臺灣博碩士論文加值系統

CD20單株抗體–莫須瘤的治療會在B肝病毒表面抗原（HBsAg）陰性的CD20陽性B細胞非何傑金氏淋巴瘤（CD20+ NHL）患者引成B型肝炎病毒（HBV）活化，特別是對那些核心抗原抗體（anti-HBc）是陽性的人 。而活化後引起的肝炎通常是發生在B肝血清標記的逆轉（HBV-RS） - 也就是出現B肝表面抗原陽性以後。由於台灣B肝表面抗原陰性且未接種的成年人的anti-HBc陽性率極高，本研究的目的是找出影響莫須瘤治療引起HBV-RS的其他臨床因子或可能的遺傳變異。首先我們分析482位在2000年1月至2010年12月間，曾接受莫須瘤治療、B肝表面抗原陰性且未接種B肝疫苗的CD20+ NHL成人： 75.9％有anti-HBc血清學狀態資料，而其中的陽性率是91.4％，共有33個（6.85％）患者發生HBV-RS。當把無HBV-RS的死亡看作是競爭風險，單變數和多變數分析發現數個臨床因子會影響HBV-RS的發生，包括C型肝炎陽性，組織分型是移植後淋巴增生疾病，6療程以上的莫須瘤治療，和隨後的造血幹細胞移植。進一步使用IPLEX 單核苷酸多態性基因分型，在其中104例患者分析和免疫反應有關基因的89個基因變異，我們發現與HBV-RS發生有關的數個單核苷酸多態性，分別是在IL18和IL4基因上。因此，我們研究找出幾個和B肝表面抗原陰性的CD20+ NHL成人接受莫須瘤治療引起HBV-RS有關的臨床因子和遺傳變異，可作為臨床上針對高風險病患分級的重要利器。

Rituximab can cause hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg) seronegative patients with CD20 positive B-cell non-Hodgkin lymphoma (CD20+NHL), especially for those being seropositive to the antibody of core antigen (anti-HBc). Clinical hepatitis usually developed following reverse seroconversion of hepatitis B (HBV-RS) - appearance of HBsAg. The prevalence of anti-HBc seropositive unvaccinated HBsAg-seronegative adults is relative high in Taiwan, the study aimed to mine additional clinical and genetic factors influencing the development of rituximab associated HBV-RS among those patients. Total 482 unvaccinated HBsAg-seronegative adults with CD20+NHL who had received rituximab containing therapy but were not on anti-HBV agents between January 2000 and December 2010 were enrolled. The serological status of anti-HBc was available in 75.9% of patients, with the seropositive rates of 91.4%. At last follow-up, total 33 (6.85%) patients had HBV-RS. When death without HBV-RS considered as the competing risk, the univariate and multivariate regression analysis showed that several clinical factors were found to be independently associated with the development of HBV-RS, including anti-HCV seropositivity, histological subtype of post-transplant lymphoproliferative disorders, ≥6 cycles of rituximab therapy, and succeeding hematopoietic stem cell transplantation. Using the iPLEX SNP Genotyping, we further investigate 89 genetic variants of immune response genes in 104 patients, and found that single nucleotide polymorphisms on IL18 and IL4 genes independently associated with the development of HBV-RS. In conclusion, the findings of our studies identified additional clinical factors and genetic variants influencing the development of rituximab associated HBV-RS in HBsAg-seronegative adults with CD20+ NHL, which might be applied in clinical to further stratify high-risk populations before rituximab-based chemotherapy.

Contents
Acknowledgments i
Table of Contents iv
English Abstract ix
Chinese Abstract x
List of Abbreviations xi

1. Introduction 1
1.1 Clinical application of rituximab 1
1.2 Incidence 1
1.3 Methods to reduce clinical impact of HBV reactivation 1
1.3.1 Primary prophylaxis 1
1.3.2 Close monitoring followed by preemptive therapy 2
1.3.3 Limitations 2
1.4 Clinical risk factors 3
1.4.1 HBV serological status 3
1.4.1.1 Anti-HBc seropositivity 3
1.4.1.2 Anti-HBs seronegativity (or low titer) 3
1.4.1.3 Limitations of application 4
1.4.2 Higher number of cycles of rituximab therapy 4
1.4.2.1 Limitations of application 4
1.4.3 Statistical issue 5
1.5 Genetic factors 5
1.5.1 Available report(s) 5
1.5.2 Candidate gene approach 5

2. Aims of the thesis 8

3. Patients and methods 9
3.1 Patients 9
3.1.1 Clinical risk factors 9
3.1.2 Cytokine genetic variants 9
3.2 Data collection 9
3.3 Definition of HBV reactivation and hepatitis flare 9
3.4 Biochemistry 10
3.5 Viral serology, and virological tests 10
3.6 Lymphoma-related therapy 11
3.7 Selection and genotyping of candidate genes and SNPs 12
3.8 Statistical analysis 13
3.8.1 Clinical risk factors 13
3.8.2 Cytokine genetic variants 14

4. Results 16
4.1 Clinical risk factors 16
4.1.1 Patient characteristics 16
4.1.2 Comparison of patients with and without HBV-RS 16
4.1.3 Clinical and laboratory features of patients with HBV-RS 17
4.1.4 Association of the severity of hepatitis and rituximab cycle intensity 17
4.1.5 Factors associated with HBV-RS 17
4.2 Cytokine genetic variants 18
4.2.1 Patient characteristics according to the presence of HBV-RS 18
4.2.2 Candidate SNPs associated with HBV-RS 18
4.2.3 Haplotypes associated with HBV-RS 19
4.2.4 Competing-risks regression analysis of the association of clinical factors, SNPs, and haplotypes with HBV-RS 19
4.2.5 IL4 haplotype was not related to anti-HBs status in the risk of HBV-RS 20

5. Discussion 21
5.1 Clinical risk factors 21
5.2 Cytokine genetic variants 24

6. Conclusion 27

7. Perspectives 28

8. Figures 29
Figure 1.1 Cumulative incidence of rituximab-associated reverse seroconversion of HBsAg in 482 unvaccinated patients with CD20+ NHL, with death in the absence of reverse seroconversion of HBsAg as the competing risk. 29
Figure 1.2 Cumulative incidence of rituximab-associated reverse seroconversion of HBsAg in 482 unvaccinated patients with CD20+ NHL, with death in the absence of reverse seroconversion of HBsAg as the competing risk, according to (A) anti-HCV seropositivity, (B) PTLD histological subtype, (C) rituximab therapy ≥6 cycles, and (D) additional HSCT after rituximab therapy. 30
Figure 2.1 Cumulative incidence of rituximab-associated reverse seroconversion of HBsAg in 104 unvaccinated patients with CD20+ NHL, with “death in the absence of HBsAg reverse seroconversion” as the competing risk. 31
Figure 2.2 Cumulative incidence of rituximab-associated reverse seroconversion of HBsAg in 104 unvaccinated patients with CD20+ NHL, with “death in the absence of HBsAg reverse seroconversion” as the competing risk, according to SNPs (A) IL4 rs2243248, (B) IL4 rs2243263, (C) IL13 rs1295686, (D) IL18 rs243908, and (E) IL20 rs1518108. 32
Figure 2.3 Cumulative incidence of rituximab-associated reverse seroconversion of HBsAg in 104 unvaccinated patients with CD20+ NHL, with “death in the absence of HBsAg reverse seroconversion” as the competing risk, according to haplotypes (A) IL4 rs2243248~rs2243263, and (B) TNFSF13B rs12428930~rs12583006. 33
Figure 2.4 Cumulative incidence of rituximab-associated reverse seroconversion of HBsAg in 86 unvaccinated patients with CD20+ NHL, with “death in the absence of HBsAg reverse seroconversion” as the competing risk, according to the anti-HBs serostatus at diagnosis and IL18 SNP rs243908 (A and B), and IL4 haplotype rs2243248~rs2243263 (C and D). 34

9. Tables 35
Table 1.1 Characteristics of 482 unvaccinated HBsAg-seronegative patients with CD20+ NHL 35
Table 1.2 Reverse seroconversion of hepatitis B according to the histological subtypes of CD20+ NHL 37
Table 1.3 Comparison of 482 unvaccinated HBsAg-seronegative patients with CD20+ NHL according to the presence of rituximab-associated HBV-RS 39
Table 1.4 Characteristics of HBV-RS during/after rituximab-containing induction therapy of 10 patients with CD20+ NHL (group 1) 41
Table 1.5 Characteristics of HBV-RS during/after rituximab-containing salvage or maintenance therapy of 13 patients with CD20+ NHL (group 2) 42
Table 1.6 Characteristics of HBV-RS after rituximab-containing therapy and transplantation of 10 patients with CD20+ NHL (group 3) 43
Table 1.7 HBV-RS in 33 unvaccinated HBsAg-seronegative patients with CD20+ NHL according to the phase of rituximab therapy 44
Table 1.8 Correlation of Rituximab cycle intensity and hepatitis flare in 33 CD20+ NHL with reverse seroconversion of hepatitis B virus surface antigen 46
Table 1.9 Competing risk regression for factors influencing rituximab associated HBV-RS, with the outcome “death in the absence of HBV-RS” as the competing risk 47
Table 2.1 Eighty-nine single nucleotide polymorphisms of 49 immune response genes analyzed in the study 48
Table 2.2 Characteristics of 104 unvaccinated HBsAg-seronegative patients with CD20+ NHL according to the development of HBsAg reverse seroconversion 52
Table 2.3 Allele and genotype frequencies, and Hardy-Weinberg equilibrium of 89 single nucleotide polymorphisms analyzed 54
Table 2.4 The association of 74 single nucleotide polymorphisms with the development of HBsAg reverse seroconversion 59
Table 2.5 Candidate single nucleotide polymorphisms associated with HBsAg reverse seroconversion after rituximab therapy 65
Table 2.6 Linkage disequilibrium analysis of nine candidate single nucleotide polymorphisms 67
Table 2.7 Genotype distribution within haplotypes of IL4 rs2243263~rs2243248 and TNFSF13B rs12428930~rs12583006 69
Table 2.8 Haplotype frequencies and association analysis of IL4 and TNSSF13B according to the development of HBsAg reverse seroconversion 70
Table 2.9 Competing risk regression for predictors of HBsAg reverses seroconversion after rituximab therapy 71

10. Publications 74

11. References 75

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