Treatment with Foscarnet after Allogeneic Hematopoietic Cell Transplant (Allo-HCT) Is Associated with Long-Term Loss of Renal Function

Foster, Gena G.; Grant, Michael J.; Thomas, Samantha; Cameron, Blake; Raiff, Doug; Corbet, Kelly; Loitsch, Gavin; Ferreri, Christopher; Horwitz, Mitchell E.

doi:10.1016/j.bbmt.2020.05.007

Cited by 7 publications

(3 citation statements)

References 29 publications

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“…Antimicrobials were an important risk for post-transplant AKI. Foscarnet has been associated with both AKI and eGFR decline at 6 and 12 months (42). Vancomycin, postulated to cause oxidative stress and kidney tubular injury (43), also carried higher risk of AKI and, hence, should be used with caution.…”

Section: Discussionmentioning

confidence: 99%

Acute Kidney Injury in the Modern Era of Allogeneic Hematopoietic Stem Cell Transplantation

Abramson

Gutgarts

Zheng

et al. 2021

CJASN

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Background and objectives Acute kidney injury (AKI) is a major complication of allogeneic hematopoietic stem cell transplantation, increasing risk of non-relapse mortality. AKI etiology is often ambiguous due to heterogeneity of conditioning/graft-versus-host disease (GVHD) regimens. To date, GVHD and calcineurin inhibitor effects on AKI are not well defined. We aimed to describe AKI and assess pre/post-hematopoietic transplant risk factors in a large recent cohort. Design, setting, participants, and measurements We performed a single-center retrospective study of 616 allogeneic hematopoietic cell transplant recipients from 2014-2017. We defined AKI and CKD based on KDIGO criteria and estimated GFR using CKD-EPI equation. We assessed AKI pre/post-hematopoietic transplant risk factors using cause-specific Cox regression and association of AKI with CKD outcomes using Chi-squared test. AKI was treated as a time-dependent variable in relation to non-relapse mortality. Results Incidence of AKI by day-100 was 64%. Exposure to tacrolimus and other nephrotoxins conferred a higher risk of AKI, but tacrolimus levels were not associated with severity. Reduced intensity conditioning carried higher AKI risk compared to myeloablative conditioning. Most stage 3 AKIs were due to ischemic acute tubular necrosis and CNI nephrotoxicity. Kidney replacement therapy was initiated in 21/616 (3%) of whom 9/21 (43%) recovered and 5/21 (24%) survived to hospital discharge. T-cell depleted transplants, higher baseline albumin, and non-Hispanic ethnicity were associated with lower risk of AKI. CKD developed in 21% (73/345) of patients after 12 months. Non-relapse mortality was higher in those with AKI (HR 2.77, 95% CI: 1.8-4.27). Conclusions AKI post-hematopoietic cell transplant remains a major concern. Risk of AKI was higher with exposure to CNIs. T cell depleted hematopoietic cell transplants and higher albumin had lower risk of AKI. Forty-three percent of patients requiring KRT recovered kidney function. Prospective studies are needed to further assess modification of these risk factors.

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Section: Discussionmentioning

confidence: 99%

Acute Kidney Injury in the Modern Era of Allogeneic Hematopoietic Stem Cell Transplantation

Abramson

Gutgarts

Zheng

et al. 2021

CJASN

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“… 34 This specificity is probably one of the main reasons for its successful use in allo-HCT, in which the side effects often restrict the use of antivirals. 35 , 36 But letermovir, as a P-glycoprotein and an organic anion transporting polypeptide 1B1/3 transporter substrate, a moderate inhibitor of CYP3A, and an inducer of CYP2C9/19, has multiple drug interactions, which might prove a significant point in patients who are polymedicated. The most relevant interactions in the allo-HCT setting are the immunosuppressive drugs (cyclosporine, tacrolimus, and sirolimus) and voriconazole.…”

Section: Discussionmentioning

confidence: 99%

The promising efficacy of a risk-based letermovir use strategy in CMV-positive allogeneic hematopoietic cell recipients

et al. 2023

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Letermovir is the first approved drug for cytomegalovirus (CMV) infection prophylaxis in adult CMV-positive patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Since CMV infection risk varies from patient to patient, we evaluated whether a risk-based strategy could be effective. All consecutive CMV-positive adult patients (median age: 56.0 years, IQR: 43.5-64.0) who underwent allo-HCT between 2015 and 2021 (n=316) were included. Letermovir was not used in Period 1 (2015-2017, n=186), whereas during Period 2 (2018-2021, n=130), letermovir was used in high-risk patients but not in low-risk patients, except in those receiving corticosteroids. In high-risk patients, the incidence of clinically significant CMV infection (csCMVi) in Period 2 was lower as compared to Period 1 (p<0.001) by week 14: 10.5% (95% CI 4.6-19.2) vs 51.6% (41.0-61.3) and week 24: 16.9% (8.9-27.0) vs 52.7% (42.0-62.3), respectively. In low-risk patients, although only 28.6% of patients received letermovir in Period 2, csCMVi incidence was also significantly lower (p=0.003) by week 14: 7.9% (2.9-16.3) vs 29.0% (20.2-38.5) and week 24: 11.2% (4.9-20.5) vs 33.3% (23.9-43.0). Among low-risk patients who did not receive letermovir (n=45), 23 (51.1%) patients experienced transient positive CMV DNA without csCMVi by week 14, while it remained negative in 17 (37.8%) patients. In both risk groups, the two periods were comparable for CMV disease, overall survival, progression-free survival, relapse, and non-relapse mortality. We concluded that a risk-based strategy for letermovir use is an effective strategy which maintains the high efficacy of letermovir in high-risk patients but allows some low-risk patients not to use letermovir.

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“…Finally, there were more renal AEs and larger increases in serum BUN and creatinine over time associated with foscarnet exposure, confirming the substantial nephrotoxicity of foscarnet in children. Importantly, there is recent evidence to suggest that there is a non-dose-dependent association between foscarnet exposure and glomerular filtration rates at 6 and 12 months after HSCT [ 34 ]. This potential long-term effect of foscarnet is particularly concerning for children, as renal function progressively declines with age, and an accelerated decline in glomerular filtration rate could lead to early progression to end-stage renal disease [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Risk Factors for CMV Viremia and Treatment-Associated Adverse Events Among Pediatric Hematopoietic Stem Cell Transplant Recipients

Heston

Young

Tanaka

et al. 2021

Open Forum Infectious Diseases

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Background Cytomegalovirus (CMV) causes substantial morbidity and mortality after hematopoietic stem cell transplantation (HSCT). There are limited data on risk factors for CMV viremia and the safety of antiviral medications used to treat CMV in children. Methods We conducted a single-center retrospective study of children who underwent HSCT between 2000 and 2016. We used log-logistic regression to evaluate associations between clinical characteristics and CMV-free survival at 100 days after HSCT. We compared the incidences of laboratory-defined adverse events (AEs) during treatment with ganciclovir and foscarnet. Results Among 969 children, median (interquartile range) age was 6.5 (3.1, 11.5) years, and 80% underwent allogeneic HSCT. Two hundred forty-four (25%) children developed CMV viremia. Older age (OR=0.95; 95% CI: 0.92, 0.98), male sex (OR=0.71, 95% CI: 0.51, 0.99), non-Black non-white race (OR=0.56; 95% CI: 0.36, 0.87), umbilical cord blood donor source (OR=0.28; 95% CI: 0.08, 0.97), and CMV-seropositivity (R-/D+, OR=0.17, 95% CI: 0.07, 0.41; R+/D-, OR=0.14, 95% CI: 0.09, 0.21; R+/D+, OR=0.08, 95% CI: 0.04, 0.15) were associated with lower odds of 100-day CMV-free survival. Compared to foscarnet, ganciclovir was associated with lower incidences of thrombocytopenia (IRR: 0.38; 95% CI: 0.15, 0.97), electrolyte AEs (IRR: 0.42; 95% CI: 0.24, 0.75), endocrine AEs (IRR: 0.52; 95% CI: 0.34, 0.79), and renal AEs (IRR: 0.36; 95% CI: 0.19, 0.65). Conclusions CMV viremia occurred commonly among children after HSCT, and ganciclovir and foscarnet were associated with distinct toxicity profiles among children with CMV infection. These findings should be considered when developing CMV prevention and treatment strategies for children after HSCT.

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Treatment with Foscarnet after Allogeneic Hematopoietic Cell Transplant (Allo-HCT) Is Associated with Long-Term Loss of Renal Function

Cited by 7 publications

References 29 publications

Acute Kidney Injury in the Modern Era of Allogeneic Hematopoietic Stem Cell Transplantation

Acute Kidney Injury in the Modern Era of Allogeneic Hematopoietic Stem Cell Transplantation

The promising efficacy of a risk-based letermovir use strategy in CMV-positive allogeneic hematopoietic cell recipients

Risk Factors for CMV Viremia and Treatment-Associated Adverse Events Among Pediatric Hematopoietic Stem Cell Transplant Recipients

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