Combination of Granulocyte colony stimulating factor (GCSF) and recombinant erythropoietin (rEPO) improves transplant free survival in patients of decompensated liver cirrhosis
Chandan K. Kedarisetty1, Ankit Bhardwaj2, Chhagan Bihari3, Archana Rastogi3, Nirupma Trehanpati2, Shiv K. Sarin1
1Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India; 2Research, Institute of Liver and Biliary Sciences, New Delhi, India; 3PathoIogy, Institute of Liver and Biliary Sciences, New Delhi, India
Background: Median survival of decompensated cirrhosis is < 2 ears. The only effective treatment is liver transplantation. We had recently shown that use of GCSF enhanced survival in acute- on-chronic liver failure patients (Gastroenterology 2012). EPO has been shown to improve liver regeneration in posthepatectomy and fulminant liver failure rat models. Aim: The present study was to study whether the use of G-CSF and Darbopeitin alpha (DPO) could lead to improved survival and liver regeneration in decompensated cirrhotics. Methods: Consecutive patients with decompensated cirrhosis were enrolled after approval by IRB, to receive 5μg/kg GCSF on day 1,2,3,4,5 and then every third day (total 12) and a weekly dose 40 IU DPO for 1 month (Group A, n=29) or matched placebo (Group B, n= 26). Standard of care continued in both groups. Transjugular liver biopsy (TJLB) and hepatic venous pressure gradient (HVPG) were done at baseline and in a proportion of patients at 1 month. Follow up was done on days 2, 4, 7, 14, 28 and then at month 3, 6, 9, and 12. Results: The two groups were well matched in baseline characteristics. The most common etiology was alcohol, followed by cryptogenic and viral hepatitis. There was significant improvement in CTP scores in Group A from baseline (10.9 ±1.2) to at one (9.67± 1.8), three (9.1 ± 1.7) and six (8.8 ± 1.4) months of follow-up (p < 0.005). After combination therapy significant reduction was seen in reguirement of albumin infusion in Group A from baseline to one month (p- 0.045). There was reduction in need for large volume paracentesis in Group A. Baseline alpha fetoprotein levels were similar in both groups (7.3 ± 6.9 vs 6.6 ± 3.6) . At 1 month, it was 6.6 ± 3.6 ng/ml in Group A and 4.7 ± 2.7 in Group B (p- 0.018), suggestive of enhanced regeneration in Gr. A. No change in HVPG levels was seen from baseline to 1 month (p-0.26). Transplant free survival at 6 months was 82. % in Group A and 50% in Group B (p- 0.009) and at 12 months was 68.9% and 46.2% respectively (p- 0.049). The actuarial probability of survival at 6 and 12 months was significantly higher in Group A but not in Group B. Immunohistochemistry in repeat TJLB of a patient in Group A showed an increase in proportion of CD 34+ cells, CD 133+ cells, Ki-67 and proliferating cell nuclear antigen (PCNA) suggestive of liver regeneration. No adverse events were noted. Conclusions: This is the first RCT (NCT01384565) showing clinical benefit and an improved transplant free survival by using a combination of growth factors; G-CSF and rEPO, in patients with decompensated cirrhosis. The therapy merits further evaluation in patients waiting for liver transplantation.
The following people have nothing to disclose: Chandan K. Kedarisetty, Ankit Bhardwaj, Chhagan Bihari, Archana Rastogi, Nirupma Trehanpati, Shiv K. Sarin