Background
Diagnosis, prognosis, and current treatment
Diagnosis of DHLs
Prognosis and risk stratification
Current chemotherapy
Treatment | Response | PFS/PFS/EFS (months) | OS (months) | References |
---|---|---|---|---|
R-CHOP (n = 35) vs intense regimens (DA-EPOCH-R (n = 81), R-hyperCVAD (n = 32), R-CODOX-M/IVAC (n = 11)) | Patients with DHL who achieved first complete remission | 3-year RFS rate: R-CHOP 56% vs Intense Regimens 88% 3-year RFS rate: DA-EPOCH-R 88%, R-hyperCVAD 87%, and R-CODOX-M/IVAC 91% | 3-year OS rate: R-CHOP 77% vs Intense Regimens 90% (P = 0.13) 3-year OS rates: DA-EPOCH-R 87% vs R-hyperCVAD 90% vs R-CODOX-M/IVAC 100%, P = 0.57 | Landsburg et al. [36] |
R-CHOP (n = 5) vs R-CODOX-M/IVAC (n = 25) | CR rate: R-CHOP 0% vs R-CODOX-M/IVAC 36% ORR: R-CODOX-M/IVAC 80% | 2-year PFS rate: R-CODOX-M/IVAC 47% | 2-year OS rate: R-CODOX-M/IVAC 61% | Sun et al. [37] |
R-CHOP (n = 100) vs R-DA-EPOCH (n = 28) vs R-Hyper CVAD (n = 34) | CR rate: R-CHOP 40% vs R-DA-EPOCH 68% (P = 0.017 vs. R-CHOP) vs R-Hyper CVAD 68% (P = 0.011 vs. RCHOP) | 2-year EFS rate: R-CHOP 25% vs R-DA-EPOCH 67% vs R-Hyper CVAD 32% 3-year EFS rate: R-CHOP 20% vs R-DA-EPOCH 67% (P = 0.004 vs. R-CHOP) vs R-Hyper CVAD 32% (P > 0.05 vs. R-CHOP) | 2-year OS rate: R-CHOP 41% vs R-DA-EPOCH 76% vs R-Hyper CVAD 44% 3-year OS rate: R-CHOP 35% vs R-DA-EPOCH 76% (P = 0.057 vs. R-CHOP) vs R-Hyper CVAD 40% (P > 0.05 vs. R-CHOP) | Oki et al. [33] |
R-CHOP (n = 100) vs intense regimens (R-DA-EPOCH (n = 65), R-Hyper CVAD (n = 64), R-CODOX-M/IVAC (n = 42)) | CR rate: DA-EPOCH-R was significantly higher compared with R-CHOP, R-CODOX-M/IVAC, or “other/multiple” regimens | Median PFS: R-CHOP 7.8 months vs intense regimens 21.6 months | OS in intensive chemotherapy (R-DA-EPOCH, R-Hyper CVAD, R-CODOX-M/IVAC) is higher than R-CHOP | Petrich et al. [32] |
R-CHOP (n = 19) vs R-Hyper CVAD (n = 28) | NA | PFS: R-CHOP vs R-Hyper CVAD, P > 0.05 | OS: R-CHOP vs R-Hyper CVAD, P > 0.05 | Li et al. [38] |
Transplantation
Genetic alterations in DHL
Genetic alterations in DHL-BCL2
Category | Gene (frequency): cluster |
---|---|
Transcription factors | IRF8 (22%): E+, C, B, D(T); MEF2B (21%): E+, C, B; MYC (32%): E+, C3; FOXO1 (13%): E+, B; POU2F2 (9%): C, B; EBF1 (27%): E+ |
Epigenetic regulators | KMT2D (59%): E+, C, B, D(T); EZH2 (55%): E+, C, B, D; CREBBP (53%): E+, C, B, D(T); EP300 (11%): E+, B; BCL7A (28%): E+, B; ARID1A (27%): E+, T; C10orf12 (27%): E+; HIST1H1D (16%): B; SRSF2 (4%): B; |
Apoptosis | BCL2 (70%): E+, C, B, D(T); FAS (38%): E+ |
PI3K-mTOR | PTEN (22%): E+, C; PIK3R1 (4%): B |
NF-κB | REL (40%): E+; |
JAK-STAT | STAT6 (19%): E+, C, B; |
P53 | TP53 (44%): E+; |
Immune | TNFRSF14 (50%): E+, C, B, D(T); HLA-DMB (22%): E+ |
Cell migration | GNA13 (26.30%): E+, C, B, D(T); SIPR2 (11%): E+ |
Others | Chrom.12p (28%): E+, C; GNAI2 (13%): E+, C; DDX3X (33%): E+; 10q23.31 (24%): C; Chrom.21 (20%): E+; HVCN1 (13%): C |
Alterations relating cellular differentiation and transcription factors
Alterations relating apoptosis
Alterations relating to epigenetic regulators
Alterations relating to oncogenic pathways
Alterations relating to immune escape
Alterations relating to cell migration
Genetic alterations in DHL-BCL6
Category | Gene (frequency): cluster |
---|---|
B cell development and differentiation | BCL6 (69%): B, C, N; UBE2A*(24%): B, C; KLF2(22%): B; ETS1(17%): B; ZEB2(14%): C; POU2F2(6%): N |
BCR and NF-κB signaling | BCL10(28%): B, N, C, D; TNFAIP3(29%): B, C, N; PRKCB (16%): B; KLHL21*(12%): B |
Notch | NOTCH2(31.3%): B, N, C, D; SPEN (21%): B, C, N; DTX1*(38%): B, C |
Cell cycle | CCND3(22%): B, N; CDKN2A (29%): N |
P53 | TP63(15%): B, C; TRIP12*(12%): B; TRRAP (10%): B |
Epigenetic regulator | HIST1H2BK (16%): B, C; KMT2D (41%): N; HIST1H1D (16%): B; ARID1A (14%): N |
Immune escape | CD70(25%): B, C, N; B2M (28%): C, N; HLA-B (23%): C; CD274(14%): C |
Migration | CXCR4(6%): N |
Other | TMEM30A (19%): B, C, N; FAS (18%): C, N; NOL9(18%): B; PABPC1(10%): B; DDX3X (7%): N; PDS5B (4%): N |
Alterations relating Cellular differentiation and transcription factors
Alterations relating to oncogenic pathways
Alterations relating cell cycle and p53
Alterations relating to the ubiquitin–proteasome system
Alterations relating to immune escape
Alterations relating to cell migration
Targeted therapy
Targeted therapy for DHL-BCL2
Category | Target | Agent | Stage of development | References |
---|---|---|---|---|
MYC regulators | Myc | CX-3543 (Quarfloxin) | Phase II (B-cell chronic lymphocytic leukemia, withdrawn) | [183] |
INX-3280 | Phase II (Terminated) | [184] | ||
Oncomyc-NG | Phase I (neoplasms, Terminated) | NCT00343148 | ||
Apoptosis protein | BCL2 | Venetoclax | Phase I (NHL) | NCT01328626[185] |
BCL2 + PI3K | Venetoclax Venetoclax + PI3K inhibitor | Phase I (+ bendamustine and rituximab, r/r NHL) | NCT01594229[186] | |
Phase II (+ R-CHOP, DLBCL) | NCT02055820[187] | |||
Preclinical | [188] | |||
BCL2 + SYK/BTK | Venetoclax + SYK/BTK inhibitor | Preclinical | [189] | |
BCL2 + EZH2 | Venetoclax + EZH2 inhibitor | Preclinical | [190] | |
Mcl-1 | PRT1419 | Phase I (r/r hematologic malignancies including NHL) | NCT04543305, NCT05107856 | |
MIK665 | Phase I (multiple myeloma, lymphoma) | NCT02992483 | ||
AMG397 | Phase I (hematologic malignancies including lymphoma) | NCT03465540 | ||
cIAP1 | Xevinapant | Phase I (lymphoma) | NCT01078649 | |
cIAP1/cIAP2 | LCL-161 | Phase II (multiple myeloma) Preclinical (r/r lymphoma) | NCT02314052 [191] | |
Survivin (BIRC5) | SM1044 | Preclinical (DLBCL) | [192] | |
YM155 | Phase II (lymphoma, B-cell lymphoma, DLBCL, terminated) | NCT00498914 | ||
NMT | PCLX-001 | Phase I (lymphoma, NHL) | NCT04836195 | |
Epigenetic regulators | EZH2 | Tazemetostat | Phase II (+ R-CHOP for DLBCL; + atezolizumab for DLBCL), Approval for FL | |
Valemetostat | Phase II (adult T-cell leukemia/lymphoma) | [196] | ||
CPI-1205 | Phase I (DLBCL) | [197] | ||
PF-06821497 | Phase I (DLBCL and primary cutaneous follicle center lymphoma) | NCT03460977 | ||
SHR2554 | Phase I/II (lymphoma) | NCT03603951 | ||
EED | MAK683 | Phase I/II (DLBCL) | NCT02900651 | |
HDAC (1,2,3,6) | Vorinostat | Phase II (NHL), Approval for CTCL | [198] | |
HDAC | Panobinostat | Phase II (+ rituximab for BCL), Approval for multiple myeloma | [199] | |
Chidamide | Phase II (DLBCL), Approval for Peripheral T-cell lymphoma | [200] | ||
Romidepsin | Phase I/II (DLBCL), Approval for T-cell lymphoma | [201] | ||
Mocetinostat | Phase II (lymphoma) | [202] | ||
CUDC-907 | Phase I (B-cell lymphoma and DLBCL) | [203], NCT02674750 | ||
BRD2-4 | OTX015 | Phase II (DLBCL) | [204] | |
BRD4 | CPI-203 | preclinical | [205] | |
PLX-2853 | Phase I (DLBCL and follicular lymphoma) | [206] | ||
CPI-0610 | Phase III (myelofibrosis), Phase I (lymphoma) | [207] | ||
JQ1 | preclinical | [208] | ||
DNMT1 | Azacitidine | + R-CHOP Phase I/II (DLBCL), Approval for myelodysplastic syndromes, AML and CML | [209], NCT01004991, NCT03450343 | |
Decitabine | + R-CHOP Phase I/II (DLBCL), Approval for myelodysplastic syndromes and myelogenous leukemia | NCT02951728 | ||
JAK-STAT signaling | STAT3 | Danvatirsen (AZD9150) | Phase II (DLBCL) | NCT02983578 |
JAK1 and JAK2 | Ruxolitinib | Approval for myelofibrosis and lymphoma | NCT00952289 NCT00934544 NCT01243944 | |
JAK2 | Pacritinib | Phase III (myelofibrosis) Phase I (lymphoma) | NCT04404361 NCT01436084 NCT03601819 | |
NF-κB Signaling | IRAK4 | KT-474 | Phase I (ABC-DLBCL) | NCT04772885 |
PI3K-AKT-mTOR | PI3K | Idelalisib | Approval for chronic lymphocytic leukemia, Phase II (DLBCL), Phase II (+ Ibrutinib for NHL, withdrawn) Phase I/II (NHL, terminated) | NCT02136511 NCT03576443 NCT02662296 NCT01090414 |
Copanlisib | Approval for follicular center lymphoma, Phase III (NHL) | [210] NCT02367040 | ||
AKT | MK-2206 | Phase II (DLBCL) Phase II (anaplastic large cell lymphoma) | NCT01481129 NCT01258998 | |
mTOR | Everolimus | Phase III (DLBCL) | NCT00790036 | |
Temsirolimus | Approval for NHL, Phase II (DLBCL) | NCT01180049 NCT00290472 |
Targeting MYC
Targeting apoptosis
Targeting epigenetic regulation
Targeting oncogenic pathways
Other therapies
Targeted therapy for DHL-MYC/BCL6
Category | Target | Agent | Stage of development | References |
---|---|---|---|---|
Notch | γ-secretase | MK-0752 | Phase I (CLL, terminated) | NCT00100152 |
Z-LLNle-CHO | Preclinical (precursor B-cell acute leukemia) | [290] | ||
Z-IL-CHO | Preclinical (DLBCL) | [291] | ||
Unidentified | Crenigacestat | Phase I /II (multiple myeloma and precursor T-cell lymphoblastic leukemia) | NCT04855136 NCT02518113 | |
Unidentified | CB-103 | Phase I (NHL) | NCT03422679 | |
BCR signaling | BTK | Ibrutinib | Approval for mantle cell lymphoma, Chronic lymphocytic leukemia/small lymphocytic lymphoma, DLBCL | NCT01236391 NCT01105247 NCT01578707 |
SYK | Fostamatinib Disodium (R788) | Approval for DLBCL | NCT02076399 NCT02076412 NCT02077192 | |
NF-κB signaling | IRAK4 | KT-474 | Phase I (ABC-DLBCL) | NCT04772885 |
Ubiquitin proteasome system | CRBN | Lenalidomide | Phase II (+ DA-EPOCH-R, lymphoma including DLBCL) | NCT02213913 [292] |
Phase II (+ R-CHOP, lymphoma including DLBCL) | NCT00670358 [293] | |||
Phase II (+ R-CHOP21, lymphoma including DLBCL) | NCT00907348 [294] | |||
Phase II (+ rituximab, lymphoma including DLBCL) | NCT00294632 [295] | |||
Phase II (+ ibrutinib and rituximab, r/r DLBCL) | NCT02077166 [296] | |||
Phase III (maintenance regiment, DLBCL) | NCT01122472 [297] | |||
Proteasome | Bortezomib | Approval for multiple myeloma, Phase III (NHL and DLBCL) | NCT02268890 NCT00312845 NCT01324596 | |
ixazomib | Approval for multiple myeloma, Phase I/II (DLBCL) | NCT03173092 NCT02481310 | ||
Proteasomal USP14 and UCHL5 deubiquitinases | b-AP15 | Preclinical (DLBCL) | [298] | |
p53 signaling | p53 | Eprenetapopt (APR-246) | Phase II (Leukemia) | NCT03588078 |
MDM2 | Idasanutlin (RG7388) | Phase III (+ Cytarabine, leukemia) | NCT02545283 | |
XPO1 | XPO1 | Selinexor (KPT-330) | Approval for r/r DLBCL and r/r multiple myeloma | [299] |
Proliferation | CDK4/6 | Palbociclib | Phase II (+ Ibrutinib for mantle cell lymphoma and B-cell lymphoma) | NCT03478514 |
Abemaciclib | Phase II (MCL) | NCT01739309 | ||
CDK9 | Dinaciclib | Phase Ib (+ Pembrolizumab for DLBCL) | NCT02684617 (Terminated); [234] | |
Voruciclib | Phase I (DLBCL) | NCT03547115; [300] | ||
CXCR4 | CXCR4 | PF-06747143 | Preclinical | [301] |
CXCR4-directed auristatin E nanoconjugate | T22-AUR | Preclinical | [302] | |
CXCR4 modified | CD19 CAR T cells | Phase I (refractory NHL) | NCT04684472 | |
CXCR4-directed | radioligand therapy | Preclinical | [303] | |
Immunotherapy | PD-1 | Nivolumab | Phase 1b (r/r DLBCL) | NCT01592370 [304] |
Phase II (DLBCL, patients with relapse after or were ineligible for autologous hematopoietic cell transplantation) | NCT02038933 [305] | |||
Pembrolizumab | Phase 1 (hematology malignancies including DLBCL) | NCT01953692 [306] | ||
Preclinical (+ R-CHOP, in R-CHOP untreated DLBCL) | [307] |
Targeting oncogenic pathways
Targeting ubiquitin–proteasome system
Targeting p53 signaling
Targeting cell cycle
Targeting CXCR4
Targeting immune escape
Combined regimens for DHL
Target | Agent | Therapeutics | Stage | Status | Na | Clinical response | Adverse events | References |
---|---|---|---|---|---|---|---|---|
BCL2 | Venetoclax | + DA-EPOCH-R | Phase II/III (high-grade B-cell lymphomas, including DHL) | Suspended (2019–2028) | – | No result posted | No result posted | NCT03984448 |
Phase I (aggressive B-Cell Lymphomas, including DHL) | Active, not recruiting (2017–2021) | 31 | ORR: 96·7% (95% CI 82·8–99·9); complete response: 28 (93·3% [77·9–99·2]) of 30; partial response: 1 (3·3% [0·1–17·2]) | Grade 3–4 adverse events: cytopenias (28 [93%] of 30 patients); febrile neutropenia occurred in 19 (63%) patients. Grade 3–4 non-haematological adverse events included hypophosphataemia (n = 10), hypokalaemia (n = 7), and hyperglycaemia (n = 5) Serious adverse events: infection (n = 7) and gastrointestinal toxicities including abdominal pain (n = 3), colonic perforation (n = 1), and small intestinal obstruction (n = 1) | NCT03036904 [363] | |||
Proteasome | Bortezomib | + Cyclophosphamide, Dexamethasone, vincristine sulfate liposome | Phase II (r/r ALL, LL, Burkitt Lymphoma, DHL) | Recruiting (2017–2026) | – | No result posted | No result posted | NCT03136146 |
+ R-CHOP or RB-CHOP | Phase III (DLBCL and other B cell lymphoma, including DHL) | Completed (2011–2015) | 1132 (18 DHL) | Clinical response (DHL): + R-CHOP: 30-months PFS, 38.9%; + RB-CHOP: 30-months PFS, 58.8%; 30-months OS, DHL:DEL:DLBCL, 38·9% vs 61·5% vs75·8% | Most common AEs: Neutropenia, thrombocytopenia, and neuropathy | NCT01324596 [364] | ||
CD52 | Alemtuzumab | + Cyclophosphamide | Phase I (Aggressive lymphoma, including DHL) | Terminated (slow accrual) | 3 | No result posted | No result posted | NCT03132584 |
CD79B | Polatuzumab Vedotin | + R-CHOP or R-CHP | Phase II (DHL, THL) | Recruiting (2020–2022) | – | No result posted | No result posted | NCT04479267 |
HDAC | Tucidinostat | + BEAC | Phase II (aggressive lymphoma, including DHL) | Active, not recruiting (2018–2021) | 69 | No result posted | No result posted | NCT03629873 |
Fimepinostat | Monotherapy, or + rituximab | Phase I (r/r DLBCL, HGBL, including DHL) | Completed (2012–2020) | 106b | Monotherapy: OR 71%, mDOR 13.6 months, mPFS 21.8 months; + rituximab: OR 50%, ORR 64%, | Most common: diarrhea [21 (57%)], thrombocytopenia [20 (54%)], fatigue [15 (41%)], nausea [14 (38%)], constipation [9 (24%)], vomiting [9 (24%)], and neutropenia [8 (22%)]; Grade ≥ 3 adverse events:16 (43%) patients, thrombocytopenia [12 (32%)], neutropenia [6 (16%)], anemia [2 (5%)], diarrhea [2 (5%)], and fatigue [2 (5%)] | ||
Chidamide | + ChiCGB and auto-SCT | Phase II (r/r DLBCL) | Completed (2017–2021) | 93 (2 DHL) | Clinical response: DHL DLBCL: 8%; 4-year PFS 90.0%, 4-year OS 96.8% | Most frequent AEs: Mucositis (43.8%), dermatitis (33.3%), transaminase elevation(43.8%) | NCT03151876 [366] | |
CD3/CD20 | Epcoritamab | + BR or R-GemOx | Phase III (r/r DLBCL, DHL/THL, FL grade 3B) | Recruiting (2021–2024) | – | No result posted | No result posted | NCT04628494 |
PD-1 | Nivolumab | + DA-EPOCH-R | Phase II (DHL/THL-HGBL) | Recruiting (2018–2026) | – | No result posted | No result posted | NCT03620578 |
Pembrolizumab | + DPX-Survivac, Cyclophosphamide | Phase II (r/r DLBCL, HGBL, including DHL) | Active, not recruiting (2018–2022) | 25 | No result posted | No result posted | NCT03349450 | |
CRBN | Lenalidomide | + DA-EPOCH-R | Phase II (lymphoma including DLBCL) | Active, not recruiting (2014–2022) | 15 (5 DHL) | Clinical response: 13 CRs (87%), 1 PR (7%), and 1 case of PD (7%), 2-year OS rate87% and PFS rate 87% | Most common Aes: thromboembolism (4 patients; 27%) and hypokalemia (2 patients; 13%) SAEs: | NCT02213913 [292] |
DNMT1/2 | Azacitidine | + R-miniCHOP | Phase II/III (DLBCL, Grade 3B FL, DHL/THL-HGBL) | Recruiting (2021–2025) | – | No result posted | No result posted | NCT04799275 [367] |
+ R-CHOP | Phase I (DLBCL, FL, or Transformed lymphoma) | Completed (2015–2020) | 59 (2 DHL, 1THL) | Dosage: 100-300 mg daily Clinical response: ORR, 94.9%; CR, 88.1%; estimated 1-year PFS, 84.1%; estimated 2-PFS, 78.6% | MTD was not reached; 2 DLTs Most common grade 3/4 toxicities: Neutropenia (62.7%) and febrile neutropenia (25.4%) | NCT02343536 [368] | ||
XPO1 | Selinexor | + R-CHOP | Phase Ib/II (r/r DLBCL, DHL) | Recruiting (2017–2023) | 12b | Dosage: 60/80 mg daily Clinical response: CR, 80%; PR, 10% | Most common Aes: nausea (100%), fatigue (67%), skin/nail changes (58%), vomiting (42%), dizziness (42%), sinus congestion (42%), and constipation (42%) | NCT03147885 [369] |
+ Choline Salicylate | Phase Ib (DLBCL, MCL, DHL) | Recruiting (2021–2024) | – | No result posted | No result posted | NCT04640779 | ||
+ RICE | Phase I (aggressive B-Cell Lymphoma, including DHL) | Active, not recruiting (2015–2021) | 22 | No result posted | No result posted | NCT02471911 | ||
mTOR | Everolimus | Maintenance therapy with Rituximad | Phase II (Lymphomas) | Completed (2018–2021) | 56 (1 DHL) | 30 month OS: 93%; overall median EFS: 36.4 months; 30 months EFS: 58% | Most frequent AEs: grade 3/4 neutropenia (61.2%), hyperglycemia (18.4%), hypertriglyceridemia (18.4%), thrombocytopenia (16.3%), and anemia (8.2%) | NCT01665768 [370] |