1.
Outcomes Following Intolerance to Tacrolimus/Sirolimus Graft-Versus-Host Disease Prophylaxis for Allogeneic Hematopoietic Cell Transplantation
Mirza, A. S., Tandon, A., Jenneman, D., Cao, S., Brimer, T., Kumar, A., Kidd, M., Khimani, F., Faramand, R., Mishra, A., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Although tacrolimus and sirolimus (TAC/SIR) is an accepted graft-versus-host disease (GVHD) prophylaxis following allogeneic hematopoietic cell transplant (HCT), toxicity from this regimen can lead to premature discontinuation of immunosuppression. There are limited studies reporting outcomes and subsequent treatment of patients with TAC/SIR intolerance. OBJECTIVES To assess outcomes of patients with TAC/SIR intolerance and guide subsequent management after intolerance. STUDY DESIGN We retrospectively analyzed transplant outcomes of consecutive adult patients at Moffitt Cancer Center who received allogeneic HCT with TAC/SIR as GVHD prophylaxis from 2009 to 2018. TAC/SIR intolerance was defined as discontinuation due to toxicity of either TAC or SIR before post-transplant day 100. RESULTS 777 patients met the inclusion criteria. Median follow-up was 22 (0.2-125) months. Intolerance occurred in 13% (n = 104) of patients at a median of 30 (range 5-90) days. The most common causes of intolerance were acute kidney injury (n = 53 [51%]), thrombotic microangiopathy (n = 31 [28%]), and veno-occlusive disease (n = 23 [22%]). The cumulative incidence of grade 2 to 4 acute GVHD at 100 days in TAC/SIR-intolerant patients was 50% (95% CI, 39%-64%) and 25% (95% CI, 22%-29%) in patients tolerant to this regimen (P < .0001). In multivariate analyses, grade 2 to 4 acute GVHD was significantly higher in TAC/SIR-intolerant patients (HR 2.40; 95% CI, 1.59-3.61; P < .0001). Similarly, in multivariate analyses, TAC/SIR-intolerant patients had more chronic GVHD (HR 1.48, 95% CI, 1.03-2.12; P = .03). The non-relapse mortality (NRM) at 1 year in TAC/SIR-intolerant patients was 47% (95% CI, 38%-59%) and 12% (95% CI, 10%-15%) in those tolerant to the regimen (P < .0001). The 2-year relapse free survival of TAC/SIR-intolerant patients was 35% (95% CI, 25%-44%) and 60% (95% CI, 57%-65%) among TAC/SIR-tolerant patients, (HR 2.30; 95% CI, 1.61-3.28; P < .0001). Intolerance stratified by early (≤30 days) versus late (31-100 days) significantly affected the cumulative incidence of acute GVHD at 75% (early [95% CI, 59%-94%]) versus 33% ([late] 95% CI, 21%-50%) (P = .001) as well as the cumulative incidence of NRM at 61% ([early] 95% CI, 48%-77%) versus 35% ([late] 95% CI, 24%-51%) (P = .006). After developing TAC/SIR intolerance, most patients were switched to an alternative 2-drug regimen (71/104 [68%]), with the most common being mycophenolate mofetil in addition to continuing TAC or SIR (68/71 [96%]). CONCLUSIONS Overall, TAC/SIR intolerance was associated with poorer outcomes. Early intolerance contributed to higher risk of acute GVHD, increased NRM, and inferior survival. Patients with early intolerance were often switched to an alternative agent, and patients with late intolerance tended to be continued on single-drug therapy without substitution. Single-drug versus 2-drug regimens after intolerance did not appear to affect outcomes. Management strategies to mitigate the risks of intolerance are warranted.
2.
Hypoalbuminaemia segregates different prognostic subgroups within the refined standard risk acute graft-versus-host disease score
Kharfan-Dabaja, M. A., Sheets, K., Kumar, A., Murthy, H. S., Nishihori, T., Tsalatsanis, A., Mina, A., Mathews, J., Ayala, E., Chavez, J., et al
British journal of haematology. 2018;180(6):854-862
Abstract
Hypoalbuminaemia has been previously described to predict worse non-relapse mortality (NRM) and inferior overall survival (OS) in allogeneic haematopoietic cell transplant (allo-HCT) recipients. Here, we evaluate the role of hypoalbuminaemia (<35 g/l) at time of onset of acute graft-versus-host disease (aGVHD) when incorporated into the refined aGVHD score. The study population consisted of 522 patients, median age 53 (18-75) years, who underwent an allo-HCT mostly for haematological malignancies. Standard risk (SR) aGVHD comprised 467 patients (89%) and the number of high risk (HR) cases was 55 (11%). Median follow-up for all surviving patients was 26 (3-55) months. Two-year OS was significantly better in patients with SR aGVHD with a serum albumin ≥35 g/l compared to SR with albumin <35 g/l [70% (95% CI = 64-76%) vs. 49% (95% CI = 42-56%), P < 0·0001]. Also, patients with SR aGVHD and a serum albumin level of ≥35 g/l had a significantly lower NRM at 1-year post-transplantation [6% (95% CI = 3-10%) vs. 25% (95% CI = 20-32%), P < 0·0001]. After our findings are validated in a large cohort of patients, we propose that hypoalbuminaemia should be incorporated into the refined aGVHD risk score to further its ability to predict outcomes within this group.