Bortezomib in mantle cell lymphoma: comparative therapeutic outcomes

Figures & data

Table 1 Induction therapy trials (excluding bortezomib) for mantle cell lymphoma listed in the order of age of patients at enrollment

Study type	Induction therapy	Consolidation	Age	N	Median OS	Median PFS	ORR (%)	CR (%)
Phase III^Citation69	R-CHOP vs R-CHOP	TBI + ASCT vs TBI + interferon-α	≤65	62 vs 60	83% at 3 y vs 77% at 3 y	3.3 y vs 1.4 y	98 vs 99	81 vs 37
Phase II^Citation70,a	R-CHOP + HD-AraC	ASCT	≤65	87	66% at 4 y	36% at 4 y (PFS)	70	64
Phase II^Citation71	R-Maxi-CHOP alternating with R + HD-AraC	BEAM or BEAC ASCT	≤65	160	58% at 10 y	7.4 y (EFS)	96	54
Phase III^Citation15	R-CHOP vs R-CHOP/R-DHAP + HD-AraC	Dexa BEAM ASCT vs ASCT	≤65	455	6.8 y vs NR*	3.8 y vs 7.3 y	98 vs 97	63 vs 61
Phase II^Citation17	R-HyperCVAD	–	≤66	60	73% at 5 y	61% at 5 y	83	72
Phase II^Citation72	R-CHOP/R-DHAP + HD-AraC	TAM6 or BEAM ASCT	≤66	60	75% at 5 y	6.9 y (EFS)	100	96
Phase II^Citation67	R-CHOP + methotrexate + HD-AraC/etoposide	ASCT	≤69	77	64% at 5 y	56% at 5 y	88	69
Phase II^Citation18	R-HyperCVAD	–	<70	49	6.8 y	4.8 y	86	55
Phase II^Citation22	R-Cbl		≤74	14	2.1 y	15 m	64	36
Phase III^Citation14,b	R-CHOP vs CHOP		≤78	112	76% vs 76% at 2 y	21 m (TTF) vs 14 m* (TTF)	94 vs 75*	34 vs 7*
Phase II^Citation73	R-HyperCVAD	–	≤80	97	82% at 3 y	64% at 3 y	97	87
Phase III^Citation19	R-CHOP vs R-B		≤83	94	NR vs NR	22.1 m vs 35.4 m	91 vs 93	30 vs 40
Phase II^Citation23	R-Cbl		≤84	20	95% 3 y	84% 3 y	95	90
Phase III^Citation20	R-CHOP/CVP vs R-B		≤86	74		–	85 vs 94	27 vs 50*
Phase II^Citation74	R-CDA		≤86	29	NR	43% 2 y	66	52
Phase III^Citation13	R-CHOP vs R-FC		60–87	485	62% at 4 y vs 47% at 4 y*	28 m (TTF) vs 26 m (TTF)	86 vs 78	34 vs 40

Notes:

* P<0.05,

a One patient of 66 years was included in the study because of good performance status;

b Patients ≤65 years of age who achieved a PR/CR underwent a second randomization to either myeloablative radiochemotherapy followed by ASCT or interferon-α maintenance.

Abbreviations: ASCT, autologous stem cell transplant; BEAM, BCNU, etoposide, cytarabine, melphalan; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; CR, complete response; EFS, event-free survival; HD-AraC, high-dose cytarabine; m, months; N, number of patients; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression free survival; R-Cbl, rituximab plus chlorambucil; R-CHOP, rituximab plus CHOP; R-DHAP, rituximab, dexamethasone, cytarabine, and cisplatin; R-HyperCVAD, rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine; TAM6, total body irradiation, cytarabine, and melphalan; TTF, time to treatment failure; y, years.

Table 2 Comparison of outcomes with approved monotherapies in MCL

Study type	Therapy	Dose	N	Median OS (months)	Median PFS (months)	ORR (%)	CR/CRu (%)	PR (%)
Phase II^Citation29	Bortezomib	1.3 mg/m^2, days 1, 4, 8, 11, every 21 days	155	23.5	6.5	32	8	24
Phase II^Citation30	Lenalidomide	25 mg/day PO on days 1–21 of a 28-day cycle	134	19	4	28	8	20
Phase II^Citation27	Ibrutinib	560 mg/day	111	NR, 58% at 18 m	14	68	21	47
Phase III^Citation31	Temsirolimus	175 mg weekly for 3 weeks followed by 75 mg weekly	54	13	5	22	2	20
		175 mg weekly for 3 weeks followed by 25 mg weekly	54	10	3	6	0	6

Abbreviations: CR, complete response; CRu, complete response unconfirmed; m, months; N, evaluable patients; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression free survival; PO, per oral; PR, partial response.

Table 3 Phase II trials with bortezomib in relapsed/refractory MCL

Study type	Therapy	Dose of bortezomiba	N	Median OS (months)	Median PFS (months)	ORR (%)	CR/CRu (%)
Phase II^Citation29	V	1.3 mg/m^2; up to 17 cycles	155	23.5	6.5	32	8
Phase II^Citation45	V with rituximab	1.3–1.5 mg/m^2; 5 cycles	14	–	2	29	29
Phase II^Citation51	V	1.5 mg/m^2,b	10	–	–	50	10
Phase II^Citation52	V	1.5 mg/m^2; 6 cycles	29	–	–	41	21
Phase II^Citation53	V	1.3 mg/m^2,c	15	–	–	47	7
Phase II^Citation54	V with gemcitabine	1.0 mg/m^2 IVc	25	–	11	60	12
Phase II^Citation56	V with bendamustine and rituximab	1.3 mg/m^2; 6 cycles	7	–	–	71	–
Phase II^Citation55	VRD	1.3 mg/m^2; 6 cycles	16	37	12	81	44
Phase II^Citation75	Temsirolimus and bortezomib	Days 1, 8, 15, and 22 of a 35 day cycle; up to 6 cycles	7	–	7.5	57	43

Notes:

a Administered intravenously on days 1, 4, 8, and 11 of a 21-day cycle, unless stated otherwise.

b Cycles were continued until unacceptable toxicity or two cycles after achieving CR.

c At least two cycles after CR or stable PR, four cycles after stable disease or until progressive disease.

Abbreviations: CR, complete response; CRu, complete response unconfirmed; D, dexamethasone; N, evaluable patients; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R, rituximab; V, bortezomib; VRD, bortezomib, rituximab, dexamethasone; y, years.

Table 4 Phase II and III trials in newly diagnosed MCL

Study type	Therapy	N	Median OS	Median PFS	ORR (%)	CR/CRu (%)	PR (%)
Phase III^Citation21 (LYM-3002)	R-CHOP vs VR-CAP	244 vs 243	56.3 m vs NR	14.4 m vs 24.7 m*	89 vs 92	42 vs 53*	–
Phase II^Citation53	V	13	–	–	46.2	0	46.2
Phase II^Citation58	VR-CHOP	36	86% at 2 y	23 m	81	64	–
Phase II^Citation62	VcR-CVAD with ASCT or MR	30	86% at 3 y	63% at 3 y	90	70	13
Phase II^Citation64	VcR-CVAD with MR	75	88% at 3 y	72% at 3 y	95	68	–
Phase II^Citation65	RiPAD + C	39	NR	26 m	79	59
Phase II^Citation66 (S0601)	VR-CHOP followed by 2-year	65	85% at 2 y	62% at 2 y	–	–	–
	V maintenance

Note:

* P<0.05.

Abbreviations: CAP, cyclophosphamide, doxorubicin, prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; CRu, complete response unconfirmed; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; m, months; MR, maintenance rituximab; N, evaluable patients; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R, rituximab; RiPAD + C, rituximab, bortezomib, doxorubicin, dexamethasone, cyclophosphamide; V, bortezomib; VR or VcR-bortezomib, rituximab; y, years.

Table 5 Ongoing trials of bortezomib in mantle cell lymphoma

Phase	Identifier	Patient population	Therapy
I	NCT00671112	R/R	Everolimus and bortezomib
I	NCT01111188	R/R	Palbociclib plus bortezomib
I	NCT01695941	R/R	Alisertib, bortezomib, and rituximab
I/II	NCT02356458	R/R	Ibrutinib and bortezomib
I/II	NCT01439750	TN and R/R	Bortezomib, cladribine, and rituximab
I/II	NCT01322776	R/R	Bortezomib, fludarabine, and cyclophosphamide
II	NCT00114738	TN	EPOCH-R ± bortezomib
II	NCT01267812	Post ASCT	Weekly maintenance bortezomib and rituximab
II	NCT01415752	TN	Rituximab, bendamustine, and bortezomib followed by rituximab and lenalidomide
II	NCT00992446	Post ASCT	Bortezomib and vorinostat as maintenance therapy
II	NCT01457144	TN	Rituximab, bortezomib, bendamustine, and dexamethasone (RiBVD)
III	NCT01449344	R/R	Rituximab, cytarabine, dexamethasone, and bortezomib

Abbreviations: ASCT, autologous stem cell transplant; EPOCH-R, prednisone, etoposide, doxorubicin, vincristine, and rituximab; R/R, relapsed/refractory; TN, treatment naive.

DreylingMLenzGHosterEEarly 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 NetworkBlood200510572677268415591112

 PubMed Web of Science ®Google Scholar

van ‘t VeerMBde JongDMacKenzieMHigh-dose Ara-C and beam with autograft rescue in R-CHOP responsive mantle cell lymphoma patientsBr J Haematol2009144452453019036081

 PubMed Web of Science ®Google Scholar

GeislerCHKolstadALaurellANordic Lymphoma GroupLong-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma GroupBlood200811272687269318625886

 PubMed Web of Science ®Google Scholar

HermineOHosterEWalewskiJAlternating courses of 3× CHOP and 3× 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)ASH Annu Meet Abstr201212021151

 Google Scholar

MerliFLuminariSIlariucciFRituximab 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 LinfomiBr J Haematol2012156334635322145911

 PubMed Web of Science ®Google Scholar

DelarueRHaiounCRibragVGroupe d’Etude des Lymphomes de l’Adulte (GELA)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’AdulteBlood20131211485322718839

 PubMed Web of Science ®Google Scholar

DamonLEJohnsonJLNiedzwieckiDImmunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909J Clin Oncol200927366101610819917845

 PubMed Web of Science ®Google Scholar

BernsteinSHEpnerEUngerJMA phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213Ann Oncol20132461587159323504948

 PubMed Web of Science ®Google Scholar

BauwensDMaerevoetMMichauxLActivity and safety of combined rituximab with chlorambucil in patients with mantle cell lymphomaBr J Haematol2005131333834016225653

 PubMed Web of Science ®Google Scholar

LenzGDreylingMHosterEImmunochemotherapy 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 Oncol20052391984199215668467

 PubMed Web of Science ®Google Scholar

RomagueraJEFayadLRodriguezMAHigh 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 cytarabineJ Clin Oncol200523287013702316145068

 PubMed Web of Science ®Google Scholar

RummelMJNiederleNMaschmeyerGStudy Group Indolent Lymphomas (STIL)Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trialLancet201338198731203121023433739

 PubMed Web of Science ®Google Scholar

SachanasSPangalisGAVassilakopoulosTPCombination of rituximab with chlorambucil as first line treatment in patients with mantle cell lymphoma: a highly effective regimenLeuk Lymphoma201152338739321133713

 PubMedGoogle Scholar

FlinnIWvan der JagtRKahlBSRandomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT studyBlood2014123192944295224591201

 PubMed Web of Science ®Google Scholar

InwardsDJFishkinPAHillmanDWLong-term results of the treatment of patients with mantle cell lymphoma with cladribine (2-CDA) alone (95-80-53) or 2-CDA and rituximab (N0189) in the North central cancer treatment groupCancer2008113110811618470909

 PubMed Web of Science ®Google Scholar

Kluin-NelemansHCHosterEHermineOTreatment of older patients with mantle-cell lymphomaN Engl J Med2012367652053122873532

 PubMed Web of Science ®Google Scholar

GoyABernsteinSHKahlBSBortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE studyAnn Oncol200920352052519074748

 PubMed Web of Science ®Google Scholar

GoyASinhaRWilliamsMESingle-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) studyJ Clin Oncol201331293688369524002500

 PubMed Web of Science ®Google Scholar

WangMLRuleSMartinPTargeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphomaN Engl J Med2013369650751623782157

 PubMed Web of Science ®Google Scholar

HessGHerbrechtRRomagueraJPhase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphomaJ Clin Oncol200927233822382919581539

 PubMed Web of Science ®Google Scholar

BaiocchiRAAlinariLLustbergMEPhase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphomaCancer2011117112442245124048792

 PubMed Web of Science ®Google Scholar

O’ConnorOAWrightJMoskowitzCPhase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphomaJ Clin Oncol200523467668415613699

 PubMed Web of Science ®Google Scholar

GoyAYounesAMcLaughlinPPhase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphomaJ Clin Oncol200523466767515613697

 PubMed Web of Science ®Google Scholar

BelchAKouroukisCTCrumpMA phase II study of bortezomib in mantle cell lymphoma: the national cancer institute of Canada clinical trials group trial IND.150Ann Oncol200718111612116971665

 PubMed Web of Science ®Google Scholar

KouroukisCTFernandezLACrumpMA phase II study of bortezomib and gemcitabine in relapsed mantle cell lymphoma from the national cancer institute of Canada clinical trials group (IND 172)Leuk Lymphoma201152339439921323520

 PubMed Web of Science ®Google Scholar

FriedbergJWVoseJMKellyJLThe combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphomaBlood2011117102807281221239695

 PubMed Web of Science ®Google Scholar

LammWKaufmannHRadererMBortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphomaHaematologica20119671008101421486866

 PubMed Web of Science ®Google Scholar

FenskeTSShahNMKimKMA phase 2 study of weekly temsirolimus and bortezomib for relapsed or refractory B-cell non-Hodgkin lymphoma: a Wisconsin oncology network studyCancer2015121193465347126079295

 PubMed Web of Science ®Google Scholar

RobakTHuangHJinJLYM-3002 InvestigatorsBortezomib-based therapy for newly diagnosed mantle-cell lymphomaN Engl J Med20153721094495325738670

 PubMed Web of Science ®Google Scholar

RuanJMartinPFurmanRRBortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphomaJ Clin Oncol201129669069721189393

 PubMed Web of Science ®Google Scholar

ChangJEPetersonCChoiSVcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin oncology network studyBr J Haematol2011155219019721848883

 PubMed Web of Science ®Google Scholar

ChangJELiHSmithMRPhase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern cooperative oncology group study (E1405)Blood2014123111665167324458437

 PubMed Web of Science ®Google Scholar

HouotRLe GouillSOjeda UribeMFrench GOELAMS GroupCombination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMSAnn Oncol20122361555156122012966

 PubMed Web of Science ®Google Scholar

TillBGLiHBernsteinSHPhase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for previously untreated mantle cell lymphoma: SWOG 0601ASH Annu Meet201412421149

 Google Scholar