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Clinical Features of AKI in the Early Post-Transplant Period Following Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation
Vergara-Cadavid, J., Johnson, P. C., Kim, H. T., Yi, A., Sise, M. E., Leaf, D. E., Hanna, P. E., Ho, V. T., Cutler, C. S., Antin, J. H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplant (HCT) is a potentially curative therapy for patients with hematologic malignancies but is associated with acute kidney injury (AKI). Few studies have examined risk factors for AKI at engraftment, or its relationship with clinical outcomes. OBJECTIVE The objective of this study was to examine the incidence and risk factors for peri-engraftment AKI, as well as the association between AKI and overall survival and non-relapse mortality. METHODS We conducted a retrospective analysis of adult patients receiving reduced intensity conditioning (RIC) allogeneic HCT at the Dana-Farber Cancer Institute between 2012 and 2019. Peri-engraftment (day 0 to day 30) AKI incidence and severity was defined using modified Kidney Disease: Improving Global Outcomes criteria. Factors associated with peri-engraftment AKI risk were examined using Cox regression analysis. The impact of peri-engraftment AKI on overall survival and non-relapse mortality (defined as death without recurrent disease after HCT), was evaluated using Cox regression and Fine and Gray's competing risk model, respectively. Kidney recovery, defined as a return of serum creatinine within 25% of baseline or liberation from kidney replacement therapy (KRT), was examined at day 90 in relation to HCT. RESULTS Peri-engraftment AKI occurred in 330 of 987 patients (33.4%) at a median of 13 days [IQR 4-30] post-transplant. Factors associated with a higher multivariable-adjusted risk of AKI were supratherapeutic rapamycin (HR: 1.56, 95% CI: 1.20-2.03; p<0.001), fludarabine/melphalan conditioning (HR: 1.35, 95% CI: 1.01-1.81; p=0.05; compared to fludarabine/busulfan and fludarabine, cyclophosphamide, total body irradiation), HCT-Comorbidity Index ≥4 (HR: 1.43, 95% CI: 1.14-1.79; p=0.002), albumin <3.4 g/dl (HR: 2.04, 95% CI: 1.33-3.12; p=0.001), hemoglobin ≤12 (HR 1.96, 95% CI 1.38-2.78; p<0.001), supratherapeutic tacrolimus (HR 1.45, 95% CI 1.07 - 1.95; p=0.02), and baseline serum creatinine >1.1 mg/dl (HR: 1.87, 95% CI: 1.48-2.35; p<0.001). Peri-engraftment AKI was associated with worse overall survival (HR 1.40, 95% CI: 1.16-1.71; p<0.001) and non-relapse mortality (subdistribution HR 2.10, 95% CI: 1.52-2.89; p<0.001). Kidney recovery occurred in 18%, 15%, and 30% of patients with stage 1, 2, and 3 AKI without KRT, respectively, and 4 of 16 (25%) patients were liberated from KRT. CONCLUSION Peri-engraftment AKI is common among RIC allogeneic HCT recipients. We identified several important risk factors for peri-engraftment AKI. Peri-engraftment AKI is associated with worse overall survival and non-relapse morality, highlighting the importance of timely recognition and management of AKI.
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Cytokine release syndrome in haploidentical stem cell transplant may impact T-cell recovery and relapse
Shapiro, R. M., Kim, H. T., Ansuinelli, M., Guleria, I., Cutler, C. S., Koreth, J., Gooptu, M., Antin, J. H., Kelkar, A. H., Ritz, J., et al
Blood advances. 2023
Abstract
Cytokine release syndrome (CRS) following haploidentical hematopoietic cell transplantation (HCT) resembles the CRS after chimeric antigen receptor (CAR)-T therapy. We conducted this single-center retrospective study evaluating the association of post-haploidentical HCT CRS with clinical outcomes and immune reconstitution. One hundred sixty-nine patients who underwent haploidentical HCT between 2011 and 2020 were identified. Of these, 98 patients (58%) developed CRS after HCT. CRS was diagnosed based on the presence of fever within the first 5 days after HCT without evidence of infection or infusion reaction, and graded according to established criteria. The development of post-haploidentical HCT CRS was associated with a lower incidence of disease relapse (p=0.024) but with an increased risk of chronic GVHD (p=0.01). The association of CRS with a lower incidence of relapse was not confounded by graft source or disease diagnosis. Neither CD34 nor TNC dose was associated with CRS independently of graft type. In patients developing CRS, CD4+ Treg (p<0.0005), CD4+ Tcon (p<0.005) and CD8+ T-cells (p<0.005) were increased at 1 month following HCT compared to those who did not develop CRS, but not at later time points. The increase in CD4+ regulatory T cells at 1 month post HCT was most notable among patients with CRS who received a bone marrow graft (p<0.005). The development of post haploidentical HCT CRS is associated with a reduced incidence of disease relapse and with a transient effect on post HCT immune reconstitution of T cells and their subsets. Validation of these observations in a multicenter cohort is required.
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Cytokine release syndrome after haploidentical hematopoietic cell transplantation: an international multicenter analysis
Abboud, R., Wan, F., Mariotti, J., Arango, M., Castagna, L., Romee, R., Hamadani, M., Chhabra, S.
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
Haploidentical related donor transplantation (haplo-HCT) is associated with cytokine release syndrome (CRS). We conducted a multicenter retrospective study to analyze risk factors for CRS and outcomes after haplo-HCT. We included 451 patients from four academic centers receiving both peripheral blood and bone marrow grafts. Severe CRS was more common with PB vs. BM grafts (19.5% vs 4.9%, OR 2.9, p?=?0.05). Multivariable analysis identified recipient CMV sero-positivity, prior transplant, HCT-CI score and donor-recipient sex mismatch as risk factors for severe CRS. Outcomes were analyzed with no CRS as the comparison group. Overall survival (OS) was superior with mild CRS (HR 0.64, p?=?0.05) and worst with severe CRS (HR 2.12, p?=?0.0038). Relapse risk was significantly decreased in both mild CRS (HR 0.38, p?0.0001) and severe CRS (HR 0.17, p?0.0001) groups. The risk of non-relapse mortality was notably higher in severe CRS group (HR 8.0, p?0.0001), but not in mild CRS group. Acute GVHD was similar among groups. Chronic GVHD at 1 year was 18.5% for no CRS, 23% for mild CRS, and 4.3% for severe CRS (p?=?0.0023), with the competing risk of early mortality and short follow up of surviving patients contributing to the low chronic GVHD rates in the severe CRS group.
PICO Summary
Population
Patients receiving haploidentical bone marrow grafts in four academic centres in USA, South America and Europe (n=451)
Intervention
Retrospective study assessing the incidence and risk factors for cytokine release syndrome (CRS)
Comparison
Patients were grouped for analysis according to CRS grading, graft source and selected risk factors
Outcome
Severe CRS was more common with PB vs. BM grafts (19.5% vs 4.9%). Multivariable analysis identified recipient CMV sero-positivity, prior transplant, HCT-CI score and donor–recipient sex mismatch as risk factors for severe CRS. Outcomes were analysed with no CRS as the comparison group. Overall survival (OS) was superior with mild CRS (HR 0.64) and worst with severe CRS (HR 2.12). Relapse risk was significantly decreased in both mild CRS (HR 0.38) and severe CRS (HR 0.17) groups. The risk of non-relapse mortality was notably higher in severe CRS group (HR 8.0), but not in mild CRS group. Acute GVHD was similar among groups. Chronic GVHD at 1 year was 18.5% for no CRS, 23% for mild CRS, and 4.3% for severe CRS, with the competing risk of early mortality and short follow up of surviving patients contributing to the low chronic GVHD rates in the severe CRS group.
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Incidence, predictors, and outcomes of veno-occlusive disease/sinusoidal obstruction syndrome after reduced intensity allogeneic hematopoietic cell transplantation
Lewis, C., Kim, H. T., Roeker, L. E., Cutler, C., Koreth, J., Nikiforow, S., Armand, P., Gootpu, M., Romee, R., Glotzbecker, B., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HCT) that is felt to be triggered, at least in part, by damage to the liver sinusoidal endothelium from cytotoxic conditioning regimens. Accordingly, the incidence of VOD/SOS after reduced intensity conditioning (RIC) HCT is low compared to myeloablative transplantation, and the natural history, risk factors, and outcomes of VOD/SOS after RIC have not been well characterized. We retrospectively reviewed 1583 consecutive patients receiving RIC HCT at the Dana-Farber Cancer Institute between 2007-2017 and ascertained 26 cases of VOD/SOS. The median day of VOD/SOS onset was 26 days (range 5, 48) and the cumulative incidence at day 50 was 1.6% (95% confidence interval 1.1%, 2.4%). Day 100 non-relapse mortality rate was 23% in the VOD/SOS cohort compared to 6.4% in patients without VOD/SOS (p=0.006). Cumulative incidence of VOD/SOS at day 50 was 3.1% after RIC regimen with Flu/Bu2+/-ATG (busulfan dose 6.4 mg/kg), compared to 0.15% after Flu/Bu1+/-ATG (busulfan dose 3.2 mg/kg) (p=0.0002); the incidence rate was 2.1% after RIC HCT with sirolimus containing GVHD prophylaxis, compared to 0.8% for RIC without sirolimus (p=0.06). Significant risk factors identified in multivariable analysis for the development of VOD/SOS were sirolimus use (hazard ratio (HR) 5.1, 95% CI 1.8-14.2, p=0.002) and RIC regimen with Flu/Bu2+/-ATG (HR 34, 95% CI 4.5 - 252, p<0.001) or other (HR 32, 95% CI 3.9 - 257, p=0.001) compared to Flu/Bu1+/-ATG. Rising serum tacrolimus or sirolimus levels, new acute kidney injury, and increasing platelet transfusion requirements were significant early predictors of onset in the week preceding prior VOD/SOS diagnosis. When compared to a previously published cohort of 76 VOD/SOS pts who developed VOD/SOS after myeloablative HCT in the same time period, VOD/SOS after RIC occurred later and was associated with a lower peak bilirubin level and better overall survival. The variability in presenting features for RIC VOD/SOS highlights the importance of maintaining a high index of suspicion for this entity in RIC HCT.
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Severe Cytokine-Release Syndrome after T Cell-Replete Peripheral Blood Haploidentical Donor Transplantation Is Associated with Poor Survival and Anti-IL-6 Therapy Is Safe and Well Tolerated
Abboud, R., Keller, J., Slade, M., DiPersio, J. F., Westervelt, P., Rettig, M. P., Meier, S., Fehniger, T. A., Abboud, C. N., Uy, G. L., et al
Biology of Blood & Marrow Transplantation. 2016;22(10):1851-60
Abstract
Use of high-dose post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis has expanded the use of unmanipulated haploidentical hematopoietic cell transplantation. The immediate post-transplantation course in T cell-replete peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT) is often complicated by symptoms resembling cytokine-release syndrome (CRS), previously described in recipients of targeted cellular therapeutics. However, we know little about the incidence and impact of CRS on outcomes in these patients. To understand this syndrome in haplo-HCT patients, we reviewed data from 75 consecutive patients who received granulocyte colony-stimulating factor-mobilized T cell-replete peripheral blood haplo-HCT at a single center. Using CRS criteria described in recipients of chimeric antigen receptor T cell therapies, we found 65 of 75 (87%) met criteria for CRS, although most cases were only mild (grades 1 or 2). However, 9 patients (12%) experienced severe (grades 3 or 4) CRS. Median survival was 2.6 months (95% confidence interval [CI], .43 to 5.8) in patients with severe CRS, compared with 13.1 months (95% CI, 8.1 to not reached) in patients with mild CRS. Transplantation-related mortality was worse in the severe CRS cohort with a hazard ratio of 4.59 (95% CI, 1.43 to 14.67) compared with that in the mild CRS cohort. Severe CRS patients had a significant delay in median time for neutrophil engraftment. Serum IL-6 levels were measured in 10 haplo-HCT patients and were elevated in the early post-transplantation setting. Seven patients with CRS were treated with tocilizumab, resulting in a complete resolution of their CRS symptoms. Severe CRS represents a potential complication of peripheral blood haplo-HCT and is associated with worse outcomes. Anti-IL-6 receptor therapy is associated with rapid resolution of the CRS symptoms. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.