Barr, Paul M.

Chen, Robert W.

Fenske, Timothy S.

Friedberg, Jonathan W.

Kahl, Brad S.

Kamdar, Manali

Leblanc, Michael L.

Leonard, John P.

Li, Hongli

Phillips, Tycel J.

Rimsza, Lisa M.

Shea, Thomas C.

Smith, Sonali M.

English

Digital Commons@Becker

Washington University School of Medicine Digital Commons@Becker Open Access Publications 2019 Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma Manali Kamdar Hongli Li Robert W. Chen Lisa M. Rimsza Michael L. Leblanc See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors Manali Kamdar, Hongli Li, Robert W. Chen, Lisa M. Rimsza, Michael L. Leblanc, Timothy S. Fenske, Thomas C. Shea, Paul M. Barr, Tycel J. Phillips, John P. Leonard, Brad S. Kahl, Jonathan W. Friedberg, and Sonali M. Smith STIMULUS REPORTFive-year outcomes of the S1106 study of R-hyper-CVAD vsR-bendamustine in transplant-eligible patients withmantle cell lymphomaManali Kamdar,1 Hongli Li,2 Robert W. Chen,3 Lisa M. Rimsza,4 Michael L. Leblanc,2 Timothy S. Fenske,5 Thomas C. Shea,6 Paul M. Barr,7Tycel J. Phillips,8 John P. Leonard,9 Brad S. Kahl,10 Jonathan W. Friedberg,11 and Sonali M. Smith121Division of Hematology, Department of Medicine, University of Colorado School of Medicine, Denver, CO; 2SWOG Statistical Center, Fred Hutchinson Cancer ResearchCenter, Seattle, WA; 3Department of Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, CA; 4Department of Laboratory Medicine and Pathology, MayoClinic, Phoenix, AZ; 5Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI; 6Division of Hematology/Oncology, University of North Carolina atChapel Hill, Chapel Hill, NC; 7James P. Wilmot Cancer Center, Division of Hematology and Oncology, University of Rochester, Rochester, NY; 8Division of Hematology andOncology, University of Michigan Cancer Center, Dexter, MI; 9Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY; 10Department of Medicine,Washington University School of Medicine, St. Louis, MO; 11Wilmot Cancer Institute, University of Rochester, Rochester, NY; and 12Section of Hematology/Oncology,University of Chicago, Chicago, ILKey Points• Five-year follow-up ofS1106 demonstratessimilar efficacy, MRDnegativity, and 5-yearsurvival with RH or RB,but RH was more toxicthan RB.• RB showed excellentefficacy and survivaland less toxicity com-pared with a cytara-bine-based regimen intransplant-eligible MCLpatients.IntroductionAggressive induction chemoimmunotherapy followed by high-dose chemotherapy and autologous stemcell transplant (ASCT) is a standard option for the initial management of transplant-eligible mantle celllymphoma (MCL).1-3 However, the optimal induction regimen before ASCT is unknown. Cytarabine-based induction achieves excellent response rates and higher rates of minimal residual disease (MRD)negativity compared with anthracycline-based induction regimens.4-6 While effective, most cytarabine-based induction regimens require inpatient hospitalization and are associated with significanthematologic and nonhematologic toxicities.4-6 Rituximab-bendamustine (RB) is a less intensive,outpatient-based chemoimmunotherapy regimen with excellent long-term efficacy and good tolerabilityin transplant-ineligible MCL patients.7-9 However, its role as a pretransplant induction strategy has notbeen formerly evaluated.S1106 is a randomized phase 2 multi-institutional clinical trial comparing induction R-hyper-CVAD(rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) andmethotrexate/cytarabine (RH) with RB followed by ASCT in newly diagnosed MCL patients. Wepreviously reported that the 2-year progression-free survival (PFS) and overall survival (OS) were similarwith either regimen. However, RH was more toxic than RB, had higher stem cell mobilization failure rates,and prompted protocol-specified early study closure.10 While premature closure limited the sample size,we demonstrated for the first time in a prospective setting that outpatient RB treatment can achieveexcellent MRD negativity and could serve as an induction strategy worthy of further study. Given theincreased survival of MCL patients,2 critical assessment of long-term efficacy and toxicity is needed.Here, we report the 5-year follow-up (FU) of the S1106 study.MethodsThe study design, eligibility criteria, and statistical analyses have been previously published.10Untreated MCL patients with stage III, IV, or bulky stage II MCL were randomized to 4 cycles of RHor 6 cycles of RB followed by ASCT. Patients achieving complete response (CR) or partial responseat restaging11 were eligible to proceed to ASCT. A minimum of 1.5 3 106 CD341 cells/kg stemcells were required to proceed with ASCT. MRD was assessed at baseline and after induction on 12paired serial samples (2 RH and 10 RB) (Adaptive Biotechnologies). The primary end point of thetrial was 2-year PFS. Secondary end points were overall response rates (ORRs), CR rate, overallsurvival (OS), toxicity, and MRD status. To minimize selection bias, a non-preplanned 5-yearlandmark analysis was performed from 3 months after registration for the RH arm and from 6 monthsSubmitted 31 May 2019; accepted 14 September 2019. DOI 10.1182/bloodadvances.2019000526.Presented at the 60th annual meeting of the American Society of Hematology,San Diego, CA, 1 December 2018.© 2019 by The American Society of Hematology3132 22 OCTOBER 2019 x VOLUME 3, NUMBER 20Downloaded from https://ashpublications.org/bloodadvances/article-pdf/3/20/3132/1502745/advancesadv2019000526.pdf by WASHINGTON UNIVERSITY SCHOOL user on 07 November 2019after registration for the RB arm. The 5-year landmark analysiswas used for comparing survival between transplanted andnontransplanted patients.10This randomized phase 2 study was conducted by the SouthwestOncology Group (SWOG) through the National Clinical TrialsNetwork adult groups (SWOG/Eastern Cooperative OncologyGroup/American College of Radiology Imaging Network alliance)mechanism. Patients were recruited from 4 January 2012 through21 June 2013. The study was approved by the institutional reviewboard at each study site, and written informed consent wasobtained from all patients prior to any study-specific procedures,per the Declaration of Helsinki. The study was approved andsponsored by the Cancer Therapy Evaluation Program (https://clinicaltrials.gov/ct2/show/NCT01412879).Results and discussionAmong 53 enrolled patients, 52 patients (17 RH and 35 RB) wereevaluable, with 1 patient not starting therapy. Baseline character-istics were similar, except that more female patients were in the RHgroup.10 Median age was 59 and 57 years in the RH and RB arms,respectively. More than 90% patients on both arms had stage IVextranodal disease and bone marrow involvement. Approximately20% of patients had a Ki67 index .30%, and 35% had anintermediate/high MCL international prognostic index score in eacharm. A total of 9 out of 17 patients (5 patients on protocol and 4 offprotocol) in the RH arm and 23 out of 35 patients (21 patients onprotocol and 2 off protocol) in the RB arm underwent ASCT. Thereasons for discontinuation/stopping before ASCT have beenpreviously published. Most discontinuations in the RH arm were dueto the inability to collect stem cells (n 5 5) and cytopenias (n 5 6),whereas in the RB arm, discontinuations were primarily due topatient choice (n 5 4).10Updated efficacy results with median FU of 5 years (range,29 days to 6 years) are detailed in Table 1. Updated ORR and CRrates were similar in both arms. As previously reported,10 the2-year PFS was 82% and 81% and the 2-year OS was 88% and87% in the RH and RB arms, respectively. The 5-year PFS was62% (95% CI, 34% to 81%) and 66% (95% CI, 45% to 80%) andthe 5-year OS was 74% (95% CI, 44% to 89%) and 80% (95%CI, 62% to 91%) for RH and RB, respectively (Figure 1). Anupdated landmark analysis at the 5-year mark with and withoutASCT in each arm was also performed (Table 1). In the RH arm,the 5-year landmark PFS estimate was 50% (95% CI, 15% to77%) vs 73% (95% CI, 28% to 93%) (P 5 .34) and the 5-yearlandmark OS was 75% (95% CI, 31% to 93%) vs 73% (95% CI:28% to 93%) (P 5 .81) for patients undergoing ASCT vs thosewho did not. In the RB arm, the 5-year landmark PFS estimateswere 70% (95% CI, 43% to 86%) vs 63% (95% CI, 23% to 86%)(P 5 .44) and the 5-year landmark OS was 91% (95% CI, 69%to 98%) vs 60% (95% CI, 20% to 85%) (P 5 .055) for patientsundergoing ASCT vs those who did not.MRD assessment was performed on 12 paired serial samples (2 RHand 10 RB). Both paired RH samples were MRD positive atbaseline, and both achieved MRD negativity after induction. In theRB group, 9 out of 10 samples were MRD positive at baseline, ofwhich 7 out of 9 (78%) achieved MRD negativity. Three patientswith missing MRD assessment at baseline had negative MRD levelsafter induction/before ASCT. The 5-year PFS and OS was 90%(95% CI, 47% to 99%) for all patients who achieved MRD-negativestatus at the end of RB induction.Of 52 evaluable patients, 10 have died (4 RH and 6 RB), mainlydue to disease progression (n 5 6). Other causes of deathinclude suicide (n5 1) in the RH arm and typhlitis (n5 1), 1 lungcancer (n 5 1), and an unknown cause (n 5 1) in the RBarm. Two patients developed second malignancies. In the RHarm, 1 patient who did not undergo ASCT was diagnosed withacute myelogenous leukemia at 5.4 years after diagnosis andremains alive. In the RB arm, 1 patient who underwent ASCTdeveloped lung cancer at 2.9 years after diagnosis andsubsequently died.Long-term results of this study continue to demonstrate excellentresponse rates, 5-year PFS, 5-year OS, and MRD negativity witheither RH or RB. However, RH was more toxic and had higher stemcell mobilization failure rates. RB as induction treatment beforeASCT yielded high response rates, with an ORR of 86% (95%CI, 70% to 95%) and CR of 43% (95% CI, 26% to 61%), anddemonstrated excellent tolerability as well as durable remissions,with a 5-year PFS of 66% and 5-year OS of 80%. As previ-ously published,10 the benefit of ASCT was more pronounced inthe RB arm. The updated 5-year landmark OS estimates continueto suggest that the ASCT benefit is greater in patients receivingTable 1. Updated response rates and survival analysisRH arm (n 5 17) RB arm (n 5 35)Updated response ratesORR (95% CI), % 94.1 (71.3-99.9) 85.7 (69.7-95.2)CR, n (%) 7 (41) 15 (43)PR, n (%) 9 (53) 15 (43)Not evaluable, n (%) 1 (6) 5 (14)ASCT, n (%) 9 (53) 23 (66)No ASCT, n (%) 8 (47) 12 (34)Median duration ofresponse (range), mo51.3 (8.7-67.4) 50.8 (2.3-64.4)ASCT 37.3 (8.7-64.4) 51.4 (6.3-64.4)No ASCT 52.5 (43.4-67.4) 31.2 (2.3-55.3)Landmark analysis5-y PFS ASCT vs no ASCT(95% CI), %50 (15-77) vs 73 (28-93)(P 5 .34)70 (43-86) vs 63% (23-86)(P 5 .44)5-y OS ASCT vs No ASCT(95% CI), %75 (31-93) vs 73 (28-93)(P 5 .81)91 (69-98) vs 60 (20-85)(P 5 .055)Survival analysis,% (95%CI)PFS2 y 82 (53-94) 81 (63-91)5 y 62 (34-81) 66 (45-80)OS2 y 88 (59-97) 87 (70-95)5 y 74 (44-89) 80 (62-91)The best clinical response was determined by investigators according to the RevisedResponse Criteria for Malignant Lymphoma.11CI, confidence interval; PR, partial response.22 OCTOBER 2019 x VOLUME 3, NUMBER 20 FIVE-YEAR SWOG S1106 STUDY OUTCOMES 3133Downloaded from https://ashpublications.org/bloodadvances/article-pdf/3/20/3132/1502745/advancesadv2019000526.pdf by WASHINGTON UNIVERSITY SCHOOL user on 07 November 2019induction RB, although the limited sample size precludes definitiveconclusions.Although the optimal induction regimen is unknown, cytarabine-based induction has been favored, including the Nordic regimen,LyMa protocol and the European MCL regimens. In randomizedsettings, the reason for improved outcomes with cytarabine-basedregimens may be the higher likelihood of achieving MRDnegativity.12 However, this comes with increased cytopeniasand frequent inpatient delivery of therapy. In our trial, the RHarm had significantly more grade 3/4 neutropenia, anemia, thrombo-cytopenia, and febrile neutropenia and is consistent with ratesreported with the Nordic and European MCL Network regimens. Theupdated analysis of our study demonstrated that RB inductionachieved a 5-year PFS of 66% and OS of 80% with MRD-negativityrates of 78%. These results are provocatively similar to intensivecytarabine-based induction therapy,4-6,12,13 albeit with decreasedhematologic toxicity and outpatient treatment.In conclusion, with 5 years of FU, S1106 shows excellentsurvival, with.70% patients alive and 60% patients disease-freein both arms. The comparison with RH is underpowered due toearly closure of this arm. Patients receiving RB induction hadexcellent 5-year PFS, OS, and MRD-negativity rates. Overall,S1106 demonstrated that an outpatient-based, less intensiveinduction therapy of bendamustine plus rituximab is highlyeffective, safe, and durable in untreated transplant-eligibleMCL patients. Our results have informed the design of a futureEastern Cooperative Oncology Group–led trial (EA4181) whereina bendamustine-based induction chemotherapy backbone isbeing tested with cytarabine and/or a BTK-inhibitor in untreatedMCL patients.AcknowledgmentsResearch reported in this publication was supported by the NationalCancer Institute of the National Institutes of Health under awardnumbersCA180888,CA180819,CA180821,CA180820,CA180838,CA189957, CA189821, CA189972, CA189953, CA180846,CA180835, CA189808, CA46368, and CA11083 and in part bySequenta, Inc. (Adaptive Biotechnologies).The content is solely the responsibility of the authors and doesnot necessarily represent the official views of the National Institutesof Health or Sequenta, Inc. (Adaptive Biotechnologies).AuthorshipContribution: R.W.C., H.L., M.L.L., J.W.F., and S.M.S. designed re-search; R.W.C., J.W.F., B.S.K., T.S.F., T.C.S., T.J.P., P.M.B., L.M.R.,and J.P.L. performed research; M.K. collected data; H.L. and M.L.L.performed statistical analysis; M.K., J.W.F., and S.M.S. wrote themanuscript; and all authors analyzed and interpreted data, andreviewed the manuscript.Conflict-of-interest disclosure: M.K. is on the speakers bureauof Seattle Genetics and has received consultancy fees Gen-entech, AstraZeneca, and Celgene. R.W.C. has received con-sultancy fees from Millennium Pharmaceuticals and researchfunding from Affimed; consultancy, honoraria, and speakers bu-reau fees and research funding from Seattle Genetics; consul-tancy fees and research funding from Pharmacyclics and Merck;and consultancy and speakers bureau fees and research fundingfrom Genentech. L.M.R. is an inventor on the patent for theLymph2Cx assay (NanoString). P.M.B. has received consultancyfees from Pharmacyclics, AbbVie, Gilead, Merck, Seattle Ge-netics, Genentech, Celgene, Verastem, TG Therapeutics, andJanssen. T.J.P. has received consultancy fees from Genentech,Seattle Genetics, Bayer, Gilead, and Pharmacyclics and re-search funding from AbbVie. J.P.L. has received consultancyfees from Sutro, Bayer, Gilead, AstraZeneca, Celgene, Merck,Morphosys, Beigene, Nordic Nanovector, Roche/Genentech,ADC Therapeutics, Sandoz, Karyopharm, Miltenyi, and AkceaTherapeutics. B.S.K. has received consultancy fees from SeattleGenetics, AstraZeneca, Gilead, AbbVie, Celgene, Acerta, CTI,Juno, ADC Therapeutics, and Genentech. J.W.F. has receivedhonoraria from Bayer. S.M.S. has received honoraria from Por-tola and consultancy fees from BMS. The remaining authorsdeclare no competing financial interests.ORCID profile: P.M.B., 0000-0002-9733-401X.Correspondence: Manali Kamdar, University of Colorado, 1665Aurora Ct, MSF754, Aurora, CO 80045; e-mail: manali.kamdar@ucdenver.edu.0# at Risk0%20%40%60%80%100%24Months after registration48 7235 2528 22 1120 017R-BendamustineR-HCVAD/MTX/Ara-C 1315 13N3517R-BendamustineR-HCVAD/MTX/Ara-C5-YearEstimate66%62%Events10695%Conf. Int.(45% - 80%)(34% - 81%)710 00# at Risk0%20%40%60%80%100%24Months after registration48 967235 2729 24 114 017R-BendamustineR-HCVAD/MTX/Ara-C 14271415 13N3517R-BendamustineR-HCVAD/MTX/Ara-C5-YearEstimate80%74%Events6495%Conf. Int.(62% - 91%)(44% - 89%)08 0A BFigure 1. Five-year PFS and OS. Five-year Kaplan-Meier PFS (A) and OS (B) curves. R, rituximab; R-HCVAD/MTX/Ara-C, rituximab plus hyperfractionated cyclophospha-mide, vincristine, doxorubicin, and dexamethasone) and methotrexate/cytarabine.3134 KAMDAR et al 22 OCTOBER 2019 x VOLUME 3, NUMBER 20Downloaded from https://ashpublications.org/bloodadvances/article-pdf/3/20/3132/1502745/advancesadv2019000526.pdf by WASHINGTON UNIVERSITY SCHOOL user on 07 November 2019References1. Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34(11):1256-1269.2. Epperla N, Hamadani M, Fenske TS, Costa LJ. Incidence and survival trends in mantle cell lymphoma. Br J Haematol. 2018;181(5):703-706.3. Zhou Y,Wang H, FangW, et al. Incidence trends of mantle cell lymphoma in the United States between 1992 and 2004.Cancer. 2008;113(4):791-798.4. Geisler CH, Kolstad A, Laurell A, et al; Nordic Lymphoma Group. Long-term progression-free survival of mantle cell lymphoma after intensive front-lineimmunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008;112(7):2687-2693.5. Hermine O, Hoster E, Walewski J, et al; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy beforeautologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3trial of the European Mantle Cell Lymphoma Network. Lancet. 2016;388(10044):565-575.6. Pott C, Hoster E, Delfau-Larue MH, et al. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma aftercombined immunochemotherapy: a European MCL intergroup study. Blood. 2010;115(16):3215-3223.7. Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab asfirst-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet.2013;381(9873):1203-1210.8. Flinn IW, van der Jagt R, Kahl B, et al. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustineplus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019;37(12):984-991.9. Rummel MJ, Maschmeyer G, Ganser A, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patientswith indolent lymphomas: Nine-year updated results from the StiL NHL1 study [abstract]. J Clin Oncol. 2017;35(suppl 15). Abstract 7501.10. Chen RW, Li H, Bernstein SH, et al. RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG StudyS1106. Br J Haematol. 2017;176(5):759-769.11. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J ClinOncol. 2007;25(5):579-586.12. Pott C, Schrader C, Gesk S, et al. Quantitative assessment of molecular remission after high-dose therapy with autologous stem cell transplantationpredicts long-term remission in mantle cell lymphoma. Blood. 2006;107(6):2271-2278.13. Le Gouill S, Thieblemont C, Oberic L, et al; LYSA Group. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med.2017;377(13):1250-1260.22 OCTOBER 2019 x VOLUME 3, NUMBER 20 FIVE-YEAR SWOG S1106 STUDY OUTCOMES 3135Downloaded from https://ashpublications.org/bloodadvances/article-pdf/3/20/3132/1502745/advancesadv2019000526.pdf by WASHINGTON UNIVERSITY SCHOOL user on 07 November 2019

Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma

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Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma

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