Effect of GVHD prophylaxis on renal function and survival outcomes in allogeneic hematopoietic cell transplant patients with pre-existing renal impairment

Abstract

Abstract Background: Renal impairment (RI) is a common comorbidity identified during pre-transplant evaluation and is a well-established risk factor for non-relapse mortality (NRM) after allogenic hematopoietic cell transplantation (HCT). Conversely, renal injury is a frequent complication associated with HCT. The advent of post-transplant cyclophosphamide (PTCy) permitted calcineurin inhibitor free graft-versus-host disease (GVHD) prophylaxis when combined with sirolimus (SIR), offering an HCT option that is less nephrotoxic. We hereby present HCT clinical outcomes in patients (pts) with pre-existing RI comparing commonly used GVHD prevention regimens. Methods: This single-center retrospective study included all pts with pre-existing RI who underwent HCT between 2018 – 2022. GVHD prevention regimens included PTCy/SIR, PTCy with tacrolimus (PTCy/TAC), TAC/SIR, and Tac with methotrexate (TAC/MTX).RI was defined as eGFR< 90 ml/min/m2 estimated by the MDRD (Modification of Diet and Renal Disease) equation using creatinine prior to start of the conditioning. RI was graded based on eGFR as grade (G) 1 (60-89), G2 (45-59), G3 (30-44) and G4 (<30). The primary outcome was the development of acute kidney injury (AKI) defined as increase in serum creatinine from day of admission by > 0.3 mg/dl within 48 hours or > 1.5 times within 7 days at any time within 3 months post-HCT. AKI was staged using KDIGO criteria (Kidney Disease Improving Global Outcomes). Secondary outcomes included 1-year NRM, progression-free survival (PFS), and overall survival (OS). Results: Atotal of 355 pts were included: 83 in PTCy/SIR, 86 in PTCy/TAC, 143 in TAC/SIR, and 43 in TAC/MTX groups. Median age was 64 yrs (range: 25-78), and median follow up was 39.6 months (range: 38.3-42). The study cohort consisted of 59% male, 85% non-Hispanic White, 30% KPS <90, 53% HCT-CI >3, 90% myeloid malignancies, 82% reduced intensity conditioning and 63% matched unrelated donor HCT. Pre-HCT RI was 83.7% G1, 13.8% G2, 2.5% G3. None of the study pts had pre-HCT G4 RI. GVHD prophylaxis in pts with >G2 RI was 29.3% PTCy/SIR, 10.8% PTCy/TAC, 48.3% TAC/SIR, and 12 % TAC/MTX. Diabetes mellitus was present in 15% and essential hypertension in 42% of pts prior to HCT. At 3 months post-HCT, the cumulative incidence of AKI was 47% (95% CI: 42-53) in all pts: 33% (95% CI: 24-44) in PTCy/SIR, 56% (95% CI: 46-67) in PTCy/TAC, 45% (95% CI: 37-54) in TAC/SIR, and 65% (95% CI: 52- 81) in TAC/MTX. Incidence of AKI based on pre-HCT RI was 45% G1, 53% G2, and 67% G3. Most AKIs were pre-renal (78%) and stage I (54%), primarily due to dehydration (38%) followed by medications (20%), while 26 pts required temporary and 1 pt permanent dialysis. The average peak creatinine was 2.2 mg/dl (range: 1.1 – 11.2) and average lowest eGFR was 33.7 ml/min/m2 (range: 4-63.6). In multivariate analysis, renal toxicity risk was significantly lower with PTCy/SIR as compared to PTCy/TAC (HR 1.9, 95% CI 1.19- 2.98, p=0.006) and TAC/MTX (HR 2.4, 95% CI 1.46- 4.08, p=<0.001) but not TAC/SIR (HR 1.5, 95% CI 0.97- 2.41, p=0.06). Additionally, pre-HCT RI > G2 (HR 1.5, 95% CI 0.99-2.26, p=0.054) and HCT-CI >3 (HR 1.4, 95% CI 1.02-1.88, p=0.04) influenced higher risk of AKI post-HCT. At 1-year post-HCT, NRM was 19% (95% CI: 16- 24), PFS was 63% (95% CI: 58-68) and OS was 74% (95% CI: 70-79) for the entire cohort. NRM based on pre-HCT RI was 18% for G1, 23% for G2, and 56% for G3 (p=0.024). In multivariate analysis, GVHD prophylaxis type had no independent impact on HCT survival outcomes. NRM was higher with age >60 yrs (HR 1.9, 95% CI 1.13- 3.1, p=0.02) and HCT-CI >3 (HR 1.7, 95% CI 1.11- 2.54, p=0.02). PFS was negatively affected by recipient CMV seropositivity (HR 1.6, 95% CI 1.05- 2.27, p=0.03) and HCT-CI >3 (HR 1.3, 95% CI 1.00- 1.80, p=0.05). OS was significantly worse with age >60 yrs (HR 1.6, 95% CI 1.10- 2.32, p=0.01) and HCT-CI >3 (HR 1.6, 95% CI 1.14- 2.18, p=0.006). Conclusions: Half of the patients with pre-existing RI, particularly those with eGFR <60, are at high risk of developing AKI post-HCT. While immunosuppression can significantly influence the risk of AKI, PTCy/SIR demonstrates a more favorable impact on renal function after HCT. These findings support the preferential use of PTCy/SIR as GVHD prophylaxis to reduce the risk of renal toxicity and associated morbidities, including need for dialysis post-HCT.