Background
Current and future approaches to relapsed/refractory MCL
Small molecule targeted therapies
BTK inhibitors
BTKi | NCT#/publication | Phase | Sample size [median f/up*] | Median lines of prior therapy | ORR% [CR%] | Median PFS (months) | % bleeding events [grade ≥ 3] | % A.fib [grade ≥ 3] |
---|---|---|---|---|---|---|---|---|
Ibrutinib | II | 111 [26.7] | 3 | 67 [23] | 13 | 59 [5] | 6 [5] | |
Ibrutinib | NCT01646021 [10] | III | 139a [20] | 2 | 72 [19] | 14.6 | 10 [8] | 4 [4] |
Acalabrutinib | II | 124 [15.2] | 2 | 81 [40] | 20 | 33 [2] | 0 [0] | |
Zanubrutinib | NCT02343120 [14] | Ib | 43b [10.3] | 1 | 90c [20] | 18 | 30.2 [7] | 4.7 [NP] |
Zanubrutinib | NCT03206970 [15] | II | 86 [9] | 2 | 84 [59] | NR | 4.7 [1.2] | 0 [0] |
LOXO-305 | NCT03740529 [16] | I | 8 [NP] | 3 | 37.5 [0] | NP | 11 [0] | 0 [0] |
ARQ-531 | NCT03162536 [17] | I | 1 [NP] | NP | NP | NP | NP | NP |
BCL2 inhibitors
Proteasome inhibitors
Non-cellular immune therapies
Lenalidomide
Monoclonal antibodies
Antibody-drug conjugates
Combination therapy
Combinations of individually active agents
Combination therapy | NCT#/publication | Phase | Sample size [median f/u*] | Median lines of prior therapy | ORR% [CR%] | Median PFS (months) | Grade ≥ 3 (%)a |
---|---|---|---|---|---|---|---|
Ibrutinib/rituximab | NCT01880567 [75] | II | 50 [16.5] | 3 | 88 [44] | NR | A.fib (12), renal and urinary disorder (6) |
Ibrutinib/ venetoclax | II | 23 [37.5] | 2 | 71 [62] | 29 | Diarrhea (12), soft tissue infection (8), lower respiratory tract infection (8) TLS (8), a.fib (8) | |
Ibrutinib/ venetoclax | NCT03112174 | III | ongoing | ||||
Obinutuzumab/ibrutinib | NCT02558816 [78] | I | 9 [23.5] | 1 | 87 [87] | NR | none |
Obinutuzumab/ibrutinib/ venetoclax | NCT02558816 [78] | I | 12 [6.5] | 2 | 66.6 [25] | NR | none |
Lenalidomide/rituximab | NCT00294632 [79] | II | 44 [23.1] | 2 | 57 [36] | 11.1 | Fatigue (14), non-neutropenic infection (7), hypercalcemia (7), hyperuricemia (7) |
Lenalidomide/rituximabb | NCT00783367 [80] | II | 11 [39.2] | 3 | 55 [55] | 24.4 | Hypokalemia (10), hypophosphatemia (6) |
Lenalidomide/obinutuzumab | NCT01582776 | II | 13 [14.5] | 2 | 46.2 [15.4] | NP | Infections (12.5) |
Ibrutinib/lenalidomide/ rituximab | NCT02460276 [81] | II | 50 [17.8] | 2 | 76 [56] | 16 | Infections (26), rash (14), GI (12), vascular (10) |
Palbociclib/ibrutinib | NCT02159755 [82] | I | 27 [25.6] | 1 | 67 [37] | NP | Hypertension (15), febrile neutropenia (15), lung infection (11), URI (7), fatigue (7), transaminitis (7) rash (7) |
Palbociclib/ibrutinib | NCT03478514 | II | ongoing |
Combination of active therapies with investigational agents
CDK4/6 inhibitors
Cellular immune therapies
CAR-T cell therapy
BiTe antibodies
BiTe | NCT#/publication | Route/administration schedule | Phase | Sample size* [follow-up**] | Median lines of prior therapy | ORR% [CR%] | CRS [grade ≥ 3] | Neurotoxicity [grade ≥ 3] |
---|---|---|---|---|---|---|---|---|
Blinatumomab | IV continuous infusion over 4 or 8 weeks | I | 24 [5.2] | 3 | 71.1a [42.8] | NP [NP] | 71 [22] | |
Mosunetuzumab | NCT02500407 [97] | IV once every 21 days | I/Ib | 23 [NP] | 3 | NP [NP] | 28.9 [1.4] | 43.7 [3.2] |
REGN1979 | NCT03888105 [98] | IV weekly for 12 weeks, then every 2 weeks for 24 weeks | I | 6 [NP] | 3 | NP [NP] | 57 [7.2] | NP [3.1] |
GEN3013 | NCT03625037 [99] | Subcutaneous weekly: cycle 1–2; every 2 weeks cycle 3-6; every 28 days thereafter | I/II | NP | 3 | NP [NP] | 50 [0] | 0 [0] |
Current approaches to the upfront treatment of MCL
Therapy | NCT#/publication | Phase | Sample size [follow-up*] | ORR% [CR%] | Median PFS | Grade ≥ 3 (%)a |
---|---|---|---|---|---|---|
R-HyperCVAD+ bortezomib | [101] | II | 95 [44] | 100 [82] | 55 | Neutropenic fever (9) |
v-BEAM | [102] | I/II | 23 [58.5] | 95 [86]b | NR | Neutropenic fever (59), anorexia (21), peripheral neuropathy (19), orthostatic hypotension (16), ileus (9) |
Maintenance bortezomib days 1, 4, 8, 11 of 21 days × 4 cycles vs. maintenance bortezomib weekly for 4 weeks on /4 weeks off × 9 cycles | NCT00310037 [103] | III | 151c [96] | – | 106.8 v NR | NPd |
Maintenance bortezomib every 2 weeks × 2 years vs observation | III | 135e [77.5] | – | NR v NR | Infections (7) | |
Lenalidomide + R-CHOP → R-HIDAC → R2 | NCT02633137 | II | ongoing | |||
Maintenance R2 vs rituximab | NCT02354313 | III | ongoing | |||
R2 | II | 38 [64] | 92 [64] | NR | Infections (19.4), tumor flare (11), abdominal pain (5), serum sickness (5), syncope (5), neutropenic fever (5) | |
(R-CHOP/R-DHAP → auto-HCT) vs (R-CHOP/R-DHAP + ibrutinib → auto-HCT → ibrutinib) vs (R-CHOP/R-DHAP + ibrutinib → ibrutinib) | NCT02858258 [108] | III | ongoing | |||
Acalabrutinib + BR/R-HiDAC → auto-HCT | NCT03623373 | II | ongoing | |||
Ibrutinib + Rituximab → R-hyperCVAD | NCT02427620 [109] | II | 131 [22] | 100 [94]f | NR | Fatigue (8), myalgia (8), rash (8)g |
Upfront treatment approaches for the transplant eligible patient
Bortezomib in frontline therapy
Lenalidomide in frontline therapy
BTK inhibitors in frontline therapy
Novel upfront approaches for the transplant-ineligible patient
Therapy | NCT#/publication | Phase | Sample size [follow-up*] | ORR% [CR%] | Median PFS (mos) | Grade ≥ 3 (%) |
---|---|---|---|---|---|---|
BR + lenalidomide → lenalidomide | NCT00963534 [113] | I/II | 51 [31] | 80 [64] | 42 | Infection (42), rash (18), allergic reaction (12), mucositis (6), musculoskeletal pain (6), anorexia (6) |
(R-CHOP/R-HAD X 4 vs R-CHOP X 8) ≥ (R2 vs rituximab) | NCT01865110 | III | Ongoing | |||
(BR vs BR + bortezomib) → (R2 vs rituximab) | NCT01415752 | II | Ongoing | |||
(BR + ibrutinib → rituximab + ibrutinib) | NCT01776840 | III | Ongoing | |||
BR + acalabrutinib vs BR | NCT02972840 | III | Ongoing | |||
BR + venetoclax | NCT03834688 | II | Ongoing | |||
Bendamustine/obinutuzumab/venetoclax | NCT03872180 | II | Ongoing | |||
Ibrutinib + rituximab | NCT01880567 | II | 49 [28] | 98 [60] | NR | Myalgias (14), fatigue (14), dyspnea (10), a.fib (8) |
R2 | II | 38 [64]a | 92 [64] | NR | Infections (19.4), tumor flare (11), abdominal pain (5), serum sickness (5), syncope (5), neutropenic fever (5) | |
Acalabrutinib + R2 | NCT03863184 | II | ongoing | |||
Venetoclax + ibrutinib + obinutuzumab | NCT02558816b [85] | I | 15 [NP] | 100 [47] | NP | Hepatobiliary disorder (27), rash (7) |
Acalabrutinib + rituximab + (bendamustine or venetoclax) | NCT02717624 | I | ongoing |