The reported incidence of acute kidney injury (AKI) after allogeneic hematopoietic cell transplantation (allo-HCT) varies from 10 to 73%. The association between GVHD, calcineurin inhibitors (CNIs) ...and risk for kidney injury remains controversial. We sought to describe the incidence of AKI and identify modifiable risk factors in large cohort of patients undergoing allo-HCT in our institution.
All consecutive patients undergoing allo-HCT from 2014 to 2017 in our institution were included. Pre-HCT variables including patient and graft characteristics, as well as post-HCT variables, including nephrotoxic medication exposure, ICU admission, and CNI levels were analyzed in association with AKI. AKI was defined using KDIGO criteria, grades 1, 2 and 3, through post-transplant day 100. Severe AKI was defined as grades 2 or 3. Differences across groups were assessed using either Wilcoxon rank-sum tests or Fisher's exact tests. AKI risk factors were estimated using cause-specific Cox proportional hazards regression.
A total of 616 patients underwent allo-HCT during the study period. Median age was 58 (19-79) years, 59% male, 83% Caucasian. Indication for HCT was leukemia in 49%, myelodysplastic syndrome in 16%, and lymphoma in 17%. Median baseline creatinine was 0.8 (0.3-2.7) mg/dL. Median age-adjusted HCT-comorbidity index was 3 (range 0-9). Median baseline albumin was 3.5 (IQR 3.3-3.8) mg/dL and BMI 27.2 (IQR 23.8-30.8). Incidence of acute GVHD was 47%, and 60 patients had severe (grades 3-4) GVHD. Bacteremia occurred in 19% of patients. Amphotericin preceded max-grade AKI in 3.1%, cidofovir in 0.8%, and Foscarnet in 4.4% of patients. Median tacrolimus level preceding AKI was 7.88 (range 4.2-23.2) mg/dL. By day 100 post-HCT, 403 (65.4%) had any AKI, 220 (35.7%) patients had grade 1 AKI, 119 (19.3%) grade 2 AKI, and 64 (10.4%) grade 3 AKI; 19 (3.1%) required hemodialysis. Median time to AKI was 17 (IQR 8-35) days, and median time to max-grade AKI was 31 (IQR 13-53) days. Ex vivo CD34-selected HCT patients had a lower risk for AKI, hazard ratio 0.46 (0.35-0.62), p<0.001 (Table 1).
AKI in patients undergoing allo-HCT remains a major concern, affecting 65.4% of patients, with grade 2 and 3 AKI occurring in 19.3% and 10.4%, respectively. Patients receiving CNIs including tacrolimus have a significantly higher risk for AKI, whereas patients undergoing CD34-selected allo-HCT have a lower risk of AKI. The effect of AKI after HCT on long-term kidney function requires further prospective study.
Chimeric Antigen Receptor T cell (CAR T) therapy has shown significant therapeutic potential but carries risk of treatment related toxicity. There is limited data describing risk of acute kidney ...injury (AKI) related to CAR T therapy.
To identify the incidence of AKI and recovery of renal function in patients undergoing CAR T therapy.
We analyzed adult patients given FDA approved CAR T cell therapy February 2018 to 2019 for Non-Hodgkin Lymphoma (NHL) at our center. Patients received axicabtagene ciloleucel (Yescarta®) (34/46, 74%) or tisagenlecleucel (Kymriah®) (12/46, 26%). All creatinine's prior to and following CAR T infusion until last follow up were collected. Maximum (max) grade AKI grade 1 (creatinine 1.5 - < 2-fold baseline), grade 2 (2 - < 3-fold baseline) or grade 3 (> 3-fold baseline) was calculated based on KDIGO criteria. Renal recovery was assessed using creatinine 30 days post max grade AKI.
Forty six patients, median age 63 years (range 19-85) of whom 33 (72%) were men underwent CAR T therapy for relapsed/ refractory NHL. Patients had a median of 4 lines of chemotherapy (range 2-10) prior to CAR T, including autoSCT (n=9, 20%), alloHCT (n=3, 7%), and both auto and alloHCT (n=1). Lymphodepletion regimens were either cyclophosphamide/fludarabine (n=43, 93%) or bendamustine (n=3, 7%). Baseline co-morbidities were hypertension 13/46 (28%) and diabetes mellitus 1/46 (2%). Median baseline creatinine was 0.8 (range 0.5 – 2) mg/dL, and median glomerular filtration rate (GFR) was 88 (range 36-160) mL/min/1.73m2, GFR ≤ 60 in 4 patients. No patient was on dialysis prior to infusion. Five of 14 patients with baseline urinalysis had ≥30 mg/dL protein. Median overall follow up was 8.3 (95%CI: 6.8 - 11.4) months.
Fourteen patients (30%) had any grade AKI during available follow-up. Of these, 10/14 (71%) had grade 1, 2/14 (14%) had grade 2, and 1/14 (7%) had grade 3. Median day onset for max grade AKI was 48 (range 6 to 100) days. Nephrotoxic medication exposures prior to AKI included acyclovir in 10 (71%), vancomycin in 11 (79%) and ibuprofen in 1 (7%). Of the 14 patients who developed AKI, 11 (79%) also had cytokine release syndrome (CRS). For these patients, median peak C reactive protein level was 12 (range 0.4 to 34) mg/L and median interleukin-6 level was 179 (range 14 to 23,752) pg/ml.
After removing competing events (relapse, progression or death), cumulative incidence of grade 1 AKI was 15.2% (95% CI 4.7-25.7) and grade 2 AKI was 2.2% (95% CI 0-6.5) by day +100. Incidence of AKI shown in Figure 1. Creatinine returned to baseline in 11/12 (92%) patients alive at 30 days post AKI.
Our study shows that the incidence of AKI is low in patients receiving CAR T therapy. Majority of AKI was grade 1 and returned to baseline within 30 days. A larger study sample will likely help elucidate risk factors associated with development of AKI in these patients.
Deep and durable hematologic remissions following RA-ASCT are associated with improved organ function and extended overall survival in AL amyloidosis. While depth of hematologic response by standard ...criteria are important, this study assessed additional factors that influence RR and time to RR.
All patients (pts) with AL and renal involvement undergoing RA-ASCT at Memorial Sloan Kettering Cancer Center between January 1, 2007 to December 31, 2016 were included. Pts with follow up <12 months (mos) post RA-ASCT and hemodialysis prior to RA-ASCT were excluded. Melphalan dose was assigned based on age, cardiac involvement and renal compromise. Hematologic and organ response was assessed at 3 (early) and 12 mos post RA-ASCT. Consolidation with bortezomib and dexamethasone was offered to pts with less than complete response (CR) at 3 mos. Logistic regression models were used to assess association with RR (Palladini Blood 2014) by 12 mos. Covariates for adjustment in multivariate models were chosen based on univariate analyses and clinical relevance.
Sixty-four patients with renal AL meeting the inclusion criteria were identified; 3 died within 12 mos post RA-ASCT were excluded. Median age was 61 years (44-73), 51% female and 34% had cardiac involvement. Median 24 hr proteinuria pre ASCT was 5014 mg/day (2632-7514) and eGFR 68 ml/min/1.73 m2 (44-91). Renal amyloid stage I:II:III was 33%:52%:15%. Mayo cardiac stage (2004) I:II:III was 28%:61%:11% and revised Mayo stage (2012) I:II:III:IV was 13%:57%:21%:8%. Median BM plasma cells pre ASCT was 9% (2-14%). 46% received treatment prior to ASCT. Melphalan dose (mg/m2) 200:140:100 was 44%:43%:11% and 46% received consolidation.
Hematologic response early post ASCT was CR 44%, very good partial (VGPR) 29% and partial response (PR) 20%. dFLC <1mg/dL was achieved in 63%. RR by 12 mos was achieved in 32 pts (53%); median time to RR was 5.8 mos (5.1 – 11.3). Amongst renal responders, 50% achieved CR, 53% MRD negative, and 78% dFLC <1mg/dL early post RA-ASCT. In pts with dFLC <1mg/dL early post RA-ASCT, 66% achieved RR.
By univariate analysis, early post ASCT dFLC <1mg/dL (OR 3.00, 95% CI 1.01-8.93, p = 0.048) and VGPR (7.80, 1.69-36.06, p = 0.009), at 12 mos dFLC <1mg/dL (7.20, 2.14-24.21, p = 0.001) and CR (10.27, 1.14-92.26, p = 0.038) were associated with RR. By multivariate analysis, dFLC <1mg/dL early post ASCT (OR 4.52, 95% CI 1.26-16.24, p = 0.021) was associated with RR when adjusted for renal amyloid stage and Mayo cardiac stage (2004).
In this single center study, we found that RA-ASCT results in RR in more than half (53%) of pts at 1 year. Achieving dFLC <1mg/dL early post ASCT is prognostic of RR independent of renal stage. Early MRD-negativity did not predict RR. Our study suggests maximal suppression of the pathologic light chains is important for organ recovery. Larger studies using dFLC <1mg/dL as an end point are warranted.
Allogeneic hematopoietic cell transplantation (allo-HCT) allows for the possibility of cure in patients (pts) with Non-Hodgkin Lymphoma (NHL) as it provides an immunologic graft-versus-lymphoma ...effect. Non-relapse mortality (NRM) was prohibitive in myeloablative regimens, but technical advances with the advent of reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) regimens have decreased these rates. RIC regimens are generally associated with more toxicity and higher NRM than NMA regimens. Though studies showed both approaches are safe and effective, there is lack of direct comparison between these different intensities in NHL.
This retrospective study identified pts aged ≥ 18 years who underwent allo-HCT for relapsed/refractory NHL between 3/2008-6/2017 at our center. Outcomes were compared between pts who received NMA and RIC conditioning, with intensity defined per CIBMTR. Progression-free survival (PFS) was the primary outcome. Secondary outcomes included overall survival (OS) and non-relapse mortality (NRM). Additional outcomes included rates of acute GVHD at Day 100, chronic GVHD, and CMV reactivation at Day 100. Regimen intensity and other variables significant by univariate analysis were included in the multivariate analysis
For the 144 pts identified, median age was 56 years (range, 19-79). More pts received NMA regimens (n=80, 56%) and most did not undergo prior autologous HCT (n=103, 72%). NMA regimens were given more frequently to pts with indolent B-cell lymphoma and were more likely to receive ATG and/or rituximab (p = 0.008, p < 0.001, and p < 0.001, respectively). At a median overall follow-up of 57.8 months (range 49 - 75.1) neither median PFS or OS were reached. In univariate analysis, NMA conditioning was associated with a longer PFS than RIC HR 1.9 (1.11-3.24), p = 0.019). No difference was found in OS HR 1.56 (0.85-2.85), p = 0.15). There was an increase in all grades of aGVHD HR 3.68 (2.16, 6.28), p < 0.001) with RIC regimens, but only 12 events of grade III/IV aGVHD overall. In multivariate analyses (with histology and ATG as covariates) NMA with rituximab had improved PFS compared to RIC without rituximab HR 0.43 (95% CI 0.22, 0.81; p=0.009). However, PFS was similar comparing NMA and RIC groups HR 0.72 (95% CI 0.37, 1.41; p=0.3). Similarly, aGVHD (any grade) risk was lower in NMA pts receiving rituximab compared to RIC pts who did not HR 0.15 (0.07-0.32), p < 0.001). No significant differences were noted in NRM or CMV reactivation between groups.
Our study suggests that there are comparable and favorable outcomes between RIC and NMA regimens in allo-HCT for NHL with careful patient and regimen selection. Further studies are needed to better define criteria in choosing between NMA and RIC allo-HCT regimens for pts with NHL.
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