Anti-CD20 treatment for B-cell malignancies: current status and future directions

Figures & data

Figure 1. CD20 binding of type I and type II anti-CD20 monoclonal antibodies. Adapted from Goede et al. [62] and Klein et al. [47], with permission

Table 1. Characteristics of anti-CD20 monoclonal antibodies (mAbs) [46,47,59,61,90,101]

mAb	Status	Characteristics	ADCC	CDC	Direct effects	Epitope	Activity relative to rituximab*
Rituximab	Approved for NHL, CLL	Type I** Mouse/human chimeric IgG1	++	++	+	Class I Large extracellular loop Core epitope: ^168EPANPS^173 region Secondary epitope from cryo-EM: Ile76 of ECL1 and Pro160 of ECL2	NA
Obinutuzumab	Approved for CLL, FL	Type II** Humanized IgG1	++++	–	++++	Class II Large extracellular loop Core epitope: ^170ANPSEKNSP^178 region	↑ cell death mediated by non-apoptotic pathway involving ↑ ROS production + membrane permeabilization Fc modification ↑ affinity for Fcγ receptors: ↑ ADCC/ADCP Compensates for inhibitory KIR/HLA interactions ↑ overall B-cell depletion in whole blood
Ofatumumab	Approved for CLL	Type I** Human IgG1	++	++++	+	Class I Large extracellular loop Core epitope: ^146FLKMESLNFIRAHT^159 region Small extracellular loop: ^72IPAGIYAPI^80 region	↑ cell membrane proximity and slower dissociation ↑ CDC, maintained in presence of ↓ CD20 expression Does not induce apoptosis Similar ADCC
Ublituximab	In Phase 3 for NHL; Phase 2 CLL	Type I** Chimeric IgG1	++++	++	+	Class I Large extracellular loop Core epitope: ^158HT^159 and ^168EPAN^171 regions	Fc modification ↑ affinity for Fcγ receptors: ↑ ADCC ↑↑ NK cell-mediated ADCC regardless of surface CD20 expression ↑ NK cell-mediated degranulation in presence of CLL cells

+ to ++++ indicates level of cytotoxic activity, from low to very high; – indicates lack of cytotoxic activity; ↑ indicates increase; ↓ indicates decrease.

*See main text for full discussion and references.

**Type I characteristics include CD20 localization to lipid rafts, weak homotypic aggregation, high FcγRIIb-mediated CD20 modulation, and caspase-dependent or independent apoptosis induction; Type II characteristics include no CD20 lipid raft localization, strong homotypic aggregation, low FcγRIIb-mediated CD20 modulation, and caspase-independent apoptosis induction.

ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cell-mediated phagocytosis; CDC, complement-dependent cytotoxicity; CLL, chronic lymphocytic leukemia; cryo-EM, cryo-electron microscopy; FL, follicular lymphoma; HLA, class I human leukocyte antigen; Ig, immunoglobulin; KIR, killer cell immunoglobulin-like receptors; NA, not applicable; NHL, non-Hodgkin lymphoma; ROS, reactive oxygen species.

Figure 2. Structure and topology of CD20 and epitopes recognized by rituximab, obinutuzumab (GA101), ofatumumab, and ublituximab. Epitopes recognized by the different antibodies are highlighted as follows: ofatumumab (red), rituximab (yellow), obinutuzumab (purple), and the core epitope of ublituximab (boxed). Adapted from Klein et al. [47], with permission

Table 2. Survival and adverse events in key clinical studies of novel anti-CD20 monoclonal antibodies (mAbs) in chronic lymphocytic leukemia (CLL)

Study	No. and type of patients	Treatments*	Survival (median unless stated otherwise)	Significant differences between groups	Safety/tolerability
Obinutuzumab as first-line therapy
CLL11: primary analysis (May 2013) [114] NCT01010061 Phase 3	118	CLB 0.5 mg/kg d1 + d15 × 6 q28d	PFS 11.1 mo		AE grade ≥3 50% IRR grade ≥3 0% Neutropenia grade ≥3 16% Thrombocytopenia grade ≥3 4% Infection grade ≥3 14%SAE 38%Death due to AE 9%
	333	G 1000 mg d1–2, d8, + d15, then d1 c2–6 +  CLB 0.5 mg/kg d1 + d15 q28d	PFS 26.7 mo	p < 0.001 vs. RIT-CLB	AE grade ≥3 70% IRR grade ≥3 20% Neutropenia grade ≥3 33% Thrombocytopenia grade ≥3 10% Infection grade ≥3 12%SAE 39%Death due to AE 4%
	330	RIT 375 mg/m^2 d1 c1, then 500 mg/m^2 d1 c2–6 +  CLB 0.5 mg/kg d1 + d15 q28d	PFS 15.2 mo		AE grade ≥3 55% IRR grade ≥3 4% Neutropenia grade ≥3 28% Thrombocytopenia grade ≥3 3% Infection grade ≥3 14%SAE 32%Death due to AE 6%
CLL11: final analysis (October 2017) [112]	333	G 1000 mg d1–2, d8, + d15, then d1 c2–6 + CLB 0.5 mg/kg d1 + d15 q28d	PFS 28.9 mo	p < 0.0001 vs. RIT-CLB
			OS NR	p = 0.0245 vs. RIT-CLB
	330	RIT 375 mg/m^2 d1 c1, then 500 mg/m^2 d1 c2–6 +  CLB 0.5 mg/kg d1 + d15 q28d	PFS 15.7 mo
			OS 73.1 mo
Ofatumumab in relapsed or refractory disease
Hx-CD20-406 [118] NCT00349349 Phase 2	117 prior RIT (98 RIT-refractory)	OFA 300 mg d1, then 2000 mg wkly × 7, then 2000 mg monthly (12 doses total)	PFS 5.3 (95% CI 4.0–5.7) mo		IRR (related) grade ≥3 5%Neutropenia grade ≥3 16%Infection grade ≥3 31%
			PFS (RIT-refractory) 5.5 (95% CI 4.1–6.3) mo
			OS (all) 15.5 (95% CI 10.4–18.6) mo
	89 RIT-naïve		PFS 5.6 (95% CI 4.8–7.1) mo		IRRs (related) grade ≥3 9%Neutropenia grade ≥3 13%Infection grade ≥3 25%
			OS 20.2 (13.7–22.8) mo
Ublituximab in relapsed or refractory disease
GENUINE [120] NCT02301156 Phase 3	117 high-risk	IBR 420 mg daily	PFS 35.9 (17–NE) mo		Neutropenia grade ≥3 12%
		IBR 420 mg daily + UTX 900 mg d1, 8, 15 c1, then d1 c2–6, then q3c	PFS NR (NE–NE)		IRR grade ≥3 3%Neutropenia grade ≥3 19%

*Two G doses separated by forward slash = day 1/day 8 dose in cycle 1, with the second (day 8) dose given on day 1 of subsequent cycles.

AE, adverse event; c, cycle(s); CLB, chlorambucil; CI, confidence interval; d, day(s); G, obinutuzumab; IBR, ibrutinib; IRR, infusion-related reaction; mo, month(s); NE, not estimable; NR, not reached; OFA, ofatumumab; OS, overall survival; PFS, progression-free survival; q, every; RIT, rituximab; SAE, serious adverse event; UTX, ublituximab; wkly, once weekly.

Table 3. Progression-free and overall survival, and adverse events in key clinical studies of novel anti-CD20 monoclonal antibodies (mAbs) in indolent non-Hodgkin lymphoma (iNHL)

Study	No. and type of patients	Treatments*	Survival (median unless stated otherwise)	Significant differences between groups	Safety/tolerability
Obinutuzumab as first-line therapy
GALLIUM [121] NCT01332968 Phase 3	601 FL	CHOP, CVP, or BEN + G 1000 mg d1 + d8 + d15, then d1 c2–6 or 8 (CTX-dependent), then q2mo if response for ≤2 y	3-y PFS 80.0% (95% CI 75.9–83.6%)	p = 0.001 vs. RIT	AE grade ≥3 74.6% IRR grade ≥3 6.7% Neutropenia grade ≥3 43.9% Thrombocytopenia grade ≥3 6.1% Infection grade ≥3 19.8% SAE 46.1%Death due to AE 4.0%
			3-y OS 94.0% (95% CI 91.6–95.7%)	NS vs. RIT
	601 FL	CHOP, CVP, or BEN + RIT 375 mg/m^2 d1 c1–6 or 8 (CTX-dependent), then q2mo if response for ≤2 y	3-y PFS 73.3% (95% CI 68.8–77.2%)		AE grade ≥3 67.8% IRR grade ≥3 3.7% Neutropenia grade ≥3 37.9% Thrombocytopenia grade ≥3 2.7% Infection grade ≥3 15.6% SAE 39.9%Death due to AE 3.4%
			3-y OS 92.1% (95% CI 89.5–94.1%)
Obinutuzumab in relapsed or refractory disease
GAUSS [127] NCT00576758 Phase 2	88 relapsed (74 FL)	G 1000 mg wkly × 4, then maintenance if response for ≤2 y	PFS 17.6 mo (FL)	NS vs. RIT	IRR grade ≥3 11%Neutropenia grade ≥3 3%SAE 15%18 deaths (10 PD)
	87 relapsed (75 FL)	RIT 375 mg/m^2 wkly × 4, then maintenance if response for ≤2 y	PFS 25.4 mo (FL)		IRR grade ≥3 5%Neutropenia grade ≥3 7%SAEs 15%11 deaths (5 PD)
GADOLIN: primary analysis (September 2014) [128] NCT01059630 Phase 3	202 RIT-refractory (166 FL)	BEN 120 mg/m^2 d1 + d2 c1–6	PFS 14.9 mo		AE grade ≥3 62% IRR grade ≥3 6% Neutropenia grade ≥3 26% Thrombocytopenia grade ≥3 16% Anemia grade ≥3 10% SAE 33%Death due to AE 6%
			OS NR
	194 RIT-refractory (155 FL)	BEN 90 mg/m^2 d1 + d2 c1–6 +  G 1000 mg d1, d8, d15 c1, then d1 c2–6, then q2mo × 2y or until response	PFS NR	p = 0.0001 vs. BEN	AE grade ≥3 68% IRR grade ≥3 11% Neutropenia grade ≥3 33% Thrombocytopenia grade ≥3 11% Anemia grade ≥3 8% SAE 38%Death due to AE 6%
			OS NR	NS vs. BEN
GADOLIN: updated analysis (April 2016) [129] NCT01059630	209 RIT-refractory (171 FL)	BEN 120 mg/m^2 d1 +  d2 c1–6	PFS 14.1 mo		AE grade ≥3 65.5% IRR grade ≥3 3.4% Neutropenia grade ≥3 27.1% Thrombocytopenia grade ≥3 10.8% Infection grade ≥3 19.2% SAE 36.9%Death due to AE 6.4%
			OS NR; events 34.9%
	204 RIT-refractory (164 FL)	BEN 90 mg/m^2 d1 + d2 c1–6 +  G 1000 mg d1, d8, d15 c1, then d1 c2–6, then q2mo × 2y or until response	PFS 25.8 mo	p < 0.001 vs. BEN	AE grade ≥3 72.5% IRR grade ≥3 9.3% Neutropenia grade ≥3 34.8% Thrombocytopenia grade ≥3 15.8% Infection grade ≥3 22.5%SAE 43.6%Death due to AE 7.8%
			OS NR; events 25.5%	p = 0.0269 vs. BEN
Ofatumumab in relapsed or refractory disease
Maloney et al. (HOMER) [132] NCT01200589 Phase 3	205 (179 FL) relapsed after RIT	OFA 1000 mg wkly × 4, then q2mo × 4	PFS (IR) 16.2 mo (95% CI 15.7–21.5)	Study halted for futility	Any AE 93% IRR grade ≥3 4% Neutropenia any grade 3% Pyrexia any-grade 4%SAE NA
			PFS (investigator) 16.1 mo (95% CI 15.5–18.5)
			OS 45.9 mo (95% CI 39.2–NA)
	204 (167 FL) relapsed after RIT	RIT 375 mg/m^2 wkly × 4, then q2mo × 4	PFS (IR) 21.2 mo (95% CI 16.3–25.2)		Any AE 82% IRR grade ≥3 0% Neutropenia 7% Pyrexia any-grade 10% SAE NA
			PFS (investigator) 17.9 mo (95% CI 16.1–21.6)
			OS 47.1 mo (95% CI 45.5–NA)
Czuczman et al. [133] NCT00394836 Phase 3	30 RIT-refractory FL	OFA 300 mg d1, then 500 mg wkly from d8 (8 doses total)	PFS 5.8 mo (overall population) OS NR		IRR grade ≥3 3%Neutropenia grade ≥3 15%Thrombocytopenia grade ≥3 3%Infection grade ≥3 3%Death due to AE 4%
	86 RIT-refractory FL	OFA 300 mg d1, then 1000 mg wkly from d8 (8 doses total)

*Two G doses separated by forward slash = day 1/day 8 dose in cycle 1, with the second (day 8) dose given on day 1 of subsequent cycles.

AE, adverse event; BEN, bendamustine; c, cycle(s); CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CI, confidence interval; CTX, chemotherapy; CVP, cyclophosphamide, vincristine, and prednisone; d, day(s); FL, follicular lymphoma; G, obinutuzumab; IR, independent review; IRR, infusion-related reaction; mo, month(s); NA, not available; NR, not reached; NS, non-significant; OFA, ofatumumab; OS, overall survival; PD, disease progression; PFS, progression-free survival; q, every; RIT, rituximab; SAE, serious adverse event; wkly, once weekly; y, year(s).

Table 4. Survival and adverse events in key clinical studies of novel anti-CD20 monoclonal antibodies (mAbs) in aggressive non-Hodgkin lymphoma (aNHL)

Study	No. and type of patients	Treatments*	Survival (median unless stated otherwise)	Significant differences between groups	Safety/tolerability
Obinutuzumab as first-line therapy
GOYA: primary analysis (April 2016) [134] NCT01287741 Phase 3	706 DLBCL	CHOP + G 1000 mg d1 + d8 + d15, then d1 c2–8	3-y PFS 69.6%	NS vs. RIT	AE grade ≥3 73.7% IRR all grades 36.1% Neutropenia grade ≥3 46.2% Infection grade ≥3 19.2%SAE 42.6%Death due to AE 5.8%
			3-y OS 81.2% (95% CI 77.9–84.1%)	NS vs. RIT
			3-y EFS 69.9% (95% CI 66.2–73.2%)	NS vs. RIT
	712 DLBCL	CHOP + RIT 375 mg/m^2 d1 c1–8	3-y PFS 66.9%		AE grade ≥3 64.7% IRR all grades 23.5% Neutropenia grade ≥3 38.1% Infection grade ≥3 15.5%SAE 37.6%Death due to AE 4.3%
			3-y OS 81.4% (95% CI 78.1–84.3%)
			3-y EFS 66.5% (95% CI 62.7–70.1)
GOYA: final analysis (January 2018) [135]	704 DLBCL	CHOP + G 1000 mg d1 + d8 + d15, then d1 c2–8	5-y PFS 63.8% (95% CI 59.3–68.0)	NS vs. RIT	AE grade ≥3 75.1% Neutropenia grade ≥3 47.9%SAE 44.4%Death due to AE 6.1%
			5-y OS 77.0% (95% CI 73.3–80.3)	NS vs. RIT
			5-y EFS 60.6% (95% CI 56.3–64.6)	NS vs. RIT
	710 DLBCL	CHOP + RIT 375 mg/m^2 d1 c1–8	5-y PFS 62.6% (95% CI 58.1–66.8)		AE grade ≥3 65.8% Neutropenia grade ≥3 39.5%SAE 38.4%Death due to AE 4.4%
			5-y OS 77.7% (95% CI 74.1–80.9)
			5-y EFS 58.9% (95% CI 54.5–63.1)
Ofatumumab in relapsed or refractory disease
van Imhoff et al. (ORCHARRD) [139] NCT01014208 Phase 3	222 DLBCL	OFA 1000 mg d1 + d8, then d22 & d43 + DHAP	2-y PFS 24%	p = 0.33 vs. RIT	Neutropenia grade 4 22%Thrombocytopenia grade 4 35%SAE 52% across study; similar between groups
			2-y EFS 16%	p = 0.35 vs. RIT
			OS 13.9 mo	p = 0.38 vs. RIT
	223 DLBCL	RIT 375 mg/m^2 d1 + d8, then d22 & d43 + DHAP	2-y PFS 26%		Neutropenia grade 4 26%Thrombocytopenia grade 4 35%
			2-y EFS 18%
			OS 13.2 mo

*Two G doses separated by forward slash = day 1/day 8 dose in cycle 1, with the second (day 8) dose given on day 1 of subsequent cycles.

AE, adverse event; c, cycle(s); CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CI, confidence interval; d, day(s); DHAP, cisplatin, cytarabine, and dexamethasone; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; G, obinutuzumab; IRR, infusion-related reaction; mo, month(s); NS, non-significant; OFA, ofatumumab; OS, overall survival; PFS, progression-free survival; q, every; RIT, rituximab; SAE, serious adverse event; wkly, once weekly; y, year.

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