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Fcγ Receptor Polymorphisms and Clinical Efficacy of Rituximab in Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia
Review
Fcγ Receptor Polymorphisms and Clinical Efficacy of Rituximab in Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia Yun Zhuang,1,2 Wei Xu,2 Yunfeng Shen,1 Jianyong Li2 Abstract It has been 40 years since the discovery of Fcγ receptors (FcγRs) and their function. FcγRs regulate a variety of immune responses, including phagocytosis, degranulation, antibody-dependent cellular cytotoxicity, transcriptional regulation of cytokines, chemokine expression, B-cell activation, and immune complex clearance. It is well known that FcγRs serve as a critical link between the humoral and cellular branches of the immune system and play an important role in many conditions, including infection, cancer, and autoimmune diseases. Recent studies suggest that FcγR polymorphisms influence efficacy and side effects of monoclonal antibody–based immunotherapy, which might provide a useful prognostic marker for treatment in the future. Rituximab has been proven effective in treating patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Some FcγR genotypes correlate with rituximab efficacy in patients with NHL but not in patients with CLL. In this review, FcγR function and the association between FcγR polymorphisms and rituximab efficacy in NHL and CLL are discussed. Clinical Lymphoma, Myeloma & Leukemia, Vol. 10, No. 5, 347-352, 2010; DOI: 10.3816/CLML.2010.n.067 Keywords: Monoclonal antibody, Natural killer cell, Rituximab
Introduction Rituximab is a mouse/human chimeric immunoglobulin (Ig)G1 monoclonal antibody (MoAb) that targets the CD20 antigen on the surface of malignant and normal B lymphocytes.1 After being approved to treat resistant and relapsed indolent lymphoma by US Food and Drug Administration (FDA) in 1997, rituximab alone or in combination with chemotherapy has changed the clinical approach and improved the outcome of patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).24 The precise biologic mechanism is still debatable, but several in vitro and in vivo studies have shown that rituximab mediates its antitumor effect by antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and the induction of apoptosis.5 Antibody-dependent cellular cytotoxicity is the leading candidate for rituximab’s antitumor effect and is exerted 1Department
of Hematology, Wuxi People Hospital Affiliated of Nanjing Medical University, Wuxi, Jiangsu, China 2Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu, China Submitted: May 17, 2010; Revised: Jun 16, 2010; Accepted: Jul 12, 2010 Address for correspondence: Jianyong Li, PhD, Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Rd, Nanjing, Jiangsu, 210029, China Fax: 86-25-8378-1120; e-mail: [email protected]
by effector cells such as natural killer (NK) cells and macrophages via the Fc receptors (FcRs) on their cell surface. FcRs belong to Ig superfamilies that have corresponding structure to each subclass of Ig. Fcγ receptors (FcγRs) react specifically with the Fc region of IgG.6 Rituximab, an IgG1 MoAb, binds to CD20 on the surface of tumor cells and then bridges effector cells via the FcγRs. The effector cells then become activated and kill the antibodycoated tumor cells. The effectiveness of ADCC may depend on the degree of activation of effector cells after engagement to FcγRs. Polymorphisms for FcγR genes have been shown to alter interaction between the Fc region of IgG and FcγRs, thereby leading to different ADCC and rituximab efficacy. This review will focus on the polymorphisms of FcγRs and summarize the application of this information to the treatment of patients with NHL and CLL with rituximab.
Fcγ Receptor Structure and Function Fcgγ receptors are divided into 3 classes, FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16), comprising 8 isoforms (FcγRIa/b/c, FcγRIIa/b/c, FcγRIIIa/b). These receptors differ in molecular weight, structure, cellular distribution, affinity for IgG subclasses, and role in immunity (Table 1), although they are encoded by genes clustered on the long arm of chromosome 1 (1q21-q24) and show extensive nucleotide sequence homology.6-8
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #2152-2650, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
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FcγR Polymorphisms and Rituximab Efficacy in NHL and CLL Table 1 General Characteristics of Fcγ Receptors Characteristic
FcγRI
Isoforms
FcγRIa/b/c
Molecular
72 kD
Celluar Distribution Affinity
FcγRII FcγRIIa
FcγRIII
FcγRIIb
FcγRIIc
FcγRIIIa
40 kD
Phagocytes
All myeloid cells
High
FcγRIIIb 50-80 kD
Phagocytes, B cells NK cells
Monocytes, γg/δd T cells, macrophages, NK cells
Low
Neutrophils Low
IgG1 ≥ IgG3 > IgG4 > IgG2
IgG3 ≥ IgG1/IgG2 > IgG4
IgG3 ≥ IgG1 > IgG4 > IgG2
NR
IgG1/IgG3 > IgG2 /IgG4
NR
Antigen presentation
Phagocytosis and degranulation
Inhibitory effects on antibody
NR
ADCC lymphokine production
Synergism with FcγRIIa
Polymorphisms
None
131H/131R
232I/232T
NR
158V/158F
NA1/NA2
Affinity for MoAbs
None
131H > 131R
232I > 232T
NR
158V > 158F
NA1 > NA2
Affinity for IgG Subclass Functions
Abbreviations: ADCC = antibody-dependent cellular cytotoxicity; Ig = immunoglobulin; MoAbs = monoclonal antibodies; NK = natural killer; NR = not reported
Structurally, all FcγRs bear an extracellular portion made of 2 or 3 Ig-like domains, a transmembrane region, and an intracytoplasmic tail.8,9 Functionally, FcγRs are classified in 2 categories: stimulatory FcγRs and inhibitory FcγRs. Stimulatory FcγRs include FcγRI, FcγRIIa, FcγRIIc, and FcγRIIIa. They transmit signals via immunoreceptor tyrosine-based activation motifs (ITAMs) in cytoplasmic domain, cause tyrosine phosphorylation of protein Src and Cb1, and activation of phosphoinositide 3-kinase and phospholipase C and D. Then those activated molecules induce the generation of second messengers and a series of changes that finally mediate cell activation.10,11 FcγRIIb, the unique inhibitory FcγR, downregulates the above molecules by recruiting Src homology 2-containing inositol phosphatase (SHIP) to immunoreceptor tyrosine-based inhibitory motifs (ITIMs).12,13 Coexpression of stimulatory and inhibitory FcγRs maintains protective and pathogenic innate effector responses in immune homeostasis, whereas imbalances between them can contribute to autoimmune disorders.13,14 FcγRs regulate a variety of humoral and cellular immune responses, including phagocytosis, degranulation, ADCC, transcriptional regulation of cytokines, chemokine expression, B-cell activation, and immune complex clearance. FcγRI facilitates antigen presentation to T cells. FcγRIIa induces phagocytosis and degranulation. FcγRIIa is unique in its capacity to interact with IgG2, and may be crucial for clearance of encapsulated bacteria. FcγRIIb may exert inhibitory effects on antibody responses. FcγRIIIa induces ADCC and lymphokine production, implying a role for this receptor in host defense against viral infections and malignancies. FcγRIIIb and FcγRIIa have been shown to trigger synergistic responses. FcγRIIa is essential for the induction of efficient effector functions, whereas FcγRIIIb may guarantee efficient interaction with IgG complexes (Table 1).6,8,9,15,16
Fcγ Receptor Polymorphisms Four principal polymorphisms for FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb have garnered particular attention (Table 1). FcγIIa displays a G to A point mutation in the second extracellular Ig-like domain of the FcγRIIa, causing an arginine (R) to histidine (H) substitution at amino acid position 131. The H allele results in greater affinity of
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FcγIIa, whereas the R allele correlates with decreased binding. This affinity variation leads to functional difference: phagocytes from homozygous 131H individuals are much more effective than those from homozygous 131R donors in terms of phagocytosis of IgG2-opsonized particles.17 A single T to C nucleotide change specifying an isoleucine (I) or threonine (T) at position 232 is present in the transmembrane region of FcγRIIb. The 232 I allele attenuates B-cell receptor (BCR)mediated calcium mobilization more efficiently, and thereby affects the downstream signaling pathways more efficiently than the 232 T allele does.18 Similarly, FcγIIIa displays a T to G point mutation at nucleotide 559 resulting in a valine (V) to phenylalanine (F) substitution at position 158. Expression of the V allele results in tighter binding of FcγIIIa to IgG1, IgG3, and IgG4, whereas the F allele is associated with decreased binding.19,20 The genetic polymorphism of FcγIIIb is quite complex. At gene level the variants differ in 5 nucleotides leading to 4 amino acid exchanges, resulting in 2 isoforms: the neutrophil antigen 1 (NA1) and the neutrophil antigen 2 (NA2). NA1 isotype displays a more efficient interaction with IgG1- and IgG3-opsonized bacteria and better phagocytic activity than NA2 (Table 1).21 Additionally, a number of nonfunctional FcγR polymorphisms, and polymorphisms with unknown functional significance, have been described. The FcγRIIa gene contains a second polymorphic site. CA to GA mutation results in a glutamine or tryptophan at position 27. This substitution does not affect receptor affinity for IgG.22 Seven additional FcγRIIb point mutations have been described in Japanese individuals, possibly altering FcγRIIb function.23 FcγRIIc correlates with a C to T point mutation, resulting in either a glutamine (Q) or a null allele at position 13. FcγRIIc was reported to induce NK cell functions, including Ca2+ mobilization and ADCC. It remains to be determined whether expression of this receptor is important for host defense.24 At position 48, polymorphism of the FcγRIIIa receptor results in expression of leucine, arginine or histidine, but is in itself not functional.20 Finally, FcγRIIIb varying at amino acid position 266 bears either an aspartate or an alanine. This change causes the expression of the FcγRIIIb-SH allo-antigen, which has been associated with neonatal neutropenia. It is not known whether this polymorphism influences FcγRIIIb function.25
Yun Zhuang et al Table 2 Selective Studies of FcγRIIa and FcγRIIIa Polymorphisms and Monoclonal Antibody Efficacy for Cancer Therapy
Disease
Study Carton et al33
Number of Patients
MoAb
Efficacy for FcγRIIa Polymorphisms, % H/H
H/H
R/R
P Value
Efficacy for FcγRIIIa Polymorphisms, % V/V
V/F
FL
49
Rituximab
95
92
75
NS
100
Kim et al34
DLBCL
113
Rituximab
95
92
76
.18
88
79
Zhang et al35
DLBCL
48
Rituximab
–
82
83
Weng et al36
FL
87
Rituximab
80
.01
85
DLBCL
58
Rituximab
83
FL
75
Rituximab
Mitrovic et
al37
Boettcher et al38 Galimberti et
al39
NR
MCL
24
Rituximab
44
FL
94
Rituximab
67
Farag et al51
CLL
54
Rituximab
Lin et al52
CLL
32
Alemtuzumab
40
Musolino et
75
30
11 73
NR
Breast cancer
54
Trastuzumab
70
Zhang et al55
Colorectal cancer
35
Cetuximab
0
al56
Colorectal cancer
69
Cetuximab
29
Bibeau et
85 NR
Carlotti et al40
al54
43
32
33 43
6
14 9
P Value
F/F 67
.03 50
.002
60
.04
45
.01
.51
75
84
90
.36
–
100
97
97
NS
48
NS
19
.49
78
19 70
NS .49
–
33
42
50
.78
NS
25
40
32
NS
.17
82
.14
14
.15
20
40 0
.03 0
15
.05 .25
Abbreviations: CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; MCL = mantle cell lymphoma; NR = not reported; NS = not significant
The polymorphisms of the FcγR genes exhibit great clinical significance. First, FcγR polymorphisms have been shown to influence the genetic risk, the clinical course, and the response to therapy of chronic inflammatory diseases and autoimmune diseases.26-30 FcγR polymorphisms have been thought to determine the vigor of the inflammatory response. The high-affinity alleles (FcγRIIa-131H and FcγRIIIa-158V) may enhance capture of IgG opsonized pathogen or IgG immune complexes and feed them into the antigen-processing pathway, while the low-affinity alleles (FcγRIIa-131R and FcγRIIIa-158F) bind fewer immune complexes and reduce inflammatory response. Second, FcγR polymorphisms play an important role in MoAb therapy. FcγR polymorphisms can predict MoAb efficacy. It is postulated that patients with high-affinity alleles show a better response because they have a more efficient ADCC activity. MoAb dose or administration schedule may be adjusted with FcγR polymorphisms status to ensure effective concentrations to obtain a better clinical response.31
Fcγ Receptor Polymorphisms and Non-Hodgkin Lymphoma With the successful use of rituximab in NHL, there still have been a fraction of patients exhibiting no clinical response, and the actual causes of heterogeneous responses in different patients remain unknown. FcγR polymorphisms and NK cell function could be one of the explanations, as Hatjiharissi et al demonstrated in vivo that both rituximab binding and rituximab-mediated ADCC activity by NK cells increased with the presence of FcγRIIIa-158V/V and V/F genotype.32 Cartron et al first reported that FcγRIIIa polymorphism correlated with rituximab efficacy in clinical study, followed by extensive research of FcγR polymorphisms in NHL.33 We performed a search for studies that examined the association between FcγR polymorphisms and mature B-cell lymphoproliferative diseases on PubMed. Key words such as FCGR, Fcgamma receptor,
polymorphism, rituximab, lymphoma, and CLL were used. Studies were eligible when they were published before January 2010 and included original data. We excluded the studies in which patients were of different pathologic types (Table 2).
Fcγ Receptor Polymorphisms and the Clinical Efficacy of Rituximab In Cartron et al’s research, 49 patients with follicular lymphoma (FL) were administered with rituximab as monotherapy. Those with FcγRIIIa-158 V/V had a significantly higher (100%) clinical response rate (RR) than those with V/F or F/F genotype (67%; P = .03). For FcγRIIa, the RR was 95%, 92%, and 75% in FcγRIIIa-131H/H, H/R, and R/R groups, respectively (P = not significant).33 This study showed an association between the FcγRIIIa genotypes and clinical responses to rituximab monotherapy in FL. Many studies have been conducted to investigate the influence of FcγRIIIa and FcγRIIa polymorphisms on response to rituximab in patients with different sample sizes, ethnicities, treatments, and histologies. There has always been a debate whether FcγRIIIa and FcγRIIa polymorphisms actually influence the response to rituximab. Kim et al and Zhang et al obtained the same results in diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (rituximab plus cyclophosphamide/doxorubicin/ vincristine/prednisone).34,35 Weng et al reported that the RR was 80% for FcγRIIa-131 H/H compared with 43% for FcγRIIa-131 HR/RR (P = .01), and demonstrated that FcγRIIa polymorphism also had effect on rituximab efficacy in FL.36 On the other hand, Mitrovic et al demonstrated that complete remission (CR) rates were 62%, 81%, 80% (P = .36) for FcγRIIIa-158 V/V, V/F, F/F and 83%, 74%, 62% (P = .51) for FcγRIIa-131 H/H, H/R, and R/R, respectively. There was no significant difference in RR of FcγRIIa or FcγRIIIa genotypes in patients with DLBCL.37 Three other authors also obtained negative results.38-40
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FcγR Polymorphisms and Rituximab Efficacy in NHL and CLL There was no effect of FcγR polymorphisms on the prognosis of NHL with only 1 exception. In a group of 24 patients with mantle cell lymphoma (MCL) patients treated with R-hyperCVAD (rituximab, fractionated cyclophosphamide/vincristine/ doxorubicin/dexamethasone, alternating with high-dose methotrexate and cytarabine), the 2-year progression-free survival (PFS) was 82% for FcγRIIa-131 H/H versus 75% for FcγRIIa-131 HR/ RR (P = .26), the 2-year PFS was 78% for FcγRIIIa-158 V/V versus 75% for FcγRIIIa-158VF/FF (P = .88).39 In a cohort of 94 patients with FL treated with R-CHOP, the event-free survival (EFS) was 39% for FcγRIIa-131H/H compared with 41% for FcγRIIa-131 HR/RR (P = not significant), the EFS was 43% for FcγRIIIa-158 V/V compared with 40% for FcγRIIIa-158 VF/FF (P = not significant).40 Other studies achieved the same results.33-35,37,38 The only exception was from Weng et al in FL. The PFS at 2 years was 37% for FcγRIIa-131 H/H and 14% for R carrier with mean time to progression (TTP) of 445 days and 158 days for each group (P = .001). Similarly, the PFS at 2 years was 45% for FcγRIIIa-158 V/V and 14% for F carriers with TTP of 534 days and 170 days for each group (P = .02). The logistic regression analysis showed that the FcγRIIa-131 H/H and FcγRIIIa-158 V/V were independent predictive factors for rituximab response and prognosis.36 On the other hand, 232 I/T polymorphism of FcγRIIb was found to affect its inhibitory ability in B cells and probably effector cells during ADCC.18,41 Knocking out the inhibitory FcγRIIb enhanced the response to rituximab in mice model.42 One hundred one patients with FL were examined by Weng et al and demonstrated that the RR in 3 FcγRIIb genotypes were similar to rituximab therapy. The 2-year PFS and TTP were not different between FcγRIIb-232 I/I and I/T groups.43 Camilleri-Broet et al also failed to identify a correlation between FcγRIIb polymorphisms and the clinical response to R-CHOP in patients with DLBCL.44 The lack of association between FcγRIIb-232 T polymorphism and rituximab efficacy does not rule out a role for inhibitory FcγRIIb in rituximab’s antitumor effect as the animal model has suggested. The true contribution of FcγRIIb in rituximab’s clinical efficacy is still unclear. FcγRIIIb is expressed only by neutrophils and its NA1/NA2 polymorphism influences phagocytosis of IgG1-opsonized particles. In Cartron’s study, no difference for PFS and overall survival (OS) by FcγRIIIb-NA1/NA2 genotypes was found.45 The results indicate the lack of influence of FcγRIIIb-NA1/NA2 polymorphism on rituximab activity, which are in discrepancy with expected. Because rituximab is also an IgG1, these results remain unexplained and are needed more investigation. Recently, the FcγRIIa-131 H/R, FcγRIIIa-158 V/F, and FcγRIIb-232 I/T polymorphisms were analyzed in a group of 188 patients with FL who were treated with chemotherapy without rituximab. There was no difference in the OS rate or CR rate in patients with different FcγR genotypes, the TTP or OS was not different either.46 The study confirms that the correlation between FcγR polymorphisms and clinical outcome is specific to immunotherapy such as rituximab and Ig idiotype (Id) vaccination, and not because of any effect on chemotherapy or underlying biology of FL related with FcγR polymorphisms.
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Fcγ Receptor Polymorphisms and Vaccination Recently, Weng et al found that patients with FcγRIIIa-158 V/V had a longer PFS (V/V, 8.21 years vs. V/F, 3.38 years, P = .004; vs. F/F, 4.47 years, P = .035) after Id vaccination in FL patients who had already achieved CR with induction chemotherapy. However, the FcγRIIa-131 H/R polymorphism had no such effect on these patients.47 One possibility is that the majority of the induced antiId antibodies were of IgG1 isotype. FcγR polymorphisms provide a way to predict who may benefit from Id vaccination and should be examined in Id vaccination trials.
Fcγ Receptor Polymorphisms and Neutropenia Weng et al found that the high-affinity FcγRIIIa-158 V allele was associated with rituximab-induced neutropenia after autologous stem cell transplantation. Each additional V allele was associated with a 3-fold increase in the odds of neutropenia. The FcγRIIa-131 H/R polymorphism was not associated with rituximab-induced neutropenia.48 This is a potential tool to identify a high-risk population for developing neutropenia after antibody therapy by which we could predict who might have an increased risk of developing neutropenia and need closer monitoring after rituximab-based therapies.
Fcγ Receptor Polymorphisms and Chronic Lymphocytic Leukemia The combination of fludarabine and cyclophosphamide with rituximab (FCR) has become the gold standard for the therapy of active CLL as it achieves the highest CR rates. A total of 224 patients with untreated CLL were treated with FCR regimen, and the CR rate was 70% with an overall RR of 95%.4 A retrospective comparison of FCR (n = 143) and FC (n = 111) patients with recurrent/refractory CLL demonstrated that FCR produced a higher CR rate compared with FC (20% for FCR vs. 11% for FC; P < .05).49 An international, multicenter, randomized trial compared FCR (n = 276) with FC alone (n = 276) in patients with previously treated CLL; after a median follow-up time of 25 months, rituximab significantly improved PFS (median, 30.6 months for FCR vs. 20.6 months for FC; P < .001).50 Farag et al examined FcγRIIIa polymorphism of 30 CLL patients treated with rituximab, and the response to rituximab was similar in the different genotypes (V/V, 33%; V/F, 42%; F/F, 50%; P = .78).51 Both FcγRIIIa and FcγRIIa polymorphisms were examined in 36 patients with relapsed CLL treated with alemtuzumab; the response rate to alemtuzumab was also similar regardless of FcγRIIIa polymorphism (V/V, 25%; V/F, 40%; F/F, 32%; P = not significant) or FcγRIIa polymorphism (R/R, 40%; H/R, 32%; H/H, 33%; P = not significant).52 These findings are in contrast to the FL results reported by Cartron et al and demonstrate that FcγRIIIa and FcγRIIa polymorphisms do not predict response to rituximab or other antibodies in B-cell CLL.33 This may be attributed to the weak expression of the CD20 antigen by CLL cells.53
Fcγ Receptor Polymorphisms and Other Monoclonal Antibodies Because most of the MoAbs available for cancer therapy are of IgG1, another 2 therapeutic MoAbs, trastuzumab and cetuximab, have drawn much attention (Table 2). FcγRIIIa-158 V/V was
Yun Zhuang et al significantly correlated with RR and PFS in HER2/neu–positive metastatic breast cancer patients treated with trastuzumab, but it was not so for FcγRIIa polymorphism.54 Two studies for patients with metastatic colorectal cancer treated with cetuximab yielded inconsistent results. In Zhang’s study, FcγRIIa polymorphism showed no association with response (P = .14) and significant association with PFS (H/H, 24.0 months; H/R, 3.7 months; R/R, 1.1 months; P = .04). FcγRIIIa polymorphism showed association with response (P = .05). To our surprise, FcγRIIIa-158 V/V was associated with a shorter PFS compared with F carriers (1.1 months vs. 2.3 months; P = .05).55 In Bibeau’s study, no statistically significant difference in response to cetuximab or PFS based on the FcγRIIa polymorphism was observed. FcγRIIIa polymorphism showed no association with response (P = .25). The PFS for FcγRIIIa-158 V/V was 6.9 months compared with 3.2 months for F carriers (P = .05).56 The explanations of the discrepancy between 2 studies were treatment (cetuximab as single-agent in Zhang’s study vs. combination with irinotecan in Bibeau’s study) and a smaller series in Zhang’s study. A number of anti-CD20 MoAbs that attempt to optimize Fc binding to enhance the efficacy are under development or are already on the market. Ofatumumab is the most clinically advanced new anti-CD20 MoAb. It binds a novel, membrane-proximal epitope, and dissociates from its target at a slower rate compared with rituximab. Positive phase III interim data for ofatumumab in patients with CLL refractory to fludarabine and alemtuzumab led to FDA approval of this agent in this population in October 2009.57 Other novel candidate anti-CD20 MoAbs including ocrelizumab, veltuzumab, GA101, AME-133v, and PRO131921 have also shown positive results in clinical trials.58
Conclusion There had been a debate whether FcγR polymorphisms correlated with rituximab efficacy in patients with NHL. The FcγRIIIa polymorphism was associated with clinical outcomes after Id vaccination and rituximab side effects in NHL. FcγR polymorphisms were revealing themselves to be associated with other MoAbs for solid tumor. These data clearly suggest that FcγR polymorphims have the potential to alter the interaction between the MoAbs and the host, but the final results are not really striking for the most part. FcγR polymorphisms had no effect on the prognosis of NHL or CLL with only one exception. New generations of MoAbs are expected to enrich the pipeline of MoAb therapy for NHL and CLL.
Disclosures The authors have no relevant relationships to disclose.
References 1. Plosker GL, Figgitt DP. Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs 2003; 63:803-43. 2. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106:3725-32. 3. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23:4117-26. 4. Keating MJ, O’Brien S, Albita M, et al. Early results of a chemoimmunotherapy regimen of flñudarabine, cyclophosphamide, and rituximab as initial therapy for
chronic lymphocytic leukemia. J Clin Oncol 2005; 23:4079-88. 5. Jazirehi AR, Bonavida B. Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin’s lymphoma: implications in chemosensitization and therapeutic intervention. Oncogene 2005; 24:2121-43. 6. Masuda A, Yoshida M, Shiomi H, et al. Role of Fc receptors as a therapeutic target. Inflamm Allergy Drug Targets 2009; 8:80-6. 7. Qiu WQ, de Bruin D, Brownstein BH, et al. Organization of the human and mouse low-affinity Fcgamma R genes: duplication and recombination. Science 1990; 248:732-5. 8. van Sorge NM, van der Pol WL, van de Winkel JG. FcgammaR polymorphisms: implications for function, disease susceptibility and immunotherapy. Tissue Antigens 2003; 61:189-202. 9. Li X, Ptacek TS, Brown EE. Fcgamma receptors: structure, function and role as genetic risk factors in SLE. Genes Immun 2009; 10:380-9. 10. Pain S, Falet H, Saci A, et al. Tyrosine phosphorylation and association of FcgammaRII and p72(Syk) are not limited to the FcgammaRII signalling pathway. Cell Signal 2000; 12:165-71. 11. Cooney DS, Phee H, Jacob A, et al. Signal transduction by human-restricted Fc gamma RIIa involves three distinct cytoplasmic kinase families leading to phagocytosis. J Immunol 2001; 167:844-54. 12. Ravetch JV, Lanier LL. Immune inhibitory receptors. Science 2000; 290:84-9. 13. Nimmerjahn F. Activating and inhibitory FcgammagRs in autoimmune disorders. Springer Semin Immunopathol 2006; 28:305-19. 14. Tedder TF, Baras A, Xiu Y. Fcgamma receptor-dependent effect or mechanisms regulate CD19 and CD20 antibody immunotherapies for B lymphocyte malignancies and autoimmunity. Springer Semin Immunopathol 2006; 28:351-64. 15. Takai T. Fc receptors and their role in immune regulation and autoimmunity. J Clin Immunol 2005; 25:1-18. 16. Nimmerjahn F, Ravetch JV. Fc receptors as regulators of immunity. Adv Immunol 2007; 96:179-204. 17. Parren PW, Warmerdam PA, Boeije LC, et al. On the interaction of IgG subclasses with the low affinity Fc gamma RIIa(CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG2. J Clin Invest 1992; 90:1537-46. 18. Li X, Wu J, Carter RH, et al. A novel polymorphism in the Fcgamma receptor IIB (CD32B) transmembrane region alters receptor signaling. Arthritis Rheum 2003; 48:3242-52. 19. Wu J, Edberg JC, Redecha PB, et al. A novel polymorphism of FcgammaRIIIa(CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 1997; 100:1059-70. 20. Koene HR, Kleijer M, Algra J, et al. Fc gammaRIII158V/F polymorphism inflñuences the binding of IgG by natural killer cell Fc gammaRIIIA, independently of the Fc gammaRIIIA-48L/R/H phenotype. Blood 1997; 90:1109-14. 21. Ory PA, Clark MR, Kwoh EE, et al. Sequences of complementary DNAs that encode the NA1 and NA2 forms of Fc receptor III on human neutrophils. J Clin Invest 1989; 84:1688-91. 22. Warmerdam PA, van de Winkel JG, Vlug A, et al. A single amino acid in the second Ig-like domain of the human Fcgamma receptor II is critical for human IgG2 binding. J Immunol 1991; 147:1338-43. 23. Yasuda K, Sugita N, Yamamoto K, et al. Seven single nucleotide substitutions in human Fc(gamma) receptor IIB gene. Tissue Antigens 2001; 58:339-42. 24. Ernst LK, Metes D, Herberman RB, et al. Allelic polymorphisms in the FcgammaRIIC gene can influence its function on normal human natural killer cells. J Mol Med 2002; 80:248-57. 25. Koene HR, Kleijer M, Roos D, et al. FcgammaRIIIB gene duplication: evidence for presence and expression of three distinct FcgammaRIIIB genes in NA(1+, 2+) SH(+) individuals. Blood 1998; 91:673-9. 26. Mølle I, Ostergaard M, Melsvik D. Infectious complications after chemotherapy and stem cell transplantation in multiple myeloma: implications of Fc gamma receptor and myeloperoxidase promoter polymorphisms. Leuk Lymphoma 2008; 49:1116-22. 27. Dimou NL, Nikolopoulos GK, Hamodrakas SJ, et al. Fcgamma receptor polymorphisms and their association with periodontal disease: a meta-analysis. J Clin Periodontol 2010; 37:255-65. 28. Lee YH, Ji JD, Song GG. Associations between FCGR3A polymorphisms and susceptibility to rheumatoid arthritis: A metaanalysis. J Rheumatol 2008; 35:2129-35. 29. Kim I, Kim YJ, Kim K, et al. Genetic studies of systemic lupus erythematosus in Asia: where are we now? Genes Immun 2009; 10:421-32. 30. Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum 2003; 48:1484-92. 31. Dall’Ozzo S, Tartas S, Paintaud G, et al. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration- effect relationship. Cancer Res 2004; 64:4664-9. 32. Hatjiharissi E, Xu L, Santos DD, et al. Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V/V and V/F polymorphism. Blood 2007; 110:2561-4. 33. Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002; 99:754-8. 34. Kim DH, Jung HD, Kim JG, et al. FcgammaRIIIa gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lym-
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FcγR Polymorphisms and Rituximab Efficacy in NHL and CLL phoma. Blood 2006; 108:2720-5. 35. Zhang W, Wang X, Li J, et al. Fcgamma receptor IIIA polymorphisms and efficacy of rituximab therapy on Chinese diffuse large B-cell lymphoma. Chin Med J (Engl) 2010; 123:198-202. 36. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphism independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003; 21:3940-7. 37. Mitrovic Z, Aurer I, Radman I, et al. FCgammaRIIIA and FCgammaRIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphoma. Haematologica 2007; 92:998-9. 38. Boettcher S, Pott C, Ritgen M, et al. Evidence for Fcγg receptor IIIA-independent rituximab effector mechanisms in patients with follicular lymphoma treated with combined immuno-chemotherapy. Paper presented at: the 46th Annual Meeting of the American Society of Hematology; December 4-7, 2004; San Diego, CA. Abstrcat 590. 39. Galimberti S, Palumbo GA, Caracciolo F, et al. The efficacy of Rituximab plus hyper-CAVD regimen in mantle cell lymphoma is indepentdent of FcgammaRIIIA and FcgammaRIIA polymorphisms. J Chemother 2007; 19:315-21. 40. Carlotti E, Palumbo GA, Oldani E, et al. FcgammaRIIIA and FcgammaRIIA polymorphisms do not predict clinical outcome of follicular non-Hodgkin’s lymphoma patients treated with sequential CHOP and rituximab. Haematologica 2007; 92:1127-30. 41. Kono H, Kyogoku C, Suzuki T, et al. FcgammaRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet 2005; 14:2881-92. 42. Clynes RA, Towers TL, Presta LG, et al. Inhibitory Fc receptor modulate in vivo cytotoxicity against tumor targets. Nat Med 2000; 6:443-6. 43. Weng WK, Levy R. Genetic polymorphism of the inhibitory IgG Fc receptor FcgammaRIIb is not associated with clinical outcome in patients with follicular lymphoma treated with rituximab. Leuk Lymphoma 2009; 50:723-7. 44. Camilleri-Broet S, Mounier N, Delmer A, et al. FcgammaRIIB expression in diffuse large B-cell lymphomas does not alter the response to CHOP + rituximab (R-CHOP). Leukemia 2004; 18:2038-40. 45. Cartron G, Ohresser M, Salles G, et al. Neutrophil role in in vivo anti-lymphoma activity of rituximab: FCGR3B-NA1/NA2 polymorphism does not inflñuence response and survival after rituximab treatment. Ann Oncol 2008; 19:1485-7. 46. Weng WK, Levy R. Immunoglobulin G Fc receptor polymorphisms do not correlate with response to chemotherapy or clinical course in patients with follicular
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lymphoma. Leuk Lymphoma 2009; 50:1494-500. 47. Weng WK, Czerwinski D, Timmerman J, et al. Clinical outcome of lymphoma patients after idiotype vaccination is correlated with humoral immune response and immunoglobulin G Fc receptor Genotype. J Clin Oncol 2004; 22:4717-24. 48. Weng WK, Negrin SR, Lavori P, et al. Immunoglobulin G Fc receptor FcgammaRIIIa 158 V/F polymorphism correlates with rituximab-induced neutropenia after autologous transplantation in patients with non-Hodgkin’s lymphoma. J Clin Oncol 2010; 28:279-84. 49. Wierda W, O’Brien S, Faderl S, et al. A retrospective comparison of three sequential groups of patients with recurrent/refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer 2006; 106:337-45. 50. Robak T, Dmoszynska A, Solal-Céligny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010; 28:1756-65. 51. Farag SS, Flinn IW, Modali R, et al. Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood 2004; 103:1472-4. 52. Lin TS, Flinn IW, Modali R, et al. FCGR3A and FCGR2A polymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia. Blood 2005; 105:289-91. 53. Ginaldi L, De Martinis M, Matutes E, et al. Levels of expression of CD19 and CD20 in chronic B cell leukaemias. J Clin Pathol 1998; 51:364-9. 54. Musolino A, Naldi N, Bortesi B, et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 2008; 26:1789-96. 55. Zhang W, Gordon M, Schultheis AM, et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 2007; 25:3712-8. 56. Bibeau F, Lopez-Crapez E, Di Fiore F, et al. Impact of Fc{gamma}RIIa- Fc{gamma} RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 2009; 27:1122-9. 57. Lemery SJ, Zhang JZ, Rothmann MD, et al. U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab. Clin Cancer Res 2010; 16:4331-8. 58. Czuczman MS, Gregory SA. The furure of CD20 monoclonal therapy in B-cell maligancies. Leuk Lymphoma 2010; 51:983-94.
Fcγ Receptor Polymorphisms and Clinical Efficacy of Rituximab in Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia Yun Zhuang,1,2 Wei Xu,2 Yunfeng Shen,1 Jianyong Li2 Abstract It has been 40 years since the discovery of Fcγ receptors (FcγRs) and their function. FcγRs regulate a variety of immune responses, including phagocytosis, degranulation, antibody-dependent cellular cytotoxicity, transcriptional regulation of cytokines, chemokine expression, B-cell activation, and immune complex clearance. It is well known that FcγRs serve as a critical link between the humoral and cellular branches of the immune system and play an important role in many conditions, including infection, cancer, and autoimmune diseases. Recent studies suggest that FcγR polymorphisms influence efficacy and side effects of monoclonal antibody–based immunotherapy, which might provide a useful prognostic marker for treatment in the future. Rituximab has been proven effective in treating patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Some FcγR genotypes correlate with rituximab efficacy in patients with NHL but not in patients with CLL. In this review, FcγR function and the association between FcγR polymorphisms and rituximab efficacy in NHL and CLL are discussed. Clinical Lymphoma, Myeloma & Leukemia, Vol. 10, No. 5, 347-352, 2010; DOI: 10.3816/CLML.2010.n.067 Keywords: Monoclonal antibody, Natural killer cell, Rituximab
Introduction Rituximab is a mouse/human chimeric immunoglobulin (Ig)G1 monoclonal antibody (MoAb) that targets the CD20 antigen on the surface of malignant and normal B lymphocytes.1 After being approved to treat resistant and relapsed indolent lymphoma by US Food and Drug Administration (FDA) in 1997, rituximab alone or in combination with chemotherapy has changed the clinical approach and improved the outcome of patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).24 The precise biologic mechanism is still debatable, but several in vitro and in vivo studies have shown that rituximab mediates its antitumor effect by antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and the induction of apoptosis.5 Antibody-dependent cellular cytotoxicity is the leading candidate for rituximab’s antitumor effect and is exerted 1Department
of Hematology, Wuxi People Hospital Affiliated of Nanjing Medical University, Wuxi, Jiangsu, China 2Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu, China Submitted: May 17, 2010; Revised: Jun 16, 2010; Accepted: Jul 12, 2010 Address for correspondence: Jianyong Li, PhD, Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Rd, Nanjing, Jiangsu, 210029, China Fax: 86-25-8378-1120; e-mail: [email protected]
by effector cells such as natural killer (NK) cells and macrophages via the Fc receptors (FcRs) on their cell surface. FcRs belong to Ig superfamilies that have corresponding structure to each subclass of Ig. Fcγ receptors (FcγRs) react specifically with the Fc region of IgG.6 Rituximab, an IgG1 MoAb, binds to CD20 on the surface of tumor cells and then bridges effector cells via the FcγRs. The effector cells then become activated and kill the antibodycoated tumor cells. The effectiveness of ADCC may depend on the degree of activation of effector cells after engagement to FcγRs. Polymorphisms for FcγR genes have been shown to alter interaction between the Fc region of IgG and FcγRs, thereby leading to different ADCC and rituximab efficacy. This review will focus on the polymorphisms of FcγRs and summarize the application of this information to the treatment of patients with NHL and CLL with rituximab.
Fcγ Receptor Structure and Function Fcgγ receptors are divided into 3 classes, FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16), comprising 8 isoforms (FcγRIa/b/c, FcγRIIa/b/c, FcγRIIIa/b). These receptors differ in molecular weight, structure, cellular distribution, affinity for IgG subclasses, and role in immunity (Table 1), although they are encoded by genes clustered on the long arm of chromosome 1 (1q21-q24) and show extensive nucleotide sequence homology.6-8
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #2152-2650, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
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FcγR Polymorphisms and Rituximab Efficacy in NHL and CLL Table 1 General Characteristics of Fcγ Receptors Characteristic
FcγRI
Isoforms
FcγRIa/b/c
Molecular
72 kD
Celluar Distribution Affinity
FcγRII FcγRIIa
FcγRIII
FcγRIIb
FcγRIIc
FcγRIIIa
40 kD
Phagocytes
All myeloid cells
High
FcγRIIIb 50-80 kD
Phagocytes, B cells NK cells
Monocytes, γg/δd T cells, macrophages, NK cells
Low
Neutrophils Low
IgG1 ≥ IgG3 > IgG4 > IgG2
IgG3 ≥ IgG1/IgG2 > IgG4
IgG3 ≥ IgG1 > IgG4 > IgG2
NR
IgG1/IgG3 > IgG2 /IgG4
NR
Antigen presentation
Phagocytosis and degranulation
Inhibitory effects on antibody
NR
ADCC lymphokine production
Synergism with FcγRIIa
Polymorphisms
None
131H/131R
232I/232T
NR
158V/158F
NA1/NA2
Affinity for MoAbs
None
131H > 131R
232I > 232T
NR
158V > 158F
NA1 > NA2
Affinity for IgG Subclass Functions
Abbreviations: ADCC = antibody-dependent cellular cytotoxicity; Ig = immunoglobulin; MoAbs = monoclonal antibodies; NK = natural killer; NR = not reported
Structurally, all FcγRs bear an extracellular portion made of 2 or 3 Ig-like domains, a transmembrane region, and an intracytoplasmic tail.8,9 Functionally, FcγRs are classified in 2 categories: stimulatory FcγRs and inhibitory FcγRs. Stimulatory FcγRs include FcγRI, FcγRIIa, FcγRIIc, and FcγRIIIa. They transmit signals via immunoreceptor tyrosine-based activation motifs (ITAMs) in cytoplasmic domain, cause tyrosine phosphorylation of protein Src and Cb1, and activation of phosphoinositide 3-kinase and phospholipase C and D. Then those activated molecules induce the generation of second messengers and a series of changes that finally mediate cell activation.10,11 FcγRIIb, the unique inhibitory FcγR, downregulates the above molecules by recruiting Src homology 2-containing inositol phosphatase (SHIP) to immunoreceptor tyrosine-based inhibitory motifs (ITIMs).12,13 Coexpression of stimulatory and inhibitory FcγRs maintains protective and pathogenic innate effector responses in immune homeostasis, whereas imbalances between them can contribute to autoimmune disorders.13,14 FcγRs regulate a variety of humoral and cellular immune responses, including phagocytosis, degranulation, ADCC, transcriptional regulation of cytokines, chemokine expression, B-cell activation, and immune complex clearance. FcγRI facilitates antigen presentation to T cells. FcγRIIa induces phagocytosis and degranulation. FcγRIIa is unique in its capacity to interact with IgG2, and may be crucial for clearance of encapsulated bacteria. FcγRIIb may exert inhibitory effects on antibody responses. FcγRIIIa induces ADCC and lymphokine production, implying a role for this receptor in host defense against viral infections and malignancies. FcγRIIIb and FcγRIIa have been shown to trigger synergistic responses. FcγRIIa is essential for the induction of efficient effector functions, whereas FcγRIIIb may guarantee efficient interaction with IgG complexes (Table 1).6,8,9,15,16
Fcγ Receptor Polymorphisms Four principal polymorphisms for FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb have garnered particular attention (Table 1). FcγIIa displays a G to A point mutation in the second extracellular Ig-like domain of the FcγRIIa, causing an arginine (R) to histidine (H) substitution at amino acid position 131. The H allele results in greater affinity of
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FcγIIa, whereas the R allele correlates with decreased binding. This affinity variation leads to functional difference: phagocytes from homozygous 131H individuals are much more effective than those from homozygous 131R donors in terms of phagocytosis of IgG2-opsonized particles.17 A single T to C nucleotide change specifying an isoleucine (I) or threonine (T) at position 232 is present in the transmembrane region of FcγRIIb. The 232 I allele attenuates B-cell receptor (BCR)mediated calcium mobilization more efficiently, and thereby affects the downstream signaling pathways more efficiently than the 232 T allele does.18 Similarly, FcγIIIa displays a T to G point mutation at nucleotide 559 resulting in a valine (V) to phenylalanine (F) substitution at position 158. Expression of the V allele results in tighter binding of FcγIIIa to IgG1, IgG3, and IgG4, whereas the F allele is associated with decreased binding.19,20 The genetic polymorphism of FcγIIIb is quite complex. At gene level the variants differ in 5 nucleotides leading to 4 amino acid exchanges, resulting in 2 isoforms: the neutrophil antigen 1 (NA1) and the neutrophil antigen 2 (NA2). NA1 isotype displays a more efficient interaction with IgG1- and IgG3-opsonized bacteria and better phagocytic activity than NA2 (Table 1).21 Additionally, a number of nonfunctional FcγR polymorphisms, and polymorphisms with unknown functional significance, have been described. The FcγRIIa gene contains a second polymorphic site. CA to GA mutation results in a glutamine or tryptophan at position 27. This substitution does not affect receptor affinity for IgG.22 Seven additional FcγRIIb point mutations have been described in Japanese individuals, possibly altering FcγRIIb function.23 FcγRIIc correlates with a C to T point mutation, resulting in either a glutamine (Q) or a null allele at position 13. FcγRIIc was reported to induce NK cell functions, including Ca2+ mobilization and ADCC. It remains to be determined whether expression of this receptor is important for host defense.24 At position 48, polymorphism of the FcγRIIIa receptor results in expression of leucine, arginine or histidine, but is in itself not functional.20 Finally, FcγRIIIb varying at amino acid position 266 bears either an aspartate or an alanine. This change causes the expression of the FcγRIIIb-SH allo-antigen, which has been associated with neonatal neutropenia. It is not known whether this polymorphism influences FcγRIIIb function.25
Yun Zhuang et al Table 2 Selective Studies of FcγRIIa and FcγRIIIa Polymorphisms and Monoclonal Antibody Efficacy for Cancer Therapy
Disease
Study Carton et al33
Number of Patients
MoAb
Efficacy for FcγRIIa Polymorphisms, % H/H
H/H
R/R
P Value
Efficacy for FcγRIIIa Polymorphisms, % V/V
V/F
FL
49
Rituximab
95
92
75
NS
100
Kim et al34
DLBCL
113
Rituximab
95
92
76
.18
88
79
Zhang et al35
DLBCL
48
Rituximab
–
82
83
Weng et al36
FL
87
Rituximab
80
.01
85
DLBCL
58
Rituximab
83
FL
75
Rituximab
Mitrovic et
al37
Boettcher et al38 Galimberti et
al39
NR
MCL
24
Rituximab
44
FL
94
Rituximab
67
Farag et al51
CLL
54
Rituximab
Lin et al52
CLL
32
Alemtuzumab
40
Musolino et
75
30
11 73
NR
Breast cancer
54
Trastuzumab
70
Zhang et al55
Colorectal cancer
35
Cetuximab
0
al56
Colorectal cancer
69
Cetuximab
29
Bibeau et
85 NR
Carlotti et al40
al54
43
32
33 43
6
14 9
P Value
F/F 67
.03 50
.002
60
.04
45
.01
.51
75
84
90
.36
–
100
97
97
NS
48
NS
19
.49
78
19 70
NS .49
–
33
42
50
.78
NS
25
40
32
NS
.17
82
.14
14
.15
20
40 0
.03 0
15
.05 .25
Abbreviations: CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; MCL = mantle cell lymphoma; NR = not reported; NS = not significant
The polymorphisms of the FcγR genes exhibit great clinical significance. First, FcγR polymorphisms have been shown to influence the genetic risk, the clinical course, and the response to therapy of chronic inflammatory diseases and autoimmune diseases.26-30 FcγR polymorphisms have been thought to determine the vigor of the inflammatory response. The high-affinity alleles (FcγRIIa-131H and FcγRIIIa-158V) may enhance capture of IgG opsonized pathogen or IgG immune complexes and feed them into the antigen-processing pathway, while the low-affinity alleles (FcγRIIa-131R and FcγRIIIa-158F) bind fewer immune complexes and reduce inflammatory response. Second, FcγR polymorphisms play an important role in MoAb therapy. FcγR polymorphisms can predict MoAb efficacy. It is postulated that patients with high-affinity alleles show a better response because they have a more efficient ADCC activity. MoAb dose or administration schedule may be adjusted with FcγR polymorphisms status to ensure effective concentrations to obtain a better clinical response.31
Fcγ Receptor Polymorphisms and Non-Hodgkin Lymphoma With the successful use of rituximab in NHL, there still have been a fraction of patients exhibiting no clinical response, and the actual causes of heterogeneous responses in different patients remain unknown. FcγR polymorphisms and NK cell function could be one of the explanations, as Hatjiharissi et al demonstrated in vivo that both rituximab binding and rituximab-mediated ADCC activity by NK cells increased with the presence of FcγRIIIa-158V/V and V/F genotype.32 Cartron et al first reported that FcγRIIIa polymorphism correlated with rituximab efficacy in clinical study, followed by extensive research of FcγR polymorphisms in NHL.33 We performed a search for studies that examined the association between FcγR polymorphisms and mature B-cell lymphoproliferative diseases on PubMed. Key words such as FCGR, Fcgamma receptor,
polymorphism, rituximab, lymphoma, and CLL were used. Studies were eligible when they were published before January 2010 and included original data. We excluded the studies in which patients were of different pathologic types (Table 2).
Fcγ Receptor Polymorphisms and the Clinical Efficacy of Rituximab In Cartron et al’s research, 49 patients with follicular lymphoma (FL) were administered with rituximab as monotherapy. Those with FcγRIIIa-158 V/V had a significantly higher (100%) clinical response rate (RR) than those with V/F or F/F genotype (67%; P = .03). For FcγRIIa, the RR was 95%, 92%, and 75% in FcγRIIIa-131H/H, H/R, and R/R groups, respectively (P = not significant).33 This study showed an association between the FcγRIIIa genotypes and clinical responses to rituximab monotherapy in FL. Many studies have been conducted to investigate the influence of FcγRIIIa and FcγRIIa polymorphisms on response to rituximab in patients with different sample sizes, ethnicities, treatments, and histologies. There has always been a debate whether FcγRIIIa and FcγRIIa polymorphisms actually influence the response to rituximab. Kim et al and Zhang et al obtained the same results in diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (rituximab plus cyclophosphamide/doxorubicin/ vincristine/prednisone).34,35 Weng et al reported that the RR was 80% for FcγRIIa-131 H/H compared with 43% for FcγRIIa-131 HR/RR (P = .01), and demonstrated that FcγRIIa polymorphism also had effect on rituximab efficacy in FL.36 On the other hand, Mitrovic et al demonstrated that complete remission (CR) rates were 62%, 81%, 80% (P = .36) for FcγRIIIa-158 V/V, V/F, F/F and 83%, 74%, 62% (P = .51) for FcγRIIa-131 H/H, H/R, and R/R, respectively. There was no significant difference in RR of FcγRIIa or FcγRIIIa genotypes in patients with DLBCL.37 Three other authors also obtained negative results.38-40
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FcγR Polymorphisms and Rituximab Efficacy in NHL and CLL There was no effect of FcγR polymorphisms on the prognosis of NHL with only 1 exception. In a group of 24 patients with mantle cell lymphoma (MCL) patients treated with R-hyperCVAD (rituximab, fractionated cyclophosphamide/vincristine/ doxorubicin/dexamethasone, alternating with high-dose methotrexate and cytarabine), the 2-year progression-free survival (PFS) was 82% for FcγRIIa-131 H/H versus 75% for FcγRIIa-131 HR/ RR (P = .26), the 2-year PFS was 78% for FcγRIIIa-158 V/V versus 75% for FcγRIIIa-158VF/FF (P = .88).39 In a cohort of 94 patients with FL treated with R-CHOP, the event-free survival (EFS) was 39% for FcγRIIa-131H/H compared with 41% for FcγRIIa-131 HR/RR (P = not significant), the EFS was 43% for FcγRIIIa-158 V/V compared with 40% for FcγRIIIa-158 VF/FF (P = not significant).40 Other studies achieved the same results.33-35,37,38 The only exception was from Weng et al in FL. The PFS at 2 years was 37% for FcγRIIa-131 H/H and 14% for R carrier with mean time to progression (TTP) of 445 days and 158 days for each group (P = .001). Similarly, the PFS at 2 years was 45% for FcγRIIIa-158 V/V and 14% for F carriers with TTP of 534 days and 170 days for each group (P = .02). The logistic regression analysis showed that the FcγRIIa-131 H/H and FcγRIIIa-158 V/V were independent predictive factors for rituximab response and prognosis.36 On the other hand, 232 I/T polymorphism of FcγRIIb was found to affect its inhibitory ability in B cells and probably effector cells during ADCC.18,41 Knocking out the inhibitory FcγRIIb enhanced the response to rituximab in mice model.42 One hundred one patients with FL were examined by Weng et al and demonstrated that the RR in 3 FcγRIIb genotypes were similar to rituximab therapy. The 2-year PFS and TTP were not different between FcγRIIb-232 I/I and I/T groups.43 Camilleri-Broet et al also failed to identify a correlation between FcγRIIb polymorphisms and the clinical response to R-CHOP in patients with DLBCL.44 The lack of association between FcγRIIb-232 T polymorphism and rituximab efficacy does not rule out a role for inhibitory FcγRIIb in rituximab’s antitumor effect as the animal model has suggested. The true contribution of FcγRIIb in rituximab’s clinical efficacy is still unclear. FcγRIIIb is expressed only by neutrophils and its NA1/NA2 polymorphism influences phagocytosis of IgG1-opsonized particles. In Cartron’s study, no difference for PFS and overall survival (OS) by FcγRIIIb-NA1/NA2 genotypes was found.45 The results indicate the lack of influence of FcγRIIIb-NA1/NA2 polymorphism on rituximab activity, which are in discrepancy with expected. Because rituximab is also an IgG1, these results remain unexplained and are needed more investigation. Recently, the FcγRIIa-131 H/R, FcγRIIIa-158 V/F, and FcγRIIb-232 I/T polymorphisms were analyzed in a group of 188 patients with FL who were treated with chemotherapy without rituximab. There was no difference in the OS rate or CR rate in patients with different FcγR genotypes, the TTP or OS was not different either.46 The study confirms that the correlation between FcγR polymorphisms and clinical outcome is specific to immunotherapy such as rituximab and Ig idiotype (Id) vaccination, and not because of any effect on chemotherapy or underlying biology of FL related with FcγR polymorphisms.
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Fcγ Receptor Polymorphisms and Vaccination Recently, Weng et al found that patients with FcγRIIIa-158 V/V had a longer PFS (V/V, 8.21 years vs. V/F, 3.38 years, P = .004; vs. F/F, 4.47 years, P = .035) after Id vaccination in FL patients who had already achieved CR with induction chemotherapy. However, the FcγRIIa-131 H/R polymorphism had no such effect on these patients.47 One possibility is that the majority of the induced antiId antibodies were of IgG1 isotype. FcγR polymorphisms provide a way to predict who may benefit from Id vaccination and should be examined in Id vaccination trials.
Fcγ Receptor Polymorphisms and Neutropenia Weng et al found that the high-affinity FcγRIIIa-158 V allele was associated with rituximab-induced neutropenia after autologous stem cell transplantation. Each additional V allele was associated with a 3-fold increase in the odds of neutropenia. The FcγRIIa-131 H/R polymorphism was not associated with rituximab-induced neutropenia.48 This is a potential tool to identify a high-risk population for developing neutropenia after antibody therapy by which we could predict who might have an increased risk of developing neutropenia and need closer monitoring after rituximab-based therapies.
Fcγ Receptor Polymorphisms and Chronic Lymphocytic Leukemia The combination of fludarabine and cyclophosphamide with rituximab (FCR) has become the gold standard for the therapy of active CLL as it achieves the highest CR rates. A total of 224 patients with untreated CLL were treated with FCR regimen, and the CR rate was 70% with an overall RR of 95%.4 A retrospective comparison of FCR (n = 143) and FC (n = 111) patients with recurrent/refractory CLL demonstrated that FCR produced a higher CR rate compared with FC (20% for FCR vs. 11% for FC; P < .05).49 An international, multicenter, randomized trial compared FCR (n = 276) with FC alone (n = 276) in patients with previously treated CLL; after a median follow-up time of 25 months, rituximab significantly improved PFS (median, 30.6 months for FCR vs. 20.6 months for FC; P < .001).50 Farag et al examined FcγRIIIa polymorphism of 30 CLL patients treated with rituximab, and the response to rituximab was similar in the different genotypes (V/V, 33%; V/F, 42%; F/F, 50%; P = .78).51 Both FcγRIIIa and FcγRIIa polymorphisms were examined in 36 patients with relapsed CLL treated with alemtuzumab; the response rate to alemtuzumab was also similar regardless of FcγRIIIa polymorphism (V/V, 25%; V/F, 40%; F/F, 32%; P = not significant) or FcγRIIa polymorphism (R/R, 40%; H/R, 32%; H/H, 33%; P = not significant).52 These findings are in contrast to the FL results reported by Cartron et al and demonstrate that FcγRIIIa and FcγRIIa polymorphisms do not predict response to rituximab or other antibodies in B-cell CLL.33 This may be attributed to the weak expression of the CD20 antigen by CLL cells.53
Fcγ Receptor Polymorphisms and Other Monoclonal Antibodies Because most of the MoAbs available for cancer therapy are of IgG1, another 2 therapeutic MoAbs, trastuzumab and cetuximab, have drawn much attention (Table 2). FcγRIIIa-158 V/V was
Yun Zhuang et al significantly correlated with RR and PFS in HER2/neu–positive metastatic breast cancer patients treated with trastuzumab, but it was not so for FcγRIIa polymorphism.54 Two studies for patients with metastatic colorectal cancer treated with cetuximab yielded inconsistent results. In Zhang’s study, FcγRIIa polymorphism showed no association with response (P = .14) and significant association with PFS (H/H, 24.0 months; H/R, 3.7 months; R/R, 1.1 months; P = .04). FcγRIIIa polymorphism showed association with response (P = .05). To our surprise, FcγRIIIa-158 V/V was associated with a shorter PFS compared with F carriers (1.1 months vs. 2.3 months; P = .05).55 In Bibeau’s study, no statistically significant difference in response to cetuximab or PFS based on the FcγRIIa polymorphism was observed. FcγRIIIa polymorphism showed no association with response (P = .25). The PFS for FcγRIIIa-158 V/V was 6.9 months compared with 3.2 months for F carriers (P = .05).56 The explanations of the discrepancy between 2 studies were treatment (cetuximab as single-agent in Zhang’s study vs. combination with irinotecan in Bibeau’s study) and a smaller series in Zhang’s study. A number of anti-CD20 MoAbs that attempt to optimize Fc binding to enhance the efficacy are under development or are already on the market. Ofatumumab is the most clinically advanced new anti-CD20 MoAb. It binds a novel, membrane-proximal epitope, and dissociates from its target at a slower rate compared with rituximab. Positive phase III interim data for ofatumumab in patients with CLL refractory to fludarabine and alemtuzumab led to FDA approval of this agent in this population in October 2009.57 Other novel candidate anti-CD20 MoAbs including ocrelizumab, veltuzumab, GA101, AME-133v, and PRO131921 have also shown positive results in clinical trials.58
Conclusion There had been a debate whether FcγR polymorphisms correlated with rituximab efficacy in patients with NHL. The FcγRIIIa polymorphism was associated with clinical outcomes after Id vaccination and rituximab side effects in NHL. FcγR polymorphisms were revealing themselves to be associated with other MoAbs for solid tumor. These data clearly suggest that FcγR polymorphims have the potential to alter the interaction between the MoAbs and the host, but the final results are not really striking for the most part. FcγR polymorphisms had no effect on the prognosis of NHL or CLL with only one exception. New generations of MoAbs are expected to enrich the pipeline of MoAb therapy for NHL and CLL.
Disclosures The authors have no relevant relationships to disclose.
References 1. Plosker GL, Figgitt DP. Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs 2003; 63:803-43. 2. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106:3725-32. 3. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23:4117-26. 4. Keating MJ, O’Brien S, Albita M, et al. Early results of a chemoimmunotherapy regimen of flñudarabine, cyclophosphamide, and rituximab as initial therapy for
chronic lymphocytic leukemia. J Clin Oncol 2005; 23:4079-88. 5. Jazirehi AR, Bonavida B. Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin’s lymphoma: implications in chemosensitization and therapeutic intervention. Oncogene 2005; 24:2121-43. 6. Masuda A, Yoshida M, Shiomi H, et al. Role of Fc receptors as a therapeutic target. Inflamm Allergy Drug Targets 2009; 8:80-6. 7. Qiu WQ, de Bruin D, Brownstein BH, et al. Organization of the human and mouse low-affinity Fcgamma R genes: duplication and recombination. Science 1990; 248:732-5. 8. van Sorge NM, van der Pol WL, van de Winkel JG. FcgammaR polymorphisms: implications for function, disease susceptibility and immunotherapy. Tissue Antigens 2003; 61:189-202. 9. Li X, Ptacek TS, Brown EE. Fcgamma receptors: structure, function and role as genetic risk factors in SLE. Genes Immun 2009; 10:380-9. 10. Pain S, Falet H, Saci A, et al. Tyrosine phosphorylation and association of FcgammaRII and p72(Syk) are not limited to the FcgammaRII signalling pathway. Cell Signal 2000; 12:165-71. 11. Cooney DS, Phee H, Jacob A, et al. Signal transduction by human-restricted Fc gamma RIIa involves three distinct cytoplasmic kinase families leading to phagocytosis. J Immunol 2001; 167:844-54. 12. Ravetch JV, Lanier LL. Immune inhibitory receptors. Science 2000; 290:84-9. 13. Nimmerjahn F. Activating and inhibitory FcgammagRs in autoimmune disorders. Springer Semin Immunopathol 2006; 28:305-19. 14. Tedder TF, Baras A, Xiu Y. Fcgamma receptor-dependent effect or mechanisms regulate CD19 and CD20 antibody immunotherapies for B lymphocyte malignancies and autoimmunity. Springer Semin Immunopathol 2006; 28:351-64. 15. Takai T. Fc receptors and their role in immune regulation and autoimmunity. J Clin Immunol 2005; 25:1-18. 16. Nimmerjahn F, Ravetch JV. Fc receptors as regulators of immunity. Adv Immunol 2007; 96:179-204. 17. Parren PW, Warmerdam PA, Boeije LC, et al. On the interaction of IgG subclasses with the low affinity Fc gamma RIIa(CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG2. J Clin Invest 1992; 90:1537-46. 18. Li X, Wu J, Carter RH, et al. A novel polymorphism in the Fcgamma receptor IIB (CD32B) transmembrane region alters receptor signaling. Arthritis Rheum 2003; 48:3242-52. 19. Wu J, Edberg JC, Redecha PB, et al. A novel polymorphism of FcgammaRIIIa(CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 1997; 100:1059-70. 20. Koene HR, Kleijer M, Algra J, et al. Fc gammaRIII158V/F polymorphism inflñuences the binding of IgG by natural killer cell Fc gammaRIIIA, independently of the Fc gammaRIIIA-48L/R/H phenotype. Blood 1997; 90:1109-14. 21. Ory PA, Clark MR, Kwoh EE, et al. Sequences of complementary DNAs that encode the NA1 and NA2 forms of Fc receptor III on human neutrophils. J Clin Invest 1989; 84:1688-91. 22. Warmerdam PA, van de Winkel JG, Vlug A, et al. A single amino acid in the second Ig-like domain of the human Fcgamma receptor II is critical for human IgG2 binding. J Immunol 1991; 147:1338-43. 23. Yasuda K, Sugita N, Yamamoto K, et al. Seven single nucleotide substitutions in human Fc(gamma) receptor IIB gene. Tissue Antigens 2001; 58:339-42. 24. Ernst LK, Metes D, Herberman RB, et al. Allelic polymorphisms in the FcgammaRIIC gene can influence its function on normal human natural killer cells. J Mol Med 2002; 80:248-57. 25. Koene HR, Kleijer M, Roos D, et al. FcgammaRIIIB gene duplication: evidence for presence and expression of three distinct FcgammaRIIIB genes in NA(1+, 2+) SH(+) individuals. Blood 1998; 91:673-9. 26. Mølle I, Ostergaard M, Melsvik D. Infectious complications after chemotherapy and stem cell transplantation in multiple myeloma: implications of Fc gamma receptor and myeloperoxidase promoter polymorphisms. Leuk Lymphoma 2008; 49:1116-22. 27. Dimou NL, Nikolopoulos GK, Hamodrakas SJ, et al. Fcgamma receptor polymorphisms and their association with periodontal disease: a meta-analysis. J Clin Periodontol 2010; 37:255-65. 28. Lee YH, Ji JD, Song GG. Associations between FCGR3A polymorphisms and susceptibility to rheumatoid arthritis: A metaanalysis. J Rheumatol 2008; 35:2129-35. 29. Kim I, Kim YJ, Kim K, et al. Genetic studies of systemic lupus erythematosus in Asia: where are we now? Genes Immun 2009; 10:421-32. 30. Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum 2003; 48:1484-92. 31. Dall’Ozzo S, Tartas S, Paintaud G, et al. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration- effect relationship. Cancer Res 2004; 64:4664-9. 32. Hatjiharissi E, Xu L, Santos DD, et al. Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V/V and V/F polymorphism. Blood 2007; 110:2561-4. 33. Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002; 99:754-8. 34. Kim DH, Jung HD, Kim JG, et al. FcgammaRIIIa gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lym-
Clinical Lymphoma, Myeloma & Leukemia October 2010
|
351
FcγR Polymorphisms and Rituximab Efficacy in NHL and CLL phoma. Blood 2006; 108:2720-5. 35. Zhang W, Wang X, Li J, et al. Fcgamma receptor IIIA polymorphisms and efficacy of rituximab therapy on Chinese diffuse large B-cell lymphoma. Chin Med J (Engl) 2010; 123:198-202. 36. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphism independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003; 21:3940-7. 37. Mitrovic Z, Aurer I, Radman I, et al. FCgammaRIIIA and FCgammaRIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphoma. Haematologica 2007; 92:998-9. 38. Boettcher S, Pott C, Ritgen M, et al. Evidence for Fcγg receptor IIIA-independent rituximab effector mechanisms in patients with follicular lymphoma treated with combined immuno-chemotherapy. Paper presented at: the 46th Annual Meeting of the American Society of Hematology; December 4-7, 2004; San Diego, CA. Abstrcat 590. 39. Galimberti S, Palumbo GA, Caracciolo F, et al. The efficacy of Rituximab plus hyper-CAVD regimen in mantle cell lymphoma is indepentdent of FcgammaRIIIA and FcgammaRIIA polymorphisms. J Chemother 2007; 19:315-21. 40. Carlotti E, Palumbo GA, Oldani E, et al. FcgammaRIIIA and FcgammaRIIA polymorphisms do not predict clinical outcome of follicular non-Hodgkin’s lymphoma patients treated with sequential CHOP and rituximab. Haematologica 2007; 92:1127-30. 41. Kono H, Kyogoku C, Suzuki T, et al. FcgammaRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet 2005; 14:2881-92. 42. Clynes RA, Towers TL, Presta LG, et al. Inhibitory Fc receptor modulate in vivo cytotoxicity against tumor targets. Nat Med 2000; 6:443-6. 43. Weng WK, Levy R. Genetic polymorphism of the inhibitory IgG Fc receptor FcgammaRIIb is not associated with clinical outcome in patients with follicular lymphoma treated with rituximab. Leuk Lymphoma 2009; 50:723-7. 44. Camilleri-Broet S, Mounier N, Delmer A, et al. FcgammaRIIB expression in diffuse large B-cell lymphomas does not alter the response to CHOP + rituximab (R-CHOP). Leukemia 2004; 18:2038-40. 45. Cartron G, Ohresser M, Salles G, et al. Neutrophil role in in vivo anti-lymphoma activity of rituximab: FCGR3B-NA1/NA2 polymorphism does not inflñuence response and survival after rituximab treatment. Ann Oncol 2008; 19:1485-7. 46. Weng WK, Levy R. Immunoglobulin G Fc receptor polymorphisms do not correlate with response to chemotherapy or clinical course in patients with follicular
352
| Clinical Lymphoma, Myeloma & Leukemia
October 2010
lymphoma. Leuk Lymphoma 2009; 50:1494-500. 47. Weng WK, Czerwinski D, Timmerman J, et al. Clinical outcome of lymphoma patients after idiotype vaccination is correlated with humoral immune response and immunoglobulin G Fc receptor Genotype. J Clin Oncol 2004; 22:4717-24. 48. Weng WK, Negrin SR, Lavori P, et al. Immunoglobulin G Fc receptor FcgammaRIIIa 158 V/F polymorphism correlates with rituximab-induced neutropenia after autologous transplantation in patients with non-Hodgkin’s lymphoma. J Clin Oncol 2010; 28:279-84. 49. Wierda W, O’Brien S, Faderl S, et al. A retrospective comparison of three sequential groups of patients with recurrent/refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer 2006; 106:337-45. 50. Robak T, Dmoszynska A, Solal-Céligny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010; 28:1756-65. 51. Farag SS, Flinn IW, Modali R, et al. Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood 2004; 103:1472-4. 52. Lin TS, Flinn IW, Modali R, et al. FCGR3A and FCGR2A polymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia. Blood 2005; 105:289-91. 53. Ginaldi L, De Martinis M, Matutes E, et al. Levels of expression of CD19 and CD20 in chronic B cell leukaemias. J Clin Pathol 1998; 51:364-9. 54. Musolino A, Naldi N, Bortesi B, et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 2008; 26:1789-96. 55. Zhang W, Gordon M, Schultheis AM, et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 2007; 25:3712-8. 56. Bibeau F, Lopez-Crapez E, Di Fiore F, et al. Impact of Fc{gamma}RIIa- Fc{gamma} RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 2009; 27:1122-9. 57. Lemery SJ, Zhang JZ, Rothmann MD, et al. U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab. Clin Cancer Res 2010; 16:4331-8. 58. Czuczman MS, Gregory SA. The furure of CD20 monoclonal therapy in B-cell maligancies. Leuk Lymphoma 2010; 51:983-94.