Targeted treatment for chronic lymphocytic leukemia

Figures & data

Table 1 Monoclonal antibodies in CLL

Study	Patient population	Treatment regimen	Response (%)			Median DOR (months)
			OR	CR	PR
O’Brien et al^Citation40	Relapsed CLL	Rituximab dose escalation	36a	0	36	8
Tam et al^Citation43	Untreated CLL	Fludarabine, cyclophosphamide, rituximab (FCR)	95	72	10b	80
Wierda et al^Citation48	Relapsed CLL	Ofatumumab single agent	58c 47	0 1	58 47	5.7d and 5.9
Wierda et al^Citation49	Untreated CLL	Ofatumumab, fludarabine, cyclophosphamide (O-FC)	77e 73	32f 50	NR NR	Not reached
Morschhauser et al^Citation51	Relapsed CLL	Afutuzumab single agent	62	1g	7h	Not reached
Morschhauser et al^Citation53	Relapsed non-Hodgkin’s lymphoma	Veltuzumab single agent	0	0	0	Not reached
Osterborg et al^Citation56	Relapsed CLL	Alemtuzumab single agent	42	4i	38	12
Nabhan et al^Citation57	Relapsed CLL	Alemtuzumab and rituximab combination^*	52	8	40j	6
Furman et al^Citation64	Relapsed CLL	Dacetuzumab single agent	NR	0	0k	NR
Woodworth et al^Citation66	Relapsed CLL	Lumiliximab	NR	0	0l	NR
Byrd et al^Citation67	Relapsed CLL	Lumiliximab in combination with FCR	71	48	10	NR
Frankel et al^Citation71	Relapsed CLL	Ontak single agent	NR	0	17m	NR

a Notes: OR was 36% and ranged between 22% and 75%;

b PR nodular in 10%, PR due to cytopenias in 7%, and PR with residual disease in 6%;

c,d OR were 58% and 47% in the FA-ref and BF-ref groups, 1 CR in the BF-ref group otherwise all responses were PR, median duration of response was 5.7 months in the FA-ref group and 5.9 months in the BF-ref group;

e,f OR was 77% and CR was 32% for group A receiving ofatumumab at 500 mg after initial dose of 300 mg in combination with fludarabine and cyclophosphamide, OR was 73% and CR was 50% for group B receiving ofatumumab at 1000 mg after initial dose of 300 mg in combination with fludarabine and cyclophosphamide; both groups received total of 6 cycles;

g,h CRi 1 and 7 PR was reported;

i CR attained in bone marrow in 36% of patients;

j alemtuzumab was given at escalating dose to a maximum of 30 mg in combination with rituximab, PR 40% and partial remission nodular (PRn) was 4%;

k No patients achieved objective response, 5 patients demonstrated stable disease;

l reductions in lymphocyte counts were noted in 91% and reduction in size of lymph nodes was noted in 59% of patients;

m PR was reported as 17% and 58% minimal responses, progression free interval in responders ranged between 1 and 19+ months.

Abbreviations: CR, complete response; CCL, chronic lymphocytic leukemia; DOR, duration of response; NR, not reported; OR, overall response; PR, partial response.

Table 2 Preclinical agents in CLL

Drug	Oncogene or antigen	Mechanism of action	Developmental phase	Study
ABT-737	Bak/Bax	Restores apoptosis	Phase I/II	van Delft et al^Citation16
A-443654	Akt	Restores apoptosis	Phase I	de Frias et al^Citation100
Geldanamycin	Hsp 90	Restores apoptosis	Phase I	Lin et al^Citation107
Mapatumumab	TRAIL	Restores apoptosis	Phase I	Natoni et al^Citation80
TRU-016	CD37	ADCC	Phase I	Furman et al^Citation61
XmAb5574	CD19	ADCC	Phase I	Awan et al^Citation60

Abbreviations: ABT-737, isomer of gossypol; Akt, protein kinase; Hsp 90, heat shock protein; TRAIL, tumor necrosis factor related ligand; XmAb5574, anti-CD19 monoclonal antibody; ADCC, antibody-dependent cellular cytotoxicity; CLL, chronic lymphocytic leukemia.

Table 3 Investigational agents in chronic lymphocytic leukemia

Drug	Target
AMD3100	CXCR4 antagonist
Acadesinea	Protein kinase activator
Bafetinib	Lyn kinases
Bevacizumab	VEGF
CAT-8015	Anti-CD22 immunotoxin
CAL-101	PI3 kinase inhibitor
GS-9219b	Lymphoid cells
PR0131921c	CD 20
SCH 727965	Cyclin dependent kinase inhibitor
SDX-101d	Cytotoxic
MEDI-538e	CD 19

a Notes: 5 aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside;

b prodrug of nucleotide analog 9-(2- phosphonylmethoxyethyl) guanine (PMEG);

c third-generation monoclonal antibody;

d nonsteroidal anti-inflammatory drug;

e T cell activation.

Abbreviation: VEGF, vascular endothelial growth factor.

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