New developments in the treatment of chronic lymphocytic leukemia: role of obinutuzumab

Figures & data

Figure 1 Schematic representation of the putative mechanisms mediating rituximab’s anticancer activity in NHL cells.

Notes: The anti-CD20 monoclonal antibody rituximab has several mechanisms of action, including ADCC, which involves recruitment of effector cells, mediated by Fcγ receptors, CDC, and apoptosis induction. Adapted from Motta G, Cea M, Moran E, et al. Monoclonal antibodies for non-Hodgkin’s lymphoma: state of the art and perspectives. Clin Dev Immunol. 2010;doi:10.1155/2010/428253.⁴⁵

Figure 2 The structure and topology of CD20 and the epitopes recognized by rituximab, ofatumumab, and obinutuzumab.

Note: Adapted from Klein C, Lammens A, Schäfer W, et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MABs. 2013;5(1):22–31.²⁰

Table 1 Efficacy of obinutuzumab in CLL

Trial	Phase	n (type of patient population)	Obinutuzumab dosage and administrationa	Efficacy
GAUGUIN^Citation23,Citation27,Citation28	I	13 (R/R CLL)	400–2,000 mg Cycle 1: days 1 and 8 Cycles 2–8: day 1	ORR =62% Median PFS = NR Median DOR =10.5 months
	II	20 (R/R CLL)	1,000 mg Cycle 1: days 1, 8, and 15 Cycles 2–8: day 1	ORR =30% Median PFS =10.7 months Median DOR =8.9 months
GAUSS^Citation24	I	22 (R/R CLL, n=5)	Induction: 200–2,000 weekly ×4 weeks Maintenance: every 3 months for maximum of eight doses in patients with CR or PR at the end of induction (same dose as induction)	PR =23%
GALTON^Citation25,Citation26	Ib	41 (previously untreated CLL)	Cycle 1: 100 mg day 1, 900 mg day 2, 1,000 mg days 8 and 15 Cycles 2–6: 1,000 mg day 1	Obinutuzumab plus fludarabine and cyclophosphamide – ORR =62% (CR =10%) Obinutuzumab plus bendamustine – ORR =90% (CR =20%)
CLL11^Citation31	III	781 (untreated CLL in elderly)	1,000 mg Cycle 1: days 1, 8, and 15 Cycles 2–6: day 1	See Table 3
GAGE^Citation30	II	89 (untreated CLL)	1,000 mg cohort: Cycle 1: 100 mg day 1, 900 mg day 2, 1,000 mg days 8 and 15 Cycles 2–8: 1,000 mg day 1 2,000 mg cohort: Cycle 1: 100 mg day 1, 900 mg day 2, 1,000 mg day 3, and 2,000 mg days 8 and 15 Cycles 2–8: 2,000 mg day 1	1,000 mg cohort: ORR =49% 2,000 mg cohort: ORR =67% (P=0.08)

Notes:

a Represents all doses administered intravenously.

Abbreviations: CLL, chronic lymphocytic leukemia; R/R CLL, relapsed/refractory chronic lymphocytic leukemia; NR, not reported; DOR, duration of response; ORR, overall response rate; PFS, progression-free survival; PR, partial response.

Table 3 Ongoing or planned studies of obinutuzumab in CLL

Clinicaltrials.gov NCT Identifier	Phase	Regimen	Study population	Status
NCT02225275	NR	Obinutuzumab plus lenalidomide	Recurrent CLL/SLL	Not yet accruing
NCT02371590	I/II	Obinutuzumab plus lenalidomide	Previously untreated CLL/SLL	Not yet accruing
NCT01980875	III	Obinutuzumab plus idelalisib versus obinutuzumab plus chlorambucil	Previously untreated CLL	Not yet accruing
NCT02406742	I/II	CC-122 monotherapy, CC-122 plus rituximab, ibrutinib or obinutuzumab	R/R CLL/SLL	Not yet accruing
NCT01644253	Ib	TRU-016 plus rituximab or obinutuzumab	Three cohorts enrolling previously untreated CLL patients and 1 cohort enrolling patients with R/R CLL	Accruing
NCT02292225	Ib	Duvelisib plus obinutuzumab	R/R CLL previously treated with a BTK inhibitor	Accruing
NCT02264574	III	Ibrutinib plus obinutuzumab versus obinutuzumab plus chlorambucil	Previously untreated CLL/SLL	Accruing
NCT01414205	II	Obinutuzumab 1,000 mg versus 2,000 mg	Previously untreated CLL	Ongoing, not accruing
NCT02320487	II	Obinutuzumab plus bendamustine	Previously untreated CLL	Accruing
NCT01905943	IIIb	Obinutuzumab versus Obinutuzumab plus fludarabine, cyclophosphamide, and bendamustine or obinutuzumab plus chlorambucil	Previously untreated or relapsed/refractory CLL	Accruing
NCT02071225	II	Obinutuzumab and bendamustine	Refractory or relapsed CLL	Accruing
NCT01685892	Ib	Obinutuzumab and GDC-1099 (ABT-199)	Previously untreated or relapsed/refractory CLL	Accruing
NCT01414205	II	Obinutuzumab 1,000 mg versus 2,000 mg	Previously untreated CLL	Ongoing, not accruing
NCT02100852	I/IIb	Obinutuzumab plus TGR-1202 plus chlorambucil	CLL (exact population not defined)	Accruing
NCT01300247	Ib	Obinutuzumab plus bendamustine or fludarabine and cyclophosphamide	Previously untreated	Ongoing, not accruing
NCT02229422	I/II	Obinutuzumab plus high-dose methylprednisolone	Previously untreated	Accruing
NCT02296918	I	Obinutuzumab plus ACP-196	Cohort 1: R/R CLL Cohort 2: previously untreated	Accruing
NCT02315768	Ib/II	Ibrutinib plus obinutuzumab	Previously untreated (over 65 years of age or with co-morbidities)	Not yet open for accrual

Abbreviations: CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; NR, not reported; R/R, relapsed/refractory; BTK, Bruton’s Tyrosine Kinase.

Table 2 Efficacy and safety outcomes from CLL11

	Chlorambucil plus rituximab (safety analysis: n=321) (efficacy analysis: n=333)		Chlorambucil plus obinutuzumab (safety analysis: n=336) (efficacy analysis: n=330)
Efficacy
Median PFS, months	15.2		26.7
		P-value <0.002
Median OS, months	NR		NR
		P-value =0.09
ORR, %	65		78
CR rate, %	7		21
MRD negative, %
Bone marrow	2.6		19.5
Blood	3.3		37.7
Grade 3–5 adverse events
Overall, %	55		70
Neutropenia, %	28		33
Anemia, %	4		4
Thrombocytopenia, %	3		10
Leukopenia, %	1		4
Infections, %	7		7
Infusion-related reactions, %	4		20

Note: Adapted from Shah A. Obinutuzumab: a novel anti-CD20 monoclonal antibody for previously untreated chronic lymphocytic leukemia. Ann Pharmacother. 2014;48(10):1356–61. doi: 10.1177/1060028014543271.⁴⁶

Abbreviations: CLL, chronic lymphocytic leukemia; PFS, progression-free survival; OS, overall survival; NR, not reported; CR, complete response; ORR, overall response rate; MRD, minimal residual disease.

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