EHA Library - The official digital education library of European Hematology Association (EHA)

FCGR2A AND FCGR3A VARIANTS ARE NOT ASSOCIATED WITH RESPONSE TO RITUXIMAB IN PATIENTS WITH B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA
Author(s):
Marica Pavkovic
,
Marica Pavkovic
Affiliations:
University Clinic for Hematology,Skopje,Macedonia, The Former Yugoslav Republic Of
Slobodanka Trpkovska-Terzieva
,
Slobodanka Trpkovska-Terzieva
Affiliations:
University Clinic for Hematology,Skopje,Macedonia, The Former Yugoslav Republic Of
Rosica Angelovic
,
Rosica Angelovic
Affiliations:
University Clinic for Hematology,Skopje,Macedonia, The Former Yugoslav Republic Of
Oliver Karanfilski
,
Oliver Karanfilski
Affiliations:
University Clinic for Hematology,Skopje,Macedonia, The Former Yugoslav Republic Of
Tatjana Sotirova
,
Tatjana Sotirova
Affiliations:
University Clinic for Hematology,Skopje,Macedonia, The Former Yugoslav Republic Of
Lidija Cevreska
,
Lidija Cevreska
Affiliations:
University Clinic for Hematology,Skopje,Macedonia, The Former Yugoslav Republic Of
Aleksandar Stojanovic
Aleksandar Stojanovic
Affiliations:
University Clinic for Hematology,Skopje,Macedonia, The Former Yugoslav Republic Of
(Abstract release date: 05/18/17) EHA Library. Pavkovic M. 05/18/17; 182488; PB1774
Dr. Marica Pavkovic
Dr. Marica Pavkovic
Contributions
PDF Abstract
Abstract

Abstract: PB1774

Type: Publication Only

Background

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western world with highly variable clinical outcome. Rituximab is a monoclonal chimeric anti-CD20 agent, that has demonstrated significant benefit for patients with different form of B cell lymphoproliferative disorders. Chemoimmunotherapy with rituximab, fludarabine and cyclophosphamide (R-FC) has shown to prolong progression free survival (PFS) and overall survival in CLL patients compared with chemotherapy alone. FCGR2A is polymorphic and has two alleles, FCGR2A-131H and FCGR2A-131R. This polymorphic variation is due to a single base substitution of nucleotide adenine for guanine in position 494. FCGR2A-H131 allele has a higher affinity for human IgG2, comparing to FCGR2A-R131. The gene for FCGR3A has also two polymorphic variant alleles: 158 valine (V158) and phenylalanine (F158) due to single base substitution of timidine to guanine at nucleotide position 559. FCGR3A-158V variant has higher affinity for Fc gamma receptor than 158F variant. These Fc gamma receptor polymorphisms may influence antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and direct proapoptotic effect.

Aims

The aim of our study was to investigate a possible association of these two FCGR2A and FCGR3A variants with response to R-FC therapy in CLL patients.

Methods
We have analyzed these two polymorphisms in 90 patients with CLL treated with R-FC regimen. Median age of our patients was 62.7(36-78) and 63% were male. Number of patients with stage III/IV disease was 65(72%) and median WBC count at the start of treatment was 68.5(34-173x109/L). Percentage of previously treated patients was 51/90 (56.6%). Average numbers of R-FC cycles were 4.3 and median PFS was 35.1 months. Median time of observation after treatment was 3.6 years (range:6 months-8 years). Response was evaluated 2 months after therapy according to National Cancer Institute (NCI) criteria. Complete response (CR) was achieved in 24/90 (26.7%), partial response (PR) in 56/90 (62.2%) and no response in 10/90 (11.1%). DNA was isolated from peripheral blood mononuclear cells and genotyping was performed by using PCR/RFLP methods. The distribution of genotypes was compared by using a chi-squared test or Fisher’s exact test.

Results

Distribution of genotypes in our patients was: 33% H/H, 49% H/R and 18% R/R for FCGR2A and 43% V/V, 40% V/F and 17% F/F for FCGR3A. Rate of CR and PR were similar irrespective of the FCGR variants and our results did not demonstrate significantly different genotype distribution for FCGR2A (p=0.8001) or FCGR3A (p=0.1019) in CLL patients with complete, partial or no response to R-FC treatment (Table 1).
Table 1. Genotype distributions for FCGR2A & FCGR3A in patients with CLL.
FCGR2A/FCGR3A
Complete
Response
n=24(26.7%)
Partial
Response
n=56(62.2%)
No
Response
n=10(11.1%)
p-values
FCGR2A 131H/R
(131H/H)
(131H/R)
(131R/R)
8(26.6%)
10(22.7%)
6(37.5%)
18(60%)
29(65.9%)
9(56.3%)
4(13.4%)
5(11.4%)
1(6.2%)
0.8001
FCGR3A 158F/V
(158 F/F)
(158 F/V)
(158 V/V)
8(20.5%)
11(30.6%)
5(33.3%)
29(74.4%)
21(58.3%)
6(40%)
2(5.1%)
4(11.1%)
4(26.7%)
0.1019

Conclusion

Our results are similar with previously reported results in other studies in CLL patients, but in contrast with the results for follicular lymphoma (FL), which showed that high-affinity FCGRA-158V/V variant was associated with the highest response rates in FL patients treated with rituximab. These findings could be explained with the different mechanism of action of rituximab in CLL compared to lymphoma patients or could be due to the variations in selected patient’s population.

Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology

Keyword(s): FcGRIIIa polymorphism, Chronic Lymphocytic Leukemia, Rituximab

Abstract: PB1774

Type: Publication Only

Background

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western world with highly variable clinical outcome. Rituximab is a monoclonal chimeric anti-CD20 agent, that has demonstrated significant benefit for patients with different form of B cell lymphoproliferative disorders. Chemoimmunotherapy with rituximab, fludarabine and cyclophosphamide (R-FC) has shown to prolong progression free survival (PFS) and overall survival in CLL patients compared with chemotherapy alone. FCGR2A is polymorphic and has two alleles, FCGR2A-131H and FCGR2A-131R. This polymorphic variation is due to a single base substitution of nucleotide adenine for guanine in position 494. FCGR2A-H131 allele has a higher affinity for human IgG2, comparing to FCGR2A-R131. The gene for FCGR3A has also two polymorphic variant alleles: 158 valine (V158) and phenylalanine (F158) due to single base substitution of timidine to guanine at nucleotide position 559. FCGR3A-158V variant has higher affinity for Fc gamma receptor than 158F variant. These Fc gamma receptor polymorphisms may influence antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and direct proapoptotic effect.

Aims

The aim of our study was to investigate a possible association of these two FCGR2A and FCGR3A variants with response to R-FC therapy in CLL patients.

Methods
We have analyzed these two polymorphisms in 90 patients with CLL treated with R-FC regimen. Median age of our patients was 62.7(36-78) and 63% were male. Number of patients with stage III/IV disease was 65(72%) and median WBC count at the start of treatment was 68.5(34-173x109/L). Percentage of previously treated patients was 51/90 (56.6%). Average numbers of R-FC cycles were 4.3 and median PFS was 35.1 months. Median time of observation after treatment was 3.6 years (range:6 months-8 years). Response was evaluated 2 months after therapy according to National Cancer Institute (NCI) criteria. Complete response (CR) was achieved in 24/90 (26.7%), partial response (PR) in 56/90 (62.2%) and no response in 10/90 (11.1%). DNA was isolated from peripheral blood mononuclear cells and genotyping was performed by using PCR/RFLP methods. The distribution of genotypes was compared by using a chi-squared test or Fisher’s exact test.

Results

Distribution of genotypes in our patients was: 33% H/H, 49% H/R and 18% R/R for FCGR2A and 43% V/V, 40% V/F and 17% F/F for FCGR3A. Rate of CR and PR were similar irrespective of the FCGR variants and our results did not demonstrate significantly different genotype distribution for FCGR2A (p=0.8001) or FCGR3A (p=0.1019) in CLL patients with complete, partial or no response to R-FC treatment (Table 1).
Table 1. Genotype distributions for FCGR2A & FCGR3A in patients with CLL.
FCGR2A/FCGR3A
Complete
Response
n=24(26.7%)
Partial
Response
n=56(62.2%)
No
Response
n=10(11.1%)
p-values
FCGR2A 131H/R
(131H/H)
(131H/R)
(131R/R)
8(26.6%)
10(22.7%)
6(37.5%)
18(60%)
29(65.9%)
9(56.3%)
4(13.4%)
5(11.4%)
1(6.2%)
0.8001
FCGR3A 158F/V
(158 F/F)
(158 F/V)
(158 V/V)
8(20.5%)
11(30.6%)
5(33.3%)
29(74.4%)
21(58.3%)
6(40%)
2(5.1%)
4(11.1%)
4(26.7%)
0.1019

Conclusion

Our results are similar with previously reported results in other studies in CLL patients, but in contrast with the results for follicular lymphoma (FL), which showed that high-affinity FCGRA-158V/V variant was associated with the highest response rates in FL patients treated with rituximab. These findings could be explained with the different mechanism of action of rituximab in CLL compared to lymphoma patients or could be due to the variations in selected patient’s population.

Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology

Keyword(s): FcGRIIIa polymorphism, Chronic Lymphocytic Leukemia, Rituximab

Premium Sponsors

What's new at EHA

Browse the open-source material from EHA past Congresses and meetings.

References

EHA Terms & Conditions
2025 ©
European Hematology Association
USER TERMS AND CONDITIONS / PRIVACY POLICY
(Amended according to GDPR)

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies