Introduction
Agent | Approved date | Study | Dose schedulea | Number of patientsa | Efficacya |
---|---|---|---|---|---|
Tafasitamab-cxix (Monjuvi) | July 31, 2020 | NCT02399085 | 12 mg/kg as an intravenous infusion according to the following dosing schedule Cycle 1: Days 1, 4, 8, 15, and 22 of the 28-day cycle Cycles 2 and 3: Days 1, 8, 15, and 22 of each 28-day cycle Cycle 4 and beyond: Days 1 and 15 of each 28-day cycle | 80 | ORR: 55%; CR: 37% |
Selinexor (XPOVIO) | June 22, 2020 | NCT02227251 | 60 mg orally on days 1 and 3 of each week | 134 | CR: 13%; ORR: 29% |
Polatuzumab vedotin-piiq (Polivy) | June 10, 2019 | NCT02257567 | 1.8 mg/kg for six 21-day cycle with bendamustine and a rituximab product | 80 | CR: 40%; ORR: 63% |
Tisagenlecleucel (Kymriah) | May 1, 2018 | NCT02445248 | 0.6–6.0 × 108 CAR-positive viable T cells | 68 | CR: 32%; ORR: 50% |
Axicabtagene ciloleucel (Yescarta) | October 18, 2017 | NCT02348216 | 2.0 × 106 /kg CAR-positive viable T cells (maximum 2 × 108) | 108 | CR: 51%; ORR: 72% |
Hyaluronidase human and rituximab (RITUXAN HYCELA) | June 22, 2017 | NCT01649856 | 1400 mg subcutaneous rituximab and 23,400 units hyaluronidase human, with CHOP | 381 | CR: 51%; ORR: 83% |
Rituximab (Rituxan) | February 10, 2006 | LNH 98–5/GELA | rituximab 375 mg/m2 with CHOP | 399 | CR:75%; 2-y OS: 69% |
E4494 | rituximab 375 mg/m2 with CHOP | 632 | 2-y OS: 74%; PFS: 3.1 years | ||
MInT | rituximab 375 mg/mm2 with CHOP/CHOP-like regimens | 823 | 2-y OS: 95% |
Immunotherapy
Chimeric antigen receptor T cells and natural killer (NK) cells
Anti-CD19 CAR T cells
Dual CAR T cells or combination with immune checkpoint inhibitors
Target | Agent | Study | Study phase | Number of DLBCL patients (treated) | Dose | ORR (%) | CR (%) | References |
---|---|---|---|---|---|---|---|---|
CD19 | Axicabtagene ciloleucel | ZUMA-1 (NCT02348216) | 1/2 | 101 | 2.0 × 106 CAR T cells/kg | 83 | 58 | [13] |
CD19 | axicabtagene ciloleucel (in combination with atezolizumab) | ZUMA-6 (NCT02926833) | 1 | 12 | 2.0 × 106 CAR T cells/kg | 90 | 60 | [22] |
CD19 | tisagenlecleucel | JULIET (NCT02445248) | 2 | 93 | 0.1–6 × 108 CAR T cells | 52 | 40 | [12] |
CD19 | lisocabtagene maraleucel | TRANSCEND NHL 001 (NCT02631044) | 1 | 268 | 50–150 × 106 CAR T cells | 73 | 53 | [139] |
CD19 | CTL019 | NCT02030834 | 2a | 28 | 1.79–5.00 × 106 CAR T cells | 64 | 43 | [11] |
CD19 | ET019003 | NCT04014894 | 1 | 6 | 2–3 × 106 CAR T cells/kg | 100 | – | [140] |
CD19 | FMC63-28Z | NCT00924326 | 1/2 | 7 | 1–5 × 106 CAR T cells/kg | 85 | 71 | [141] |
CD19/CD22 | AUTO3 (in combination with pembrolizumab) | ALEXANDER (NCT03287817) | 1/2 | 24 | 50 × 106 CAR T cells | 57 | 29 | [21] |
Universal CAR T cells
Target | Drug | Toxin | Combined agents | Study | Study phase | No. | Efficacy | References |
---|---|---|---|---|---|---|---|---|
CD19/CD3 | Blinatumomab | – | R-chemotherapy | NCT 03023878 | 2 | 30 | ORR 89% | [27] |
CD19 | Coltuximab ravtansine | DM4 | – | NCT 01472887 | 2 | 61 | ORR 44% CR 15% | [71] |
CD19 | Loncastuximab tesirine | SG3199 | – | NCT 02669017 | 1 | 63 | ORR 55% CR 37% | [72] |
CD20 | MT-3724 | SLTA | – | NCT 02361346 | 1 | 13 | ORR 30% CR 10% | [57] |
CD20 | Ibritumomab tiuxetan | Yttrium-90 | Combined with R as maintenance therapy | NCT 00070018 | 2 | 33 | 5-y OS 87% 5-y PFS 82% | [59] |
CD20 | Tositumomab | Iodine-131 | R-CHOP | NCT 00107380 | 2 | 86 | ORR 86% CR 61% 2-yPFS69% 2-y OS 77% | [61] |
CD20/CD3 | RG6026 | – | Obinutuzumab | NCT 03075696 | 1b | 28 | ORR 48% CR 43% | [30] |
CD20/CD3 | Mosunetuzumab | – | – | NCT 02500407 | 1/1b | 55 | ORR 33% CR 21% | [31] |
CD20/CD3 | REGN1979 | – | – | NCT 02290951 | 1 | 53 | ORR 33% CR 18% | [32] |
CD22 | Pinatuzumab vedotin | MMAE | Rituximab | NCT 01691898 | 2 | 42 | ORR 60% CR 26% | [65] |
CD22 | Inotuzumab ozogamicin | Calicheamicin | Rituximab | NCT 00299494 | 1/2 | 42 | ORR 74% 2-y EFS 42% | [76] |
CD22 | Epratuzumab tetraxetan | Yttrium-90 | R-CHOP | NCT 00906841 | 2 | 71 | 2-y EFS 75% | [142] |
CD30 | Brentuximab vedotin | MMAE | – | NCT 02280785 | 2 | 12 | CR 17% DCR 50% | [78] |
CD30 | Brentuximab vedotin | MMAE | – | NCT 01421667 | 2 | 49 | ORR 44% CR 17% mPFS: 4 m | [80] |
CD74 | STRO-001 | Maytansinoid warhead | – | NCT 03424603 | 1 | 4 | ORR 50% CR 25% | [83] |
CD79b | Polatuzumab vedotin | MMAE | Rituximab | NCT 01691898 | 2 | 39 | ORR 54% CR 21% mDoR 13.4 m | [65] |
CD79b | Polatuzumab vedotin | MMAE | R-CHP/GHP | NCT 01992653 | 1b/2 | 66 | ORR 89% CR 77% | [64] |
CAR-NK cells
CAR T cells with safety switches
Bispecific T cell engagers
Immunomodulatory drugs
Immune checkpoint inhibitors (ICIs)
Monoclonal antibodies and antibody–drug conjugates
CD20-directed agents
CD79b-directed agents
CD19-directed agents
CD22-directed agents
CD30-directed agents
CD74-directed agents
Molecular pathway inhibitors
Agent | Agent type | Combined agent | Study | Study phase | Recruitment status | Enrollment (estimated/actual) | Indication | Results for DLBCLa |
---|---|---|---|---|---|---|---|---|
Idelalisib | PI3K inhibitor | – | NCT03576443 (ILIAD) | 2 | Recruiting | 72 | Relapsed GCB DLBCL | – |
Copanlisib | PI3Kα/δ inhibitor | Nivolumab | NCT03484819 | 2 | Recruiting | 106 | DLBCL failing or ineligible for ASCT | – |
Parsaclisib | PI3Kδ inhibitor | – | NCT02998476 (CITADEL-202) | 2 | Active, not recruiting | 60 | r/r DLBCL | [109] |
Parsaclisib | PI3Kδ inhibitor | R-CHOP | NCT04323956 | 1/1b | Not yet recruiting | 44 | Newly diagnosed, high-risk DLBCL | – |
Parsaclisib | PI3Kδ inhibitor | Rituximab, bendamustine/ibrutinib | NCT03424122 | 1 | Recruiting | 81 | r/r NHL | – |
BR101801 | PI3Kδ and DNA-PK dual inhibitor | – | NCT04018248 | 1 | Not yet recruiting | 90 | Advanced lymphomas | – |
Umbralisib (TGR-1202) | PI3Kδ and CK1 dual inhibitor | Ublituximab, bendamustine | NCT02793583 (UNITY-NHL) | 2/3 | Recruiting | 900 | Previously treated NHL | – |
Everolimus | mTORC1 inhibitor | Lenalidomide | NCT01075321 | 1/2 | Active, not recruiting | 58 | r/r NHL or HL | – |
Temsirolimus | mTORC1 inhibitor | Rituximab, DHAP | NCT01653067 | 2 | Recruiting | 88 | r/r DLBCL | – |
Venetoclax | BCL2 inhibitor | – | NCT01328626 | 1 | Recruiting | 222 | r/r CLL and NHL | [101] |
Venetoclax | BCL2 inhibitor | Lenalidomide, obinutuzumab | NCT02992522 | 1 | Suspended | 60 | r/r NHL | – |
Venetoclax | BCL2 inhibitor | Atezolizumab, obinutuzumab | NCT03276468 | 2 | Recruiting | 138 | r/r DLBCL and indolent NHL | – |
Venetoclax | BCL2 inhibitor | RICE | NCT03064867 | 1/2 | Recruiting | 64 | r/r DLBCL | – |
Venetoclax | BCL2 inhibitor | DA-EPOCH-R | NCT03036904 | 1 | Active, not recruiting | 34 | DLBCL and HGBCL | – |
Venetoclax | BCL2 inhibitor | Obinutuzumab, rituximab, polatuzumab vedotin | NCT02611323 | 1 | Recruiting | 134 | r/r DLBCL and follicular lymphoma | – |
Venetoclax | BCL2 inhibitor | Obinutuzumab | NCT02987400 | 2 | Recruiting | 21 | r/r DLBCL | – |
Entospletinib | Spleen tyrosine kinase inhibitor | R-CHOP | NCT03225924 | 1/2 | Active, not recruiting | 25 | Newly diagnosed DLBCL aaIPI ≥ 1 | – |
Ibrutinib | BTK inhibitor | ABT-199, rituximab | NCT03136497 | 1 | Recruiting | 30 | r/r DLBCL | – |
Ibrutinib | BTK inhibitor | ABT-199, prednisone, obinutuzumab, lenalidomide | NCT03223610 | 1b/2 | Recruiting | 130 | CD20 positive B cell lymphoma | – |
Ibrutinib | BTK inhibitor | Loncastuximab tesirine | NCT03684694 | 1/2 | Recruiting | 161 | Advanced DLBCL, mantle cell lymphoma | – |
Ibrutinib | BTK inhibitor | Lenalidomide, rituximab | NCT02077166 | 1/2 | Active, not recruiting | 129 | r/r non-GCB DLBCL | [119] |
Ibrutinib | BTK inhibitor | R-ICE | NCT02955628 | 2 | Recruiting | 34 | Pre-transplant r/r DLBCL | – |
Ibrutinib | BTK inhibitor | Buparlisib | NCT02756247 | 1 | Active, not recruiting | 37 | r/r DLBCL, FL, mantle cell lymphoma | [95] |
ARQ-531 | BTK inhibitor | – | NCT03162536 | 1/2 | Recruiting | 146 | Selected hematologic malignancies | – |
LOXO-305 | BTK inhibitor | Venetoclax, R-CHOP | NCT03740529 | 1/2 | Recruiting | 403 | CLL/SLL, NHL | – |
DTRMWXHS-12 | BTK inhibitor | Everolimus, pomalidomide | NCT04305444 | 2 | Recruiting | 120 | r/r CLL, NHL | – |
Acalabrutinib | BTK inhibitor | – | NCT02112526 | 1 | Recruiting | 21 | r/r ABC DLBCL | [96] |
Acalabrutinib | BTK inhibitor | RICE | NCT03736616 | 2 | Recruiting | 47 | DLBCL after first-line failure | – |
Acalabrutinib | BTK inhibitor | DA-EPOCH | NCT04002947 | 2 | Recruiting | 112 | untreated DLBCL | – |
Acalabrutinib | BTK inhibitor | R-CHOP | NCT03571308 | 1/2 | Recruiting | 39 | untreated DLBCL | – |
Acalabrutinib | BTK inhibitor | pembrolizumab | NCT02362035 | 1b/2 | Active, not recruiting | 161 | r/r hematologic malignancies | [97] |
Enzastaurin | PKCβ inhibitor | R-CHOP | NCT03263026 | 3 | Recruiting | 235 | untreated DGM1-positive DLBCL, IPI ≥ 3 | – |
Lenalidomide | Immunomodulatory agent | – | NCT04150328 (RE-MIND) | 2 | Recruiting | 500 | r/r DLBCL | [69] |
Lenalidomide | Immunomodulatory agent | MOR208 | NCT02399085 (L-MIND) | 2 | Active, not recruiting | 81 | r/r DLBCL, non-transplant eligible | [69] |
Lenalidomide | Immunomodulatory agent | R-CHOP | NCT00670358 | 1/2 | Recruiting | 47 | Untreated DLBCL | [34] |
Lenalidomide | Immunomodulatory agent | R-CHOP | NCT00907348 | 2 | Unknown | 49 | Elderly untreated DLBCL, IPI ≥ 2 | [34] |
Lenalidomide | Immunomodulatory agent | R-CHOP | NCT01856192 | 2 | Active, not recruiting | 345 | Untreated stage II–IV DLBCL | – |
Lenalidomide | Immunomodulatory agent | R-CHOP | NCT02285062 | 3 | Active, not recruiting | 570 | Untreated ABC DLBCL | [36] |
Lenalidomide | Immunomodulatory agent | miniCHOP, subcutaneous rituximab | NCT02128061 (SENIOR) | 3 | active, not recruiting | 250 | Untreated CD20 + DLBCL, aged over 80 years | [37] |
Lenalidomide | Immunomodulatory agent | Rituximab, ibrutinib | NCT02636322 | 2 | Active, not recruiting | 60 | Newly diagnosed non-GCB DLBCL | [120] |
Itacitinib | JAK1 inhibitor | Parsaclisib | NCT02018861 (CITADEL-101) | 1/2 | Active, not recruiting | 88 | r/r B cell malignancies | [122] |
Itacitinib | JAK1 inhibitor | Ibrutinib | NCT02760485 | 1/2 | Active, not recruiting | 33 | r/r DLBCL | – |
Ruxolitinib | JAK1/2 inhibitor | – | NCT01431209 | 2 | Active, not recruiting | 71 | r/r NHL failing or ineligible for SCT | [123] |
Valemetostat | EZH1/2 dual inhibitor | – | NCT02732275 | 1 | Recruiting | 70 | Adults with advanced NHL | – |
Tazemetostat | EZH2 inhibitor | – | NCT01897571 | 1/2 | Active, not recruiting | 420 | NHL and advanced solid tumors | [130] |
Tazemetostat | EZH2 inhibitor | R-CHOP | NCT02889523 | 1/2 | Suspended | 133 | Untreated high-risk DLBCL | [132] |
Tazemetostat | EZH2 inhibitor | – | NCT03456726 | 2 | Active, not recruiting | 21 | r/r NHL, EZH2 mutation | – |
Tazemetostat | EZH2 inhibitor | – | NCT02875548 | 2 | Recruiting | 300 | Patients with antecedent tazemetostat study | – |
Panobinostat | HDACi | – | NCT01261247 | 2 | Active, not recruiting | 41 | r/r NHL | – |
Vorinostat | HDACi | R-CHOP | NCT00972478 | 1/2 | Active, not recruiting | 83 | Untreated stage 2–4 DLBCL | – |
Chidamide | HDACi | – | NCT03201471 | 2 | Recruiting | 39 | High-risk DLBCL | – |
Romidepsin | HDACi | 5-Azacitidine | NCT01998035 | 1/2 | Active, not recruiting | 52 | r/r NHL | – |
Selinexor | XPO1 inhibitor | Venetoclax | NCT03955783 | 1 | Suspended | 78 | r/r high-risk DLBCL, leukemia | [143] |
Selinexor | XPO1 inhibitor | R-CHOP | NCT03147885 | 1b/2 | Recruiting | 44 | NHL | – |
Selinexor | XPO1 inhibitor | RICE | NCT02471911 | 1 | Active, not recruiting | 23 | r/r aggressive B cell lymphoma | – |