Pre-transplant Biomarkers of Immune Dysfunction Improve Risk Assessment of Post-transplant Mortality Compared to Conventional Clinical Risk Scores.

Introduction: There is a critical need to accurately stratify liver transplant (LT) candidates' risk of post-LT mortality prior to LT to optimize patient selection and avoid futility. Here, we compare previously described pre-LT clinical risk scores with the recently developed Liver Immune Frailty Index (LIFI) for prediction of post-LT mortality. LIFI measures immune dysregulation based on pre-LT plasma HCV IgG, MMP3 and Fractalkine. LIFI accurately predicts post-LT mortality, with LIFI-low corresponding to 1.4% 1-year post-LT mortality compared with 58.3% for LIFI-high (C-statistic=0.85). Methods: LIFI was compared to MELD, MELD-Na, MELD 3.0, D-MELD, MELD-GRAIL, MELD-GRAIL-Na, UCLA-FRS, BAR, SOFT, P-SOFT, and LDRI scores on 289 LT recipients based on waitlist data at the time of LT. Survival, hazard of early post-LT death, and discrimination power (C-statistic) were assessed. Results: LIFI showed superior discrimination (highest C-statistic) for post-LT mortality when compared to all other risk scores, irrespective of biologic MELD. On univariate analysis, the LIFI showed a significant correlation with mortality 6-months, as well as 1-, 3-, and 5-years. No other pre-LT scoring system significantly correlated with post-LT mortality. On bivariate adjusted analysis, African American race (p<0.05) and pre-LT cardiovascular disease (p=0.053) were associated with early- and long-term post-LT mortality. Patients who died within 1-yr following LT had a significantly higher incidence of infections, including 30-day and 90-day incidence of any infection, pneumonia, abdominal infections, and UTI (p<0.05). Conclusions: LIFI, which measures pre-LT biomarkers of immune dysfunction, more accurately predicts risk of post-LT futility compared with current clinical predictive models. Pre-LT assessment of immune dysregulation may be critical in predicting mortality after LT and may optimize selection of candidates with lowest risk of futile outcomes.

Continuous induction with lenalidomide/dexamethasone versus autologous stem cell transplantation in newly diagnosed multiple myeloma: a case for response-adapted approach.

Although upfront autologous stem cell transplantation (ASCT) generally improves progression-free survival (PFS) in newly diagnosed multiple myeloma (NDMM), the overall survival (OS) benefit and optimal timing of ASCT are not well established. Patients with early response may be able to safely continue induction and avoid ASCT without compromised outcomes. We report an extended follow-up analysis of a phase 2 trial that randomized transplant-eligible patients with NDMM who responded to induction (50/65 patients) to continued induction or ASCT; median follow-up was 8.0 years. Patients had similar 8-year PFS (55% vs. 43%), 8-year OS (83% vs. 72%), and rates of at least very good partial response (72% vs. 84%) whether continuing induction of lenalidomide and dexamethasone (Ld arm) or receiving ASCT (Ld + ASCT arm) (p = 0.5). Notably, over 50% of patients receiving continuous Ld had PFS of 5-10 years. These results suggest the need for prospective trials incorporating response-adapted therapeutic approaches to NDMM.STATEMENT OF PRIOR PRESENTATIONPresented in abstract form (interim analysis) at the 56th annual meeting of the American Society of Hematology (San Francisco, CA, 6 December 2014) and at the 57th annual meeting of the American Society of Hematology (Orlando, FL, 3 December 2015).

Clinical and biomarker assessment of frailty in liver transplantation.

PURPOSE OF REVIEW: Liver cirrhosis results in progressive decline, or frailty, which leads to poor outcomes and decreased survival. Multiple biomarkers and clinical assessment tools for quantifying frailty in liver transplant candidates exist, but a universal scoring protocol is lacking. Criteria vary between studies and correlation with patient outcome is not always clear. This review aims to summarize the pertinent biomarkers and assessment tools of frailty in cirrhosis. RECENT FINDINGS: As cirrhosis progresses, the resultant 'frailty' is an inseparable independent predictor of pre and posttransplant mortality. Pro-inflammatory, neuroendocrine, and adipokine factors are dysregulated - leading to paradoxical anorexia and downregulation of orexigenic signals. The resulting catabolic utilization of amino and fatty acids leads to progressive malnutrition and sarcopenia. Both functional and imaging criteria define sarcopenia in cirrhotic patients, and degree of debilitation correlates with mortality. Liver-disease-specific frailty biomarkers and scoring tools are optimal to assess physical dysfunction in cirrhotics to promote early diagnosis and intervention. SUMMARY: Liver cirrhosis and resulting frailty are progressive and portend a poor patient prognosis. A comprehensive, validated algorithm for detecting and quantifying frailty specific to liver disease would allow for standardization and facile application in the clinical setting. Early diagnosis is key for timely intervention and improved patient outcomes.