Harmony Follow up study renal transplant.pptx

harmony follow up study

1. Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study)

2. INTRODUCTION - Corticosteroids are widely used in immunosuppressive therapy after renal transplantation. - They come with significant side effects, including increased cardiovascular risk factors like diabetes, hyperlipidemia, and hypertension. - About one-third of kidney transplant recipients in the USA, but fewer in Europe, have corticosteroids withdrawn after transplantation. - Rapid corticosteroid withdrawal (RSWD) protocols aim to reduce side effects but lack strong evidence due to limited randomized controlled trials. - Registry data suggest RSWD may lower rates of post-transplantation diabetes and improve long-term graft and patient survival. - However, RSWD may increase the risk of T cell-mediated acute rejection. - The Harmony trial evaluated induction therapies with RSWD in low immunological risk kidney transplant recipients. - Both induction therapies combined with RSWD were effective in preventing acute rejection, with reduced PTDM compared to control. - 5-year post-trial follow-up data from the Harmony trial assessed long-term outcomes and complications like immunosensitization and humoral rejections.

3. MATERIALS AND METHODS OVERVIEW: - Investigator-initiated observational post-trial follow-up study. - Aimed to compare safety and efficacy at 3- and 5-years of basiliximab - or rATG -induced rapid steroid withdrawal (RSWD) in low-risk kidney transplant recipients. - Original Harmony trial: 1-year study in 21 German transplant centers. - Study approved by institutional review boards; written informed consent obtained. - Patients followed non- interventionally as per center standard. - FU data collected at 3- and 5-year visits for consenting patients. - Medication, inclusion/exclusion criteria, and endpoints detailed in Supplementary material.

4. Statistical Analysis: - Descriptive analysis; no imputation for missing data. - Time-to-event endpoints analyzed for entire intention-to-treat population. - Categorical variables presented as counts/percentages; continuous variables as means or median with interquartile range. - Statistical tests included Fisher’s exact test, Kruskal–Wallis H Test, analysis of variance, Kaplan–Meier method, log-rank test, and Cox regression analysis. - Significance level set at 0.05; no adjustment for multiple comparisons planned. - SAS software 9.4 used for analyses. - Follow-up conducted for prematurely eliminated patients from original study.

5. Results Patient Population Characteristics: - At 1-year post-transplantation, 135/113/111 patients in Groups A/B/C, respectively, provided data for the follow-up analysis. - By year 5, 11 recipients were lost to follow-up in total. - Baseline characteristics were well-balanced among the three study arms.

6. Medication and Treatment Frequency: - At 1-year, corticosteroid usage was 90%/16%/17% in Groups A/B/C, respectively. - At 3- and 5-year follow-up, corticosteroid usage decreased significantly, with 38.5% in Group A, and 22.8% and 21.9% in Groups B and C, respectively. - Over 80% of patients remained on tacrolimus and MMF/MPA therapy, with minimal use of alternative immunosuppressive agents. Efficacy Endpoints: - Cumulative incidence of biopsy-proven acute rejection (BPAR) was low and similar among all groups up to 5 years. - Severity of acute rejections was comparable across groups. - Overall, 52 deaths were observed, with similar rates among the three groups. - Death-censored graft survival rates were similar across groups. - Graft function was comparable among treatment groups, with a trend towards improved function in Group C.

7. Safety Endpoints:   -Monitoring of anti-HLA antibodies showed no significant differences among groups. -De novo occurrence of donor-specific anti-HLA antibodies tended to be more frequent in the steroid withdrawal groups, particularly in Group B.

8. Metabolic Profiles: PTDM Occurrence: Only 16 new cases observed over 5-year follow-up. Distribution: 5 cases in Group A, 7 in Group B, and 4 in Group C. RSWD within the first year did not lead to increased PTDM events later on. Blood pressure, lipids, weight, and BMI showed no substantial differences among study arms.

9. Cardiovascular Disease and Bone Disease: - The incidence of any cardio- or cerebrovascular disease event was around 10% and equally distributed among study arms. - Bone fracture incidence was low (2.6%) and similar across all study arms.

10. Infections, Anemia , and Cancer: - The overall incidence of severe bacterial infections requiring hospitalization decreased in Arm C compared to Arms A and B. - Arm C also showed a significant reduction in the incidences of repetitive bacterial infections. - The incidence of invasive opportunistic infections and cytomegalovirus (CMV) infections was similar across all groups. Incidence of new BK virus (BKV) infections was similar among groups. - While within the first year of the Harmony trial, the frequency of anemia was significantly higher after RSWD compared with control patients, during the 3- and 5-year FU time, anemia rates were low (around 15%) and similar in all groups - Cancer development occurred at similar rates across all groups, with 37 new malignancies observed since year 1, primarily skin-related.

11. MULTIVARIABLE ANALYSIS OF PATIENT SURVIVAL - Factors examined: age, sex, RSWD, induction therapy, donor criteria, diabetes mellitus, cardiovascular disease, arterial hypertension, anemia , elevated cholesterol, and hyperlipidemia . - No significant collinearity detected among risk factors. - RSWD (Groups B + C) associated with independent protective effect on patient death (adjusted HR: 0.554, 95% CI: 0.314–0.976, P = .041). - Induction therapy type not found to be independently associated with patient survival. - Independent risk factors for patient death: recipient age, time on dialysis, diabetes mellitus, and cardiovascular disease.

12. SUMMARY: - 5-year follow-up data from Harmony study on RSWD in kidney transplant. - No superiority of rabbit ATG over basiliximab induction for preventing BPAR. - RSWD maintained safety and efficacy over 5 years, reducing PTDM incidence by 40%. - Majority were elderly Caucasian recipients with deceased donor kidneys. - Multivariate analysis favors RSWD for patient survival. - Excellent patient and graft survival across all groups. - No significant differences in safety outcomes. - Concerns of increased immunosensitization with RSWD not supported. - Study limitations include observational design and potential selection bias. - RSWD remains a safe and effective alternative to corticosteroid therapy in low-risk kidney transplant recipients.