Eastern Cooperative Oncology Group; LDH: lactate dehydrogenase; ULN: upper limit of normal range; WBC: white blood count. Open table in a new tab For each prognostic factor, 0–3 points were given to each patient and points were summed up to a maximum of 11. Patients with 0–3 points in summary were classified as low risk, patients with 4–5 points as intermediate risk and patients with 6–11 points as high risk. ECOG performance status was weighted with 2 points if patients were unable to work or bedridden (ECOG 2–4). LDH was weighted according to the ratio to the ULN. Thus, for an ULN of 240 U/l, the limits were 180, 240 and 360 U/l. MIPI, mantle cell lymphoma international prognostic index; ECOG, Eastern Cooperative Oncology Group; LDH: lactate dehydrogenase; ULN: upper limit of normal range; WBC: white blood count. The evaluation of the Ki-67 proliferative antigen is the most applicable method to evaluate cell proliferation, and is considered the most established biological risk factor in MCL. As the reproducibility of quantitative scores among pathologists may vary, a standardised method has been suggested [5.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: 103-111Crossref PubMed Scopus (131) Google Scholar]. Most patients with MCL follow an aggressive clinical course. However, a subset of patients may exhibit a more indolent evolution. These cases are commonly characterised by a non-nodal leukaemic presentation with only bone marrow involvement, and splenomegaly [6.Fernàndez V. Salamero O. Espinet B. et al.Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma.Cancer Res. 2010; 70: 1408-1418Crossref PubMed Scopus (361) Google Scholar]. In addition, cases with low Ki-67 (≤10%) tend to have a more indolent course. SOX-11 negativity may also identify cases with more indolent clinical behaviour. However, its role is controversial and additional p53 mutations may cause an aggressive clinical evolution [7.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: 4215-4223Crossref PubMed Scopus (127) Google Scholar] (Figure 1). Unfortunately, there are no markers to definitely predict indolent behaviour, but a short watch-and-wait period under close observation seems to be appropriate in suspected indolent cases with low tumour burden [III, B] [9.Martin P. Chadburn A. Christos P. et al.Outcome of deferred initial therapy in mantle-cell lymphoma.J Clin Oncol. 2009; 27: 1209-1213Crossref PubMed Scopus (270) Google Scholar]. In the small proportion of patients with limited non-bulky stages I–II, radiotherapy (involved field, 30–36 Gy) has been suggested to achieve long-term remissions [10.Leitch H.A. Gascoyne R.D. Chhanabhai M. et al.Limited-stage mantle-cell lymphoma.Ann Oncol. 2003; 14: 1555-1561Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar]. In contrast, in a randomised study, all patients with early-stage MCL relapsed within 1 year [11.Engelhard M. Unterhalt M. Hansmann M. et al.Follicular lymphoma, immunocytoma, and mantle cell lymphoma: randomized evaluation of curative radiotherapy in limited stage nodal disease.Ann Oncol. 2008; 19: 418Google Scholar]. Thus, a shortened conventional chemotherapy induction followed by consolidating radiation (similar to diffuse large-cell lymphoma) may be most appropriate in these cases [IV, B]. In stage I–II patients with large tumour burden or adverse prognostic features, systemic therapy as indicated for advanced stages would be appropriate in most cases; a radiation consolidation may be considered, depending on tumour location and anticipated side-effects [IV, B]. In all symptomatic patients and asymptomatic cases with high tumour burden, therapy should be initiated at diagnosis [I, A]. The current therapeutic approach is based on clinical risk factors, symptoms and patient characteristics (Figure 2). Based on a median age of 65 years at first diagnosis, the majority of patients do not qualify for dose-intensified regimens. Three prospective first-line trials, a salvage trial and a systematic meta-analysis support an improved overall response, progression-free survival (PFS) and overall survival (OS) if rituximab was added to chemotherapy (Table 4) [I, A] [12.Schulz H. Bohlius J.F. Trelle S. et al.Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis.J Natl Cancer Inst. 2007; 99: 706-714Crossref PubMed Scopus (320) Google Scholar].Table 4Published clinical studies investigating first-line conventional immunochemotherapy in mantle cell lymphomaAuthorStudy featuresEvaluable patientsTherapeutic regimenORR% (CR%)Median PFS (months)2-years OSConventional immunochemotherapy Lenz et al. [13.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: 1984-1992Crossref PubMed Scopus (517) Google Scholar]Phase III, randomised112CHOP versus R-CHOP75 (7) versus 94 (34)21 versus 14 (TTF)76% versus 76% Herold et al. [14.Herold M. Haas A. Doerken B. et al.Immunochemotherapy (R-MCP) in advanced mantle cell lymphoma is not superior to chemotherapy (MCP) alone—50 months update of the OSHO phase III study (OSHO#39).Ann Oncol. 2008; 19 (abstr 12)Google Scholar]Phase III, randomised90MCP versus R-MCP63 (15) versus 71 (32)18 versus 2052% versus 55% (4-year OS) Gressin et al. [15.Gressin R. Caulet-Maugendre S. Deconinck E. et al.Evaluation of the (R)VAD+C regimen for the treatment of newly diagnosed mantle cell lymphoma. Combined results of two prospective phase II trials from the French GOELAMS group.Haematologica. 2010; 95: 1350-1357Crossref PubMed Scopus (34) Google Scholar]Phase II113Rituximab–VADC73 (46)16 (no ASCT) 58 (ASCT)aForty-nine patients received ASCT consolidation.62% (3-year OS)aForty-nine patients received ASCT consolidation. Sachanas et al. [16.Sachanas S. Pangalis G.A. Vassilakopoulos T.P. et al.Combination of rituximab with chlorambucil as first line treatment in patients with mantle cell lymphoma: a highly effective regimen.Leuk Lymphoma. 2011; 52: 387-393Crossref PubMed Scopus (27) Google Scholar]Phase II20Rituximab–chlorambucil95 (90)89% (3-year PFS)95% (3-year OS) Kluin-Nelemans et al. [17.Kluin-Nelemans H.C. Hoster E. Hermine O. et al.Treatment of older patients with mantle-cell lymphoma.N Engl J Med. 2012; 367: 520-531Crossref PubMed Scopus (396) Google Scholar]Phase III, randomised485Induction: R-CHOP versus R-FC86 (34) versus 78 (40)28 versus 28 (TTF)62% versus 47% (4-year OS)Maintenance: rituximab versus interferon alpha–58% versus 29% (4-year DOR)79% versus 67% (4-year OS) Rummel et al. [18.Rummel M.J. Niederle N. Maschmeyer G. et al.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: 1203-1210Abstract Full Text Full Text PDF PubMed Scopus (1014) Google Scholar]Phase III, randomised514 (94 MCL)R-CHOP versus rituximab–bendamustine91 (30) versus 93 (40)21 versus 35No differencesData derived from the overall population of the study, not exclusively from patients with MCL.R, rituximab; B, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; FC, fludarabine, cyclophosphamide; MCP, mitoxantrone, procarbazine, lomustine; ASCT, autologous stem-cell transplantation; VADC, vincristine, doxorubicin, oral dexamethasone, chlorambucil; TTF, time to failure; DOR, duration of response; ORR, overall response rate; CR, complete response.a Forty-nine patients received ASCT consolidation. Open table in a new tab Data derived from the overall population of the study, not exclusively from patients with MCL. R, rituximab; B, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; FC, fludarabine, cyclophosphamide; MCP, mitoxantrone, procarbazine, lomustine; ASCT, autologous stem-cell transplantation; VADC, vincristine, doxorubicin, oral dexamethasone, chlorambucil; TTF, time to failure; DOR, duration of response; ORR, overall response rate; CR, complete response. Rituximab in combination with chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or bendamustine should be used [I, B] [13.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: 1984-1992Crossref PubMed Scopus (517) Google Scholar, 18.Rummel M.J. Niederle N. Maschmeyer G. et al.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: 1203-1210Abstract Full Text Full Text PDF PubMed Scopus (1014) Google Scholar]. R-CVP (cyclophosphamide, vincristine and prednisone) combination results in inferior response rates and PFS [19.Flinn I.W. van der Jagt R. Kahl B.S. 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: 2944-2952Crossref PubMed Scopus (422) Google Scholar]. Purine analogue-based schemes [R-FC (fludarabine and cyclophosphamide) or R-FM (fludarabine and mitoxantrone)] are also discouraged due to early failures and long-lasting myelosuppression [17.Kluin-Nelemans H.C. Hoster E. Hermine O. et al.Treatment of older patients with mantle-cell lymphoma.N Engl J Med. 2012; 367: 520-531Crossref PubMed Scopus (396) Google Scholar] [I, D]. In frail patients, a less intense immunochemotherapy [chlorambucil, VADC (vincristine, doxorubicin, oral dexamethasone, chlorambucil) or PEP-C (prednisone, etoposide, procarbazine, cyclophosphamide)] may be considered, aiming primarily at palliation [II, B]. However, targeted therapy exhibiting a low toxicity profile may be used in this population. Antibody monotherapy [rituximab, radioimmunotherapy (RIT)] achieves only moderate response rates and is therefore not recommended [III, B] [20.Ghielmini M. Schmitz S.F. Cogliatti S. et al.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: 705-711Crossref PubMed Scopus (162) Google Scholar]. In patients with positive hepatitis B serology, prophylactic antiviral medication is strongly recommended [I, A] [21.Huang Y.H. Hsiao L.T. Hong Y.C. et al.Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B.J Clin Oncol. 2013; 31: 2765-2772Crossref PubMed Scopus (250) Google Scholar]. Rituximab maintenance significantly improves PFS and even OS after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) (75% versus 58% after 3 years, P < 0.0001) [I, A] [17.Kluin-Nelemans H.C. Hoster E. Hermine O. et al.Treatment of older patients with mantle-cell lymphoma.N Engl J Med. 2012; 367: 520-531Crossref PubMed Scopus (396) Google Scholar]. RIT consolidation also prolongs PFS after chemotherapy, but its benefit seems to be inferior in comparison to rituximab maintenance [II, B] [22.Smith M.R. 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: 3119-3126Crossref PubMed Scopus (66) Google Scholar]. Although no curative treatment is available for MCL so far, an intensive approach, e.g. by ASCT, has been demonstrated to induce higher response and survival rates in fit patients, independent of the addition of rituximab [I, B] [23.Dreyling M. Lenz G. Hoster E. et al.Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network.Blood. 2005; 105: 2677-2684Crossref PubMed Scopus (470) Google Scholar, 24.Hoster E. Metzner B. Forstpointner R. et al.Autologous stem cell transplantation and addition of rituximab independently prolong response duration in advanced stage mantle cell lymphoma.Blood. 2009; 114 (ASH Annual Meeting Abstracts): 880Crossref Google Scholar] (Table 5).Table 5Published clinical studies investigating first-line dose-intensified therapy in mantle cell lymphomaAuthorStudy featuresEvaluable patientsTherapeutic regimenORR% (CR%)Median PFS (years)Median OS (years)Dropout rateTRMSecondary tumours rateASCT-based regimens Dreyling et al. [23.Dreyling M. Lenz G. Hoster E. et al.Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network.Blood. 2005; 105: 2677-2684Crossref PubMed Scopus (470) Google Scholar]Phase III, randomised122R-CHOP + TBI + ASCT versus R-CHOP + TBI + interferon-α98 (81) versus 99 (37)3.3 versus 1.4NR (83% 3-year OS) versus NR (77% 3-year OS)13% versus N/A5% versus 0%5% Hermine et al. [25.Hermine O. Hoster E. Walewski J. et al.Alternating courses of 3x CHOP and 3x DHAP plus rituximab followed by a high dose ARA-C containing myeloablative regimen and autologous stem cell transplantation (ASCT) increases overall survival when compared to 6 courses of CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: final analysis of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net).Blood. 2012; 120 (ASH Annual Meeting Abstracts): 151Google Scholar]Phase III, randomised455R-CHOP + TBI + ASCT versus R-CHOP/R-DHAP + HD-araC + ASCT98 (63) versus 99 (61)3.8 versus 7.36.8 versus NRN/A4%N/A Damon et al. [26.Damon L.E. Johnson J.L. Niedzwiecki D. et al.Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909.J Clin Oncol. 2009; 27: 6101-6108Crossref PubMed Scopus (166) Google Scholar]Phase II77R-CHOP + methotrexate + HD-araC/etoposide + ASCT88 (69)NR (56% 5-year PFS)NR (64% 5-year OS)13%3%N/A Van't Veer et al. [27.van 't Veer M.B. de Jong D. MacKenzie M. et al.High-dose Ara-C and beam with autograft rescue in R-CHOP responsive mantle cell lymphoma patients.Br J Haematol. 2009; 144: 524-530Crossref PubMed Scopus (55) Google Scholar]Phase II87R-CHOP + HD-araC + ASCT70 (64)NR (36% 4-year PFS)NR (66% 4-year OS)30%5%N/A Geisler et al. [28.Geisler C.H. Kolstad A. Laurell A. Nordic Lymphoma Group et al.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: 355-362Crossref PubMed Scopus (224) Google Scholar]Phase II160R-Maxi-CHOP + HD-araC + ASCT96 (54)7.4NR (64% 10-year OS)9%5%4% Delarue et al. [29.Delarue R. Haioun C. Ribrag V. et al.CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte.Blood. 2013; 121: 48-53Crossref PubMed Scopus (201) Google Scholar]Phase II60R-CHOP/R-DHAP + HD-araC + ASCT100 (96)6.9NR (75% 5-year OS)18%1.5%18% Touzeau et al. [30.Touzeau C. Leux C. Bouabdallah R. et al.Autologous stem cell transplantation in mantle cell lymphoma: a report from the SFGM-TC.Ann Hematol. 2014; 93: 233-242Crossref Scopus (14) Google Scholar]Retrospective396Different ASCT-based schedules83 (77)NR (67% 3-year PFS)NR (83% 3-year OS)N/A2.5%6%Non-ASCT-based regimens Romaguera et al. [31.Romaguera J.E. Fayad L. Rodriguez M.A. 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: 7013-7023Crossref PubMed Scopus (466) Google Scholar]Phase II, monocentric97R-Hyper-CVAD97 (87)4.6NR (64% 10-year OS)29%8%5% Merli et al. [32.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: 346-353Crossref PubMed Scopus (109) Google Scholar]Phase II, multicentric60R-Hyper-CVAD83 (72)NR (73% 5-year PFS)NR (61% 5-year OS)63%6.5%1.5% Bernstein et al. [33.Bernstein S.H. Epner E. Unger J.M. 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: 1587-1593Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar]Phase II, multicentric49R-Hyper-CVAD86 (55)4.86.839%2%4%R, rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; DHAP, dexamethasone, HD-araC, high dose Ara-C (cytarabine), Hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, anthracycline, dexamethasone; TBI, total body irradiation; ASCT, autologous stem-cell transplantation; NR, not reached; TRM, treatment-related mortality. Open table in a new tab R, rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; DHAP, dexamethasone, HD-araC, high dose Ara-C (cytarabine), Hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, anthracycline, dexamethasone; TBI, total body irradiation; ASCT, autologous stem-cell transplantation; NR, not reached; TRM, treatment-related mortality. In addition, a randomised trial confirmed that a cytarabine-containing induction achieves a significantly improved median time to treatment failure (P = 0.038) and a trend for median OS (P = 0.045) [I, B] [25.Hermine O. Hoster E. Walewski J. et al.Alternating courses of 3x CHOP and 3x DHAP plus rituximab followed by a high dose ARA-C containing myeloablative regimen and autologous stem cell transplantation (ASCT) increases overall survival when compared to 6 courses of CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: final analysis of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net).Blood. 2012; 120 (ASH Annual Meeting Abstracts): 151Google Scholar]. In contrast, an induction based on high-dose cytarabine alone achieves only insufficient response rates [III, D] [34.Laurell A. Kolstad A. Jerkeman M. et al.High dose cytarabine with rituximab is not enough in first-line treatment of mantle cell lymphoma with high proliferation: early closure of the Nordic Lymphoma Group Mantle Cell Lymphoma 5 trial.Leuk Lymphoma. 2014; 55: 1206-1208Crossref PubMed Scopus (17) Google Scholar]. Therefore, a rituximab containing induction of CHOP and high dose Ara-C followed by high dose consolidation and ASCT is recommended. In a retrospective study comparison of the Nordic, HOVON and MCL younger protocols, total body irradiation (TBI) before ASCT was confirmed to be beneficial only in partial response (PR) patients [II, B] [35.Hoster E. Geisler G.H. Doorduijn J.K. et al.Role of high-dose cytarabine and total body irradiation conditioning before autologous stem cell transplantation in mantle cell lymphoma—a comparison of Nordic MCL2, HOVON 45, and European MCL Younger Trials.Blood. 2013; 122 (ASH Annual Meeting Abstracts): 3367Crossref Google Scholar]. In contrast, the benefit of RIT has not been demonstrated in inter-study comparisons. An upfront, dose-intensified approach (R-Hyper-CVAD, rituximab in combination with fractionated cyclophosphamide, vincristine, anthracycline and dexamethasone) with alternating high-dose methotrexate/cytarabine cycles also achieved very high response and survival rates in phase II studies, but its feasibility is hampered by a significant therapy-associated toxicity [II, C] [31.Romaguera J.E. Fayad L. Rodriguez M.A. 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: 7013-7023Crossref PubMed Scopus (466) Google Scholar, 32.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: 346-353Crossref PubMed Scopus (109) Google Scholar, 33.Bernstein S.H. Epner E. Unger J.M. 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: 1587-1593Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar]. The role of rituximab and lenalidomide maintenance after autologous transplantation is currently being investigated by the randomised LyMa [36.Le Gouill S. Callanan M. Macintyre E. et al.Clinical, metabolic and molecular responses after 4 courses of R-DHAP and after autologous stem cell transplantation for untreated mantle cell lymphoma patients included in the LyMa trial, a Lysa study.Blood. 2012;
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