Table 3 Treatment options at progression of disease for indolent lymphoma
From: How we treat mature B-cell neoplasms (indolent B-cell lymphomas)
Drug | Histology | N | Follow-up (y) | Responseˆ†: PFS**, OS, ORR, CRR | Toxicities and comments |
|---|---|---|---|---|---|
First relapse | |||||
 G versus R [192] (GAUSS) | FL (85%), Non-FL (15%) | 175 | 2.5 | G: 2yPFS 46%, ORR 44% (FL); CRR NS R: 2yPFS 50%, ORR 33% (FL); CRR NS | SAEs: 26 patients (15% each arm), majority infusion-related |
 R2 versus R-placebo [110] (AUGMENT) | FL (82%), MZL | 358 | 2.5 | R2: PFS 3y, ORR 78%, CRR 34% R-placebo: PFS 1y, ORR 53%, CRR 18% *MZL: PFS difference NS OS: data maturing | R2 AE: G3–4 neutropenia 50%; infxn 63%, cutaneous 32% R-placebo AE: G3–4 neutropenia 13%, infxn 49%, cutaneous 12% |
 BR versus G + B [242] (GADOLIN) | FL (80–82%), MZL, SLL, WM | 413 | 2 | G + B: PFS NR B: PFS 15 m OS and ORR: NS | G + B: G3–5 AEs 68% B: G3–5 AEs 62% (neutropenia, anemia, thrombocytopenia, infusion reaction) |
Multiply relapsed | |||||
 BR versus fludarabine + R (FR) [193] | FL, LPL, SLL, MZL, MCL | 230 | 8 | BR: PFS 34 m, ORR 82%, CRR 40% FR: PFS 12 m, ORR 51%, CRR 17% | SAEs: 46 total (23 each group); myelosuppression, infection |
PI3K3-inhbitors | |||||
 Idelalisib [197] (PI3Kδ-inhibitor) | FL (59%), SLL, MZL, LPL | 64 | NA | PFS 8 m, ORR 47%, DOR 18 m TTR: 1 m | AEs: infection; monitor CMV, pneumocystis jiroveci prophylaxis |
 Copanlisib [196] (CHRONOS-1) | FL (73%), MZL, SLL, LPL-WM, DLBCL (1%) | 142 | NA | PFS 11 m, OS NR, ORR 59%, CRR 15% | AEs: hyperglycemia (50%), diarrhea (35%), fatigue (30%), hypertension (30%), neutropenia (29%), fever (25%) SAEs: lung infection (13%), hyperglycemia (5%), decreased neutrophil count (4%), fever (3%), and diarrhea (2%), pneumonitis (8%) *25% discontinuation, 37% dose reduction, 74% interruptions |
 Duvelisib [195] (DYNAMO) | FL (64.3%), SLL, MZL | 129 | 3 | PFS 10 m, ORR 47% (most PR, 2 patients CR) | AEs: diarrhea (49%), nausea (30%), neutropenia (29%), fatigue (28%), cough (27%); 19% dose reduction, 66% interruption, 31% discontinued |
BTK inhibitors | |||||
 Ibrutinib [204] | MZL | 63 | 1.5 | PFS 14 m, 18mOS‡ 81%, ORR 48% TTR 4.5 m, best response 5 m | 62% discontinued treatment Pseudoprogression in 2 patients |
 Ibrutinib-R versus placebo-R [111] | WM (1st line and relapse) | 150 | 2 | Ibrutinib-R: 30mPFS 82%, MRR 72% | Ibrutinib-R G3–5 AEs: afib 12%, HTN 13%; IgM flare 8%, infusion rxn 1% Response independent of MYD88 or CXCR4 genotype |
Other novel agents: BCL-2 and EZH2 inhibitors | |||||
 Venetoclax [210] (BCL-2 inhibitor) | WM | 31 | NA | 2y PFS 76%, ORR 87%, VGPR 19%, PR 61%, TTR 2 m | AEs: G4 neutropenia (n = 5), G3 neutropenia (n = 15), G3 anemia (n = 4), diarrhea (n = 4) |
 Tazemetostat [213] (EZH2 inhibitor) | FL | 99 | NA | MT EZH2: PFS 14 m, ORR 77% WT EZH2: PFS 11 m, ORR 34% | AEs: G ≥ 3 17% (all patients), most frequent thrombocytopenia (3%), anemia (2%), asthenia (2%), vomiting (1%), fatigue (1%), no G5 AE |
Antibodies, antibody–drug conjugates (ADC) and bispecific T cell engagers (BiTE) | |||||
 R-Polatuzumab vedotin [216] (CD79b-directed AB-drug conjugate) | FL | 20 | NA | PFS 15 m, ORR 70%, CRR 45% | G3–5 AEs (50%): neutropenia (15%), diarrhea (10%); one G5 event |
 Mosunetuzumab [217] (bispecific Ab targeting CD3, and CD20) | FL | 69 | NA | ORR 64%, CRR 44% | CRS: 28.4% (FL and aggressive NHL), most G1–2 G3 CRS: 1.4%, most CRS in cycle 1 |
Magrolimab (anti-CD47 Ab) | FL (35%), MZL (2%), DLBCL (63%) | 100 | 1–1.5 | ORR 61%, CRR 24% TTR 2 m DOR NR | AEs: infusion reactions (38%), headache (34%), chills (30%), fatigue (30%), anemia (27%), nausea (24%), pyrexia (23%) vomiting (13%), back pain (11%); majority G1/2 except G3 anemia (15%) |
Auto/allo HSCT and CAR-T | |||||
 HDT/ASCT versus no transplant [221] | FL | 162 | 11 | ASCT: 5y PFS 51%, OS 77% No transplant: 5y PFS 19%, OS 59% | *Among patients without cytoreduction failure, PFS not significantly different; second-line PFS is reported for patients with POD24 |
 Allo-SCT (MSD or MUD) versus ASCT [222] | FL (R/R) | 440 | 6 | ASCT: 5yPFS 38%, 5yOS 70% MSD: 5yPFS 52%, 5yOS 73% MUD: 5yPFS 43%, 5yOS 49% *After 6 m, MSD/MUD PFS > ASCT PFS | ASCT: 5y NRM 5% MSD: 5y NRM 17% MUD: 5y NRM 33% |
 Axicabtagene ciloleucel [237] (CD19-CAR T) (ZUMA-5) | FL, MZL | 94 | 11.5 m | PFS 23.5 m, OS NR, 12mOS 94%, ORR 94% (79% CR): FL ORR 95% (80% CR), MZL ORR 86% (71% CR) | Grade ≥ 3 AEs 83%: neutropenia (33%) and anemia (28%); grade ≥ 3 CRS: 11%; grade ≥ 3 neurologic events: 19% Median time to CRS: 4d; Median time neurotoxicity: 7d |