Supplemental Table 1: Conventional therapy * = sentinel articles

Publication / Intervention / Population assessed / Type of study / Dosing and schedule / Outcomes assessed / Results / Comments
Aggressive therapy
* / Delarue, et al, Blood prepublished online June 20, 2012 / CHOP and DHAP plus R f/b autologous SCT / Stage III-IV MCL / Phase II / 3 cycles CHOP every 21 d, R 375mg/m2 with third cycle, f/b 3 cycles R-DHAP every 21 d, responders received PBSCT harvest, radiochemotherapy with TBI and HD cytarabine and melphalan f/b autologous SCT / EFS, 5 y OS / 60 patients, ORR 95% 5y, median EFS 83.9m, prob of 5y EFS 64%, median DFS 78m, PFS 84m, median OS not reached, OS 75%. 49 patients underwent SCT. Of patients who underwent SCT, 96% had CR / Cytarabine-based therapy has high RR. Improved EFS vs other studies without R, excluded patients with high mitotic count, 11 secondary malignancies likely due to MCL rather than therapy
Hermine, et al, ASH annual meeting abstracts 2010 116: #110 / CHOP vs CHOP and DHAP plus R f/b HD ara-c myeloablative chemo and autologous SCT / Previously untreated stage II-IV MCL up to 65 yoa / Phase III / Standard R-CHOP x6 f/b myeloablative radiochemotherapy and ASCT (arm A) vs alternating CHOP x3 and DHAP x3 + R f/b high dose ARA-C myeloablation and ASCT (arm B) / CR, DR, TTF, 3y OS / 497 patients, CR/Cru 41% arm A vs 60% arm B (p=0.0003), OR after transplant 97% in both arms, TTF 49m arm A vs NR arm B (p=0.0384), RD after ASCT 51m arm A vs NR arm (p=0.077), 3y OS 79% arm A vs 80% arm B / DHAP led to improved CR, DR, TTF, equivalent OS. Authors recommend ara-c induction f/b ASCT as new SOC in patients <65 yoa, increased grade 3/4 hematologic toxicity in arm B not clinically relevant
LaCasce, et al ASH annual meeting abstracts 2009 114: #403 / R-CHOP f/b HD therapy and ASCT vs R-hyperCVAD vs RCHOP alone / Previously untreated MCL / Phase III / 3y PFS, OS / 156 patients, no difference in PFS between R-hyper-CVAD and R-CHOP f/b ASCT. R-CHOP alone had poorer PFS than both other arms (p=0.001). no differences in OS. Median PFS 3 years / Authors recommend focusing on novel agents for future trials
* / Romaguera et al, Br J Haematol 2010 15:200-208; Romatuera et al, JCO 2005 23(28) 7013-7023 / R-hyperCVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone), alternating with R-MA (HD methotrexate and cytarabine) / Previously untreated MCL / Phase II / Cycles 1, 3, 5, 7 rituximab 375mg/m2, cyclophosphamide 300mg/m2 IV q12h x6 d2-4, doxorubicin 16.6mg/m2 IVCI 72h d 5-7, vincristine 1.4mg/m2 IV d5 and 12, dexamethasone 40mg d 2-5 and d12-15, cycles 2, 4, 6, 8 rituximab 375mg/m2 d1, methotrexate 200mg/m2 IV d2, methotrexate800mg/m2 IVCI 22h d2, cytarabine 3000 mg/m2 q12h x4 d3-4 / Median OS, TTF / 10 year f/u. 97 patients, 87% CR, median OS not reached, median TTF 4.6y, / Beta2 microglobulin, IPI, MIPI were predictive of OS, Ki-67 was not predictive. Significantly worse OS and TTF if age >65, increase hematologic toxicity with age
Lenz, et al, JCO 2005 23(9), 1984-1992 / CHOP vs R-CHOP, randomized to myeloablative chemo f/b autologous SCT vs IFN maintenance / Previously untreated MCL / Phase III / Standard CHOP every 21 d +/- rituximab 375mg/m2 on day 0 / ORR, CR, TTF / 122 patients, ORR 94% R-CHOP vs 75% CHOP (p=0.0054), CRR 34% vs 7% (p=0.00024), TTF 21m vs 14m (p=0.0131), no difference between auto SCT and IFN maintenance groups / Defines R-CHOP as superior to CHOP in MCL
Dreyling et al, Blood 2005 107(7): 2677 / Myeloablative radiochemotherapy f/b auto SCT in first remisison / Previously untreated MCL / Phase III / CHOP fb either IFN-alpha or myeloablative radiochemotherapy and auto SCT / PFS, 3y OS / 122 patients, ASCT arm had longer PFS 39m vs 17m (p=0.0108). 3y OS 83% ASCT vs 77% IFN (p=0.18)
Shea, et al, Biol Blood Marrow Transplant, 2011 17(9):1395-1403 / Reduced intensity allogeneic SCT / Advanced indolent B cell malignancies / Phase II / Cyclosphosphamide 1g/m2/d d1-3, fludarabine 25mg/m2/d x5, allogeneic SCT / EFS, OS / 44 patients, 4 with MCL. 6m TRM 2.4%, 3y TRM 9%. 3y EFS and OS in MCL and indolent B cell patients were 55% and 64%, / Grade II-IV aGVHD 29%, extensive chronic GVHD 18%
Elderly/nontransplant eligible / Robinson, et al, JCO 2008 26(27):4473-4479 / Bendamustine + R / R/R indolent B-cell and MCL NHL / Phase II / Rituximab 375mg/m2 d1, bendamustine 90mg/m2 d2, 3 of 28d cycle for 4-6 cycles with R one week before cycle 1 and 1m after last cycle / ORR, DR, PFS / 12 patients with MCL ORR 92%, median DR 19m / 36% grade 3 or 4 neutropenia, 9% grade 3 or 4 thrombocytopenia, good ORR even in patients with prior R exposure
* / Rummel et al, ASCO annual meeting abstract 2012: #3; Rummel et al, ASH annual abstract 2009, 114: #405 / Bendamustine + R vs R-CHOP / Upfront indolent and MCL / Phase III / Rituximab 375mg/m2 d1 plus either bendamustine 90mg/m2 days 1, 2 every 28 days or standard CHOP every 21d, max 6 cycles / PFS, OS / 514 patients, B-R improved PFS vs R-CHOP, median 69.5m vs 31.2m (p<0.001), no difference in OS between two groups / Less toxicity in B-R than R-CHOP, equivalent secondary malignancies in two groups
Forstpointner, et al, Blood 2006 108: 4003-4008 / FCM +/-R +/- maintenance rituximab / R/R Follicular and MCL / Phase III / R maintenance 375mg/m2 weekly for 4 weeks, two courses of R at 3 and 9 months after completion of R-FCM / DR / 26m f/u, 319 patients, 56 with MCL. In MCL group no improvement in DR, but increase percentage with prolonged remission / Consider in patients with good response to R with induction
* / Kluin-Nelemans ASH annual meeting abstracts 2011 118: #439 / R-CHOP vs R-FC f/b maintenance R vs IFN-alpha / Elderly MCL, not transplant eligible / Phase III / Standard R-CHOP x8 cycles vs R-FC (rituximab 375mg/m2 d1, fludarabine 30mg/m2, cyclophosphamide 250mg/m2 IV both day 1-3) x6 cycles, responders received maintenance R one dose q2m vs IFN-alpha until progression / PRR, OS, DR / 560 patients, median age 70y, ORR lower with R-FC 78% vs 87% (p=0.0508), median OS inferior with R-FC (40vs 64m p=0.0072). increased DR with MR vs IFN (4y 57% vs 26%, p=0.0109), significant OS advantage in R-CHOP with MR vs IFN (4y OS 87% vs 57%, p=0.0061) / Worse outcomes with worse toxicity in R-FC vs R-CHOP. Authors recommend R-CHOP with R maintenance as new SOC in elderly
Kahl et al, Ann Oncol 2006, 17:1418-1423 / Maintenance R following modified hyperCVAD / Mostly stage IV, previously untreated MCL / Phase II / Rituximab 375mg/m2 d1 (except cycle 1), cyclophosphamide 300mg/m2 q12 d1-3, doxorubicin 25mg/m2/d d1-2, vincristine 2mg IV d3, dexamethasone 40mg po d 1-4, every 28d for 4-6 cycles. Responders received rituximab 375mg/m2 weekly x4 every 6m for 2 years / OR / 22 patients, OR 77%, CR 64%, median PFS 37m, median OS not reached / Study authors eliminated second dose of vincristine/dexamethasone due to toxicity/deaths
* / Kluin-Nelemans, et al, NEJM 2012 / R-FC or R-CHOP, with either R maintenance or IFN-alpha / MCL age >/=60, ineligible for high dose therapy / Phase III / R-FC every 28 days up to 6 cycles, or R-CHOP every 21 days up to 8 cycles, / 532 in intention-to-treat analysis. Similar CR for R-FC and R-CHOP (40% vs 34%), increased PD with R-FC (14% vs 5%). OS better with RCHOP (62% 4yr OS vs 47% p=0.005), 316 received maintenance R, RRR of progression or death of 45% (p=0.01), maintenance R improved OS in R-CHOP group (4yr OS 87% vs 63% with IFN-alpha p=0.005) / Equivalent grade 3-4 hematologic toxicity. In elderly, R-CHOP f/b maintenance R is effective.
* / Chang et al, Br J Haematol 2011 155(2): 190-197; Kahl et al, ASH annual abstract 2009 114: #1661 / Modified R-hyperCVAD with bortezomib with maintenance rituximab / Previously untreated MCL / Phase II / VcR-CVAD (bortezomib, rituimab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) every 21d for 6 cycles, if PR, consolidation R 375mg/m2 x4 weekly doses and maintenance R, 375mg/m2 every 12 weeks x20 doses / OR, CR, 3y PFS and OS / 30 patients, 77% with CR, median f/u 42m, 3y PFS 63%, 3y OS 86% / E1405 cooperative group trial is ongoing with same regimen
Martin, et al, JCO 2009 27(8):1209-13 / Watch and wait / MCL / Retrospective analysis / n/a / Survival / 97 patients, 31 in observation arm, median TTFT 12m, median survival not reached in obs arm vs 64m in treatment arm (p=0.004), obs patients had better PS, lower standard IPI
Relapsed/refractory / Forstpointner, et al, Blood, 2004 104(10):3064 / R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone) / R/R follicular and mantle cell lymphoma in patients who had received CHOP / Phase III / Fludarabine 25mg/m2 on d 1-3, cyclophosphamide 200mg/m2 d1-3, mitoxantrone 8mg/m2 d1 of 28d cycle for 4 cycles with or without rituximab 375mg/m2 on d0 / CR, OS / 147 patients, 52 with MCL. Median obs time 18m, ORR 58% in MCL with R-FCM vs 46% with FCM, median PFS 8m for R-FCM vs 4m FCM, median OS not reached for R-FCM, was 11m for FCM
Cohen, et al, Leukemia and Lymphoma, 2001 42(5) 1015-1022 / Cyclophosfamide/fludarabine
Inwards, et al, Cancer 2008 113(1):108-116 / Cladribine +/- R / Newly diagnosed or R/R MCL, older patients / Two phase II studies, coalesced data / 2-CDA 5mg/m2 IV d1-5 every 28d, / RR, PFS, 2y OS / 51 received 2-CDA alone: ORR 81%, median PFS 13.5m, 2y OS 81%. 29 received 2-CDA +R: ORR 66%, median DR not achieved, median f/u 21.5m / Well-tolerated, may increase difficulty of SCT harvest
Rummel et al, Ann Oncol 1999 10:115-117 / 2-CDA alone / Newly diagnosed or R/R MCL / ORR 58%
Herold J, et al Cancer Res Clin Oncol 2006 132:105-112 / Bendamustine, vincristine and prednisone vs cyclophosphamide, vincristine and prednisone / Adavanced indolent NHL and MCL / Phase III / Vincristine 2mg d1, prednisone 100mg/m2 d1-5 with either bendamustine 60mg/m2 d1-5 or cyclophosphamide 400mg/m2 d1-5 in 21d cycles x8 / TTP, PFS, 5y OS / 5y OS 61% BOP vs 46% COP, in responders 74% vs 56% (p=0.05) / BOP = improved 5 y survival, can be used in younger population, similar toxicity profile with BOP and COP