Recent advances in treatment of nodal and gastrointestinal follicular lymphoma

Table 1 Summary of clinical trial results of monoclonal antibody-based therapies

Study	Target disease	No. of patients	Objective response rate	Complete response rate	Median progression-free survival	Overall survival	Adverse events or other subjects	Ref.
Tafasitamab plus lenalidomide phase-II L-MID	r/r DLBCL (no FL) > 35 mo follow up	n = 80	57.5% (n = 46/80)	40.0% (n = 32/80)	11.6 mo	33.5 mo	No unexpected toxicity	[14]
Phase-II ROMULUS, rituximab-polatuzumab vs rituximab-pinatuzumab	r/r FL	n = 42, n = 20, n = 21	70% (n = 14/20); 62% (n = 13/21)	45% (n = 9/20); 5% (n = 1/21)	Unknown	Unknown		[15]
Loncastuximab tesirine (ADTC-402) frontline therapy	Untreated FL	Total, DLBCL, MZL, FL	45.6%, 42.3%, 46.7%, 78.6%	26.7%	Unknown	Unknown	Median duration response: 5.4 mo	[16]
Magrolimab plus rituximab phase-Ib	r/r DLBCL; r/r FL	n = 22; DLBCL:15; FL: 7	50% (CR or PR); 40%, 71% (n = 5/7)	33%, 43% (n = 3/7)	Unknown	Unknown	90% response were on going, a median follow-up of 6.2 (DLBCL)/8.1 (FL) mo	[17]
Venetoclax plus obinutumab phase-I	Untreated FL	CT, PET/CT	87.5%, 84.2%	25.0%, 68.4%	77.8% (at one yr); 79.0% (at one yr); 73.2% (at 30 mo); 79.0% (at 30 mo)	Unknown; unknown		[19]
GALLIUM trial obinutuzumab + CTx rituximab + CTx	Untreated FL	n = 1202, n = 601, n = 601	88.5%, 86.9%	Unknown, unknown	80.0% (at 3 yr); 73.3% (at 3 yr)	Unknown, unknown	Obinutuzumab is better	[20,21]

“Unknown” means data not shown, unknown information or not reached. r/r: Refractory and relapsed; FL: Follicular lymphoma; DLBCL: Diffuse large B-cell lymphoma; MZL: Marginal zone lymphoma; (R-)CHOP: (Rituximab plus) cyclophosphamide, doxorubicin, vincristine, and prednisolone; CT: Computed tomography; PET/CT: Positron emission tomography/computed tomography; CTx: Traditional chemotherapy.

Table 2 Summary of clinical trial results of bispecific T cell binding antibody therapies

Study	Target disease	No.of patients	Objective response rate	Complete response rate	Median progression-free survival	Overall survival	Adverse events or other subjects	Ref.
Mosunetuzumab alone, phase-I	r/r NHL (including FL and t-FL)	n = 157	66.2% (i B-NHL)	48.5% (i B-NHL)	Median duration of response 20.4 mo (i B-NHL	Unknown	G3 and higher in 71% of iNHL patients	[24]
Mosunetuzumab alone, phase-II	r/r FL (Grade 1-3a)	n = 90 (median follow-up was 18.3 mo)	Unknown	60% (n = 54/90) (14% higher than CRR with copanlisib), high efficacy	Unknown	Unknown	High efficacy	[25]
Mosunetuzumab with lenaridomide, phase-I	r/r FL	Unknown	92%	77%	Unknown	Unknown	G3 and higher in 30% of patients	In abstruct
Glofitamab alone, phase-I	r/r B-NHL (including r/r FL)	n = 155	65.7% (at the recommended phase-II dose)	57.1% (at the recommended phase-II dose)	Unknown	Unknown	CRS occurred in 50.3% of patients	[26]
Glofitamab alone vs glofitamab with obinutuzumab	r/r FL	Unknown	81%, 100%	70%, 74%	Unknown	Unknown	Combination has a better response rate	In Abstruct
Epcoritamab, phase-I/II	r/r B-NHL	n = 68	90% (full dose)	50% (full dose)	Unknown	Unknown	Pyrexia 69%, CRS 59%	[27]
Epcoritamab with lenaridomide and rituximab	r/r FL	Unknown	100%	93%	Unknown	Unknown	High efficacy is revealed	[28]
Odronextamab alone phase-I ELM-1 trial	r/r B-NHL (including r/r FL)	n = 145	91% (r/r FL)	72% (r/r FL)	Unknown	Unknown	CRS 28%	[29]

“Unknown” means data not shown, unknown information or not reached. r/r: Refractory and relapsed; (i)NHL: (Indolent) non-Hodgkin lymphoma; i B-NHL: Indolent B-cell non-Hodgkin lymphoma; FL: Follicular lymphoma; t-FL: Transformed follicular lymphoma; G: Grade; CRS: Cytokine release syndrome.

Table 3 Summary of clinical trial results of anti-programmed death ligand 1 antibody-based therapies

Study	Target disease	No. of patients	Objective response rate	Complete response rate	Median progression-free survival	Overall survival	Adverse events or other subjects	Ref.
Atezolitumab (anti-PD-1 antibody) plus obinutumab	Total	n = 49				Unknown		[31]
phase-I	r/r FL	n = 26	54%	23%	9 mo
	r/r DLBCL	n = 23	17%	4%	3 mo
Pembrolizumab(anti-PD-1antibody) plus rituximab	r/r FL (one or more prior therapy)	n = 30	67%	50%	12.6 mo	97% (at 3 yr)	23% in remission at medianfollow-up of 35 mo	[32]

“Unknown” means data not shown, unknown information or not reached. r/r: Refractory and relapsed; FL: Follicular lymphoma; DLBCL: Diffuse large B-cell lymphoma; PD-1: Programmed death ligand 1.

Table 4 Summary of clinical trial results of immunomodulator-based therapies

Study	Target disease	No.of patients	Objective response rate	Complete response rate	Progression-free survival	Overall survival	Adverse events or other subjects	Ref.
Randomized phase-II; lenaridomide alone (L) lenaridomide + rituximab (LR)	r/r FL	n = 91, n = 45 (L); n = 46 (LR)	53%, 76%	20%, 39%	Median time to progression: 1.1 yr (at 2.5 yr); 2.0 yr (at 2.5 yr)	Unknown		[34]
Phase-III AUGMENT lenaridomide + R (R2) vs lenaridomide + placebo	r/r FL; r/r MZL	n = 358; n = 180; n = 178	Unknown	Unknown	Median duration: 39.4 mo; 14.1 mo	Unknown	Grade 3 neutropenia of R2 is higher than L	[35]
Phase-IIIb MAGNIFY trial; R maintain after R2 additional lenarimide + rituximab (R2) 18 mo after R2	r/r FL; r/r MZL	n = 393	69% (R2)	40% (R2)	40 mo (similar to AUGMENT trial)	Unknown		[36]
Phase-II GALEN study; lenarimide + obinutuzumab (R2) 18 mo followed by obinutuzumab alone maintenance therapy 1 year	r/r FL	n = 68; evaluable	95% (at 2.6 yr)	38% (n = 33/86)	65% (at 2 yr)	87% (at 2 yr); 81% (n = 70/86); 84% (n = 72/86)		[37]
Phase-III RELEVANCE study, lenaridomide + rituximab (R2) + Rituximab maintenance therapy vs CTx (R-CHOP, BR, or R-CVP)	Untreated advanced FL	n = 1030; R-maintenance, n = 513; CTx, n = 517	Unknown	48%-53%, about the same	3 years-PFS 77%-78%, almost equal to superiority of R2 in F2 frontline not proven	Unknown		[38]
	Untreated advanced FL		Unknown	All 3 groups approximately 90%, about the same	3 yr PFS (5 yr median follow-up); -R 77%, BVR-R 82%, BR-LR 76% (higher in the R- maintenance group than in the R2 group) because of more discontinuations in the R2 group)	3 yr PFS (5 yr median follow-up), BR-R 87%, BVR-R 90%, BR-LR 84%		[39]
Single center phase-II frontline therapy; lenaridomide plus obinutuzumab	Untreated advanced FL	n = 90	98% (after a median follow-up of 22 mo)	92% (after a median follow-up of 22 mo)	2 yr-PFS 96 (after a median follow-up of 22 mo)	Unknown		[40]

“Unknown” means data not shown, unknown information or not reached. r/r: Refractory and relapsed; FL: Follicular lymphoma; MZL: Marginal zone lymphoma; L: Lenaridomide; R: Rituximab; LR: Lenaridomide plus rituximab; R2: Lenaridomide plus rituximab; (R-)CHOP: (Rituximab plus) cyclophosphamide, doxorubicin, vincristine, and prednisolone; BR: Bendamustine plus rituximab; (R-)CVP: (Rituximab plus) cyclophosphamide, vincristine and prednisolone; BR-R: BR induction followed by 2-year rituximab maintenance; BVR-R: BR with bortezomib and rituximab maintenance; BB-LR: BR followed by lenalidomide (1 year) with rituximab maintenance; CTx: Traditional chemotherapy.

Table 5 Summary of Clinical Trial Results of Bruton’s Tyrosine Kinase inhibitors

Study	Target disease	No. of patients	Objective response rate	Complete response rate	Progression-free survival	Overall survival	Adverse events or others	Ref.
Zanubrutinib (other BTKi) alone	r/r FL		36.4%	18.2%	Median PFS 10.4 mo (median follow-up 33.9 mo)	Unknown		[42]
Zanubrutinib phase-II	r/r MCL	83.7%	77.9%	Unknown	33.0 mo	Unknown		[43]
	r/r FL	n = 100	21.0% (poor)	Unknown	Unknown	Unknown		[47]
Ibrutinib with rituximab phase-II trial	Untreated FL, r/r FL	n = 13, n = 27	85% (arm-1), 75% (arm-2)	Unknown	62% of untreated FL, 26% of r/r FL, continued treatment	Unknown		[48]

“Unknown” means data not shown, unknown information or not reached. r/r: Refractory and relapsed; FL: Follicular lymphoma; MCL: Mantle cell lymphoma; PFS: Progression-free survival.

Table 6 Summary of clinical trial results of epigenetic regulators

Study	Targeted disease	No. of patients	Objective response rate	Complete response rate	Progression-free survival	Overall survival	Adverse events or others	Ref.
Tazemetostat alone, phase-II	r/r FL, EZH2-mut; FL, EZH2-wt. FL	n = 99, mut FL n = 45; wt FL n = 54	69% (EZH2 mut); 35% (EZH2 wt)	Unknown; unknown	Median PFS: 13.8 mo (EZH2 mut); 13.1 mo (EZH2 wt)	Unknown	G3 or higher 27%+, treatment discontinued at 8%	[54]
Tazemetostat (first EZH2 inhibitor) vs inderalisib, duvelisib, copanlishib, umbralisib	r/r FL, systematic literature review		Tazemetostat vs inderalisib 43% vs 56; duvelisib 48% vs 47; Kopanlisib 49% vs 61; umbralisib 57% vs 47; no significant difference in either case	Unknown	Unknown	Unknown	Predominantly reduced risk of adverse events compared to PI3Ki	[57]
Vorinostat (HDACi), phase-II	r/r Inhl + MCL, median with one or more prior treatment	n = 39 (r/r FL)	49%	Unknown	Median PFS, 20 mo	Unknown	G3 or higher 8%	[58]
Vorinostat + rituximab, phase-II	Untreated and r/r FL (4 or less prior treatment)	n = 22	46% (all patients); 67% (untreated pts); 41% (r/r FL)	Unknown	Median PFS, 29.2 mo (all patients); not reached (untreated pts); 18.8 mo (r/r FL)	Unknown		[59]
Mocetinostat, phase-II	r/r DLBCL, r/r FL	n = 41, n = 31	18.9% (r/r DLBCL), 11.5% (r/r FL)	Unknown	1.8-22.8 mo (DLBCL); 11.8-26.3 mo (FL)	Unknown	Fatigue (75.0%); nausea (69.4%); diarrhea (61.1%)	[60]

“Unknown” means data not shown, unknown information or not reached. r/r: Refractory and relapsed; FL: Follicular lymphoma; EZH2: Enhancer of zeste homolog 2; mt: Mutant; wt: Wild type; (i)NHL: (Indolent) non-Hodgkin lymphoma; DLBCL: Diffuse large B-cell lymphoma; MZL: Marginal zone lymphoma; MCL: Mantle cell lymphoma; G: Grade; PI3Ki: Phosphoinositide 3 kinase inhibitor.

Table 7 Summary of Clinical Trial Results of phosphoinositide 3 kinase inhibitors

Study	Target disease	No. of patients	Objective response rate	Complete response rate	Progression-free survival	Overall survival	Adverse events or others	Ref.
Indelalisib, phase-II DELTA trial	r/r FL	n = 55	73% (highest ever reported)	Unknown	72% disease-free after 12 mo	80% alive after 12 months	54% of G3 or higher	[65]
Indelalisib phase-II open-labeled trial	r/r NHL (including FL), median of 4 lines prior therapy	iNHL, n = 72; FL, n = 42)	57%	Unknown	11 mo	Unknown	54% of G3 or higher	[66]
Duvelisib	iNHL (including FL)	n = 187	70% good	Unknown	Unknown	Unknown	63% of G3 or higher	[63,69]
Conpalisib, phase-II CHRONOS-1 trial	r/r FL, median 3-lines of prior therapy	n = 142	59%	12%	11 mo (median)	43 mo (median)	G3 84%, 6 cases of G5 events	[70,71]
Umbralisib, phase-II trial	iNHL (including FL) median 3-lines or more of prior therapy	n = 208 (FL = 117)	47.1% of (after a median follow-up of 27.7 mo)	Unknown	10.6 mo (median PFS)	Unknown		[74]
Parsaclisib, phase-Ib, CITADEL-111 trial	Japanease: r/r FL; r/r MZL; r/r DLBCL	n = 9; n = 2; n = 6	9 cases (= 100%); 2 cases (= 100%); 1 case (= 16.7%)	22.2% (n = 2/9); 100% (n = 2/2); 16.7% (n = 1/6)	Unknown	High incidence of adverse events-need to carefully select target patients	Neutropenia above G3 interrupted in 58.8% and reduced in 29.4%	[75]
Parsaclisib, phase-I/II (phase-II trial is ongoing)	r/r B-NHL	n = 72	71% (r/r FL); 78% (r/r MZL); 67% (r/r MCL); 30% (r/r DLBCL)	Unknown	Unknown	Unknown	G3/4 neutropenia occurred in 19%	[76]
Zandelisib (ME-401), phase-I trial	Japanese, r/r iNHL	n = 9	100% (n = 9/9)	22% (n = 2/9), median duration of response 7.9 mo; median time to response 1.9 mo		Unknown	G3 or higher neutropenia 6/9 (55.6%) diarrhea 3/9 (33.3%) and many events	[77]
Zandelisib alone vs zandelisib + rituximab	r/r FL	n = 12	92% (n = 11/12) in the 60 mg group; 83% (n = 5/6) in the 180 mg group	Unknown	Unknown	Unknown		[78]
	r/r iNHL, median 3-lines of prior therapy	n = 30 + BR (n = 19) vs + R-CHOP (n = 11)	90% (+ BR) vs 100% (+ R-CHOP)	Unknown	Unknown	Unknown	G3 or higher, high rate of 70% (BR), 91% (R-CHOP)	[79]

“Unknown” means data not shown, unknown information or not reached. r/r: Refractory and relapsed; FL: Follicular Lymphoma; B-NHL: B-cell non-Hodgkin lymphoma; (i)NHL: (Indolent) non-Hodgkin lymphoma; DLBCL: Diffuse large B-cell lymphoma; MZL: Marginal zone lymphoma; MCL: Mantle cell lymphoma.

Table 8 Summary of clinical trials results of chimeric antigen receptor T-cell therapies

Study	Target disease	No. of patients	Objective response rate	Complete response rate	Progression-free survival	Overall survival	Adverse events and others	Ref.
Axicabtagene ciloleucel (Axi-cell), phase-II	r/r DLBCL, t-FL	n = 101	82%	40%	Unknown	52% (overall survival rate at 18.8 mo)	Neutropenia 78%; anemia 43%; thrombocytopenia 38%	[90]
Tisagenlecleucel (Tisa-cell), phase-II JULIET trial	r/r DLBCL	n = 93	52%	40%	65% (relapse-free survival rate)	Unknown	CRS 22%; neurologic events 12%; infections 20%	[91]
Axicabtagene ciloleucel (Axi-cell), phase-II	r/r iNHL (FL and MZL) after 2 or more treatment	n = 148, n = 124 (FL), n = 24 (MZL)	92%	74%	Unknown	Unknown	Serious adverse events (any grade) occurred in 50% of all	[93]
Tisagenlecleucel (Tisa-cell), phase-II ELARA trial	r/r FL (with 2 and more prior treatments)	n = 97	86.2%	69.1%	Unknown	Unknown	CRS 48.5% (> G3) neurological events 37.1% (> G3)	[96]
Lisocabtagene maraleucel (Liso-cell), phase-II	r/r large BCL	n = 61	80% (median follow-up 12.3 mo)	Unknown	Unknown	Unknown	Neutropenia 48%, thrombocytopenia 20%, CRS 38%	[99]

“Unknown” means data not shown, unknown information or not reached. r/r: Refractory and relapsed; FL: Follicular lymphoma; t-FL: Transformed follicular lymphoma; (i)NHL: (Indolent) non-Hodgkin lymphoma; DLBCL: Diffuse large B-cell lymphoma; BCL: B-cell lymphoma; MZL: Marginal zone lymphoma; CRS: Cytokine release syndrome.