The impact of rituximab prophylaxis on hepatocellular carcinoma recurrence after living donor liver transplantation

Abstract

Aim: Rituximab is administered for ABO blood type incompatibility or donor-specific anti-HLA (human leukocyte antigen) antibody-positive liver transplantation (LT). However, the impact of rituximab administration on hepatocellular carcinoma (HCC) recurrence over a long term period remains unclear. The present study aimed to retrospectively investigate the impact of rituximab-based prophylaxis on HCC recurrence after living donor LT (LDLT).

Methods: A total of 117 patients who had undergone LDLT for HCC at Kyoto University between February 2006 and October 2018 were retrospectively enrolled for this study. Overall survival (OS) and the recurrence rate (RR) for HCC after LDLT were examined in patients who received rituximab (rituximab group: n = 31) vs. those who did not (control group: n = 86). Additional analyses were conducted as per the Milan criteria, the University of California San Francisco extended criteria (single tumor ≤ 6.5 cm, or ≤ 3 nodules with the largest tumor ≤ 4.5 cm, and total tumor diameter ≤ 8 cm), and the Kyoto criteria (KC) [maximum size ≤ 5 cm, number ≤ 10, des-gamma-carboxy prothrombin (DCP) ≤ 400]. Moreover, we analyzed risk factors associated with HCC recurrence with a focus on pretransplant factors.

Results: The one-, three-, and five-year (1/3/5-y) OS and RR for all patients were 89%/81%/79% and 5%/9%/11%, respectively. The 1/3/5-y OS and 1/3/5-y RR in the rituximab group vs. the control group were 87%/77%/69% and 4%/4%/8% vs. 89%/82%/82% and 5%/11%/12%, respectively (P = 0.11 and P = 0.55, respectively). In the subgroup analysis stratified by the selection criteria, the RR was comparable between groups. The number of patients with non-recurrence-related death tended to be higher in the rituximab group than the control group. Multivariate analysis identified maximum tumor size (P = 0.003) and preoperative treatment (P = 0.024) as independent risk factors for HCC recurrence.

Conclusion: Rituximab administration does not seem to affect HCC recurrence after LDLT.

Keywords

Rituximab / ABO incompatible / hepatocellular carcinoma / recurrence / liver transplantation

References

[1] Bray F,Soerjomataram I,Torre LA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2018;68:394-424

[2] Chen CL,Lee SG,Tanaka K.Living-donor liver transplantation: 12 years of experience in Asia.Transplantation2003;75:S6-11

[3] Yoon YI.Living donor liver transplantation for hepatocellular carcinoma: An Asian Perspective.Dig Dis Sci2019;64:993-1000

[4] Hong G,Suh SW.Preoperative selective desensitization of liver donor liver transplant recipients considering the degree of T lymphocyte cross-match titer, model for end-stage liver disease score, and graft liver volume.J Korean Med Sci2014;29:640-7 PMCID:PMC4024948

[5] Egawa H.Challenge to ABO blood type barrier in living donor liver transplantation.Hepatobiliary Pancreatic Dis Int2020;19:342-8

[6] Wesson RN,Garonzik-Wang J.Application and interpretation of histocompatibility data in liver transplantation.Curr Opin Organ Transplant2017;22:499-504

[7] Egawa H,Haga H.Impact of rituximab desensitization on blood-type-incompatible adult living donor liver transplantation: a Japanese multicenter study.Am J Transplant2014;14:102-14

[8] Kim SH,Na BG.Impact of ABO-incompatibility on hepatocellular carcinoma recurrence after living donor liver transplantation.Eur J Surg Oncol2019;45:180-6

[9] Kim JM,Joh JW.ABO-incompatible living donor liver transplantation with rituximab and total plasma exchange does not increase hepatocellular carcinoma recurrence.Transplantation2018;102:1695-701

[10] Yoon YI,Lee SG.Outcome of ABO-incompatible adult living-donor liver transplantation for patients with hepatocellular carcinoma.J Hepatol2018;68:1153-62

[11] Kamo N,Hammad A.Impact of elderly donors for liver transplantation: a single-center experience.Liver transpl2015;21:591-8

[12] Kamo N,Hamaguchi Y.Impact of enteral Nutrition with an immunomodulating diet enriched with hydrolyzed whey peptide on infection after liver transplantation.World J Surg2018;42:3715-25

[13] Ueda Y.Interferon-free therapy for hepatitis C in liver transplantation recipients.Transplantation2016;100:54-60

[14] Ueda Y,Kaido T.Efficacy and safety of prophylaxis with entecavir and hepatitis B immunoglobulin in preventing hepatitis B recurrence after living-donor liver transplantation.Hepatol Res2013;43:67-71

[15] Inomata Y,Egawa H.The evolution of immunosuppression with FK 506 in pediatric living related liver transplantation.Transplantation1996;61:247-52

[16] Takada Y,Ito T.Living donor liver transplantation as a second-line therapeutic strategy for patients with hepatocellular carcinoma.Liver Transpl2006;12:912-9

[17] Fukumitsu K,Kaido T.Validation of steroid-free immunosuppression regimen after liver transplantation.J Clin Gastroensterol Treat2015;1:1-4

[18] Egawa H,Uemoto S.Optimal dosage regimen for rituximab in ABO-incompatible living donor liver transplantation.J Hepatobiliary Pancreat Sci2017;24:89-94

[19] Takada Y,Ueda M.Living donor liver transplantation for patients with HCC exceeding the Milan criteria: a proposal of expanded criteria.Dig Dis2007;25:299-302

[20] Egawa H,Todo S.Impact of desensitization for ABO-blood bar- rier on living donor liver transplantation for hepatocellular carcinoma.Nihon Shokakibyo Gakkai Zasshi2014;111:892-8

[21] Olnes MJ,Biancotto A.Effects of systemically administered hydrocortisone on the human immunome.Sci Rep2016;14:23002 PMCID:PMC4789739

[22] Unitt E,Gelson W.Tumor lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation.J Hepatol2006;45:246-253

[23] Lee JY,Yi NJ.Impact of immunosuppressant therapy on early recurrence of hepatocellular carcinoma after liver transplantation.Cli Mol Hepatol2014;20:192-203 PMCID:PMC4099335

[24] Wu LW, Tai Q, Zhu XF, He XS. Safety and efficacy of four steroid-minimization protocols in liver transplant recipients: 3-year follow-up in a single center.J Dig Dis2013;14:38-44

[25] Yoshizawa A.The impact of donor-specific anti-HLA antibodies on liver transplantation.MHC2017;24:134-42