Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
Hedgehog (SMO) inhibitor
Glasdegib
Daurismo · GLA
Hedgehog/SMO inhibitor for AML whose QT prolongation and muscle spasms are the safety signals; renal risk is indirect via dehydration and leukemia-related tumor lysis.
MildHedgehog pathway inhibitor era (AML) · approved 2018
Newly diagnosed acute myeloid leukemia in adults >=75 years or with comorbidities precluding intensive induction (with low-dose cytarabine)
Signature kidney injury
Prerenal / Hemodynamic AKI
Muscle spasms, QT prolongation, cytopenias, edema, nausea and mucositis are the labeled toxicities; the FDA notes a use limitation in severe renal impairment (a renal-impairment trial was a post-marketing requirement). Direct nephrotoxicity is not a defined signal, and AKI is largely secondary (dehydration, sepsis, tumor lysis).
Source: Norsworthy et al., Clin Cancer Res 2019 (FDA approval summary, BRIGHT AML 1003)
Mechanism of kidney injury
Glasdegib itself has no characteristic direct renal lesion. Its renal relevance is twofold and indirect: (1) gastrointestinal toxicity (nausea, mucositis) and the underlying AML reduce intake and cause volume depletion and prerenal azotemia; (2) QT prolongation is exacerbated by electrolyte derangements (hypokalemia, hypomagnesemia) that demand renal-relevant correction. In the leukemic context, treatment-related tumor lysis can cause uric-acid/phosphate crystal nephropathy and ATN, though glasdegib's cytoreduction is modest. There is a labeling caution in severe renal impairment pending dedicated data.
Clinical presentation
Muscle cramps, fatigue, edema, nausea/mucositis and cytopenias; ECG QTc prolongation. Renally, a prerenal creatinine rise during poor intake/dehydration, and electrolyte disturbances (hypokalemia, hypomagnesemia) that aggravate QT. Tumor-lysis labs (hyperuricemia, hyperphosphatemia, hyperkalemia) if cytoreduction is brisk.
Onset
Muscle spasms and QT changes within early cycles; prerenal/electrolyte issues track intercurrent illness and intake.
Reversibility
Reversible
Anticancer mechanism
Oral Smoothened (SMO) inhibitor that blocks Hedgehog signaling implicated in leukemic stem-cell maintenance. Combined with low-dose cytarabine (LDAC) it improves survival in newly diagnosed AML patients unfit for intensive chemotherapy.
Management
Keep potassium and magnesium replete and monitor QTc; hold/adjust for significant QT prolongation. Treat prerenal AKI with volume repletion and source control of nausea/sepsis. Manage tumor lysis with hydration, urate-lowering therapy and electrolyte correction, escalating to renal replacement if needed. Use caution and monitor closely in severe renal impairment given limited data.
Risk factors
- Older, comorbid AML population with baseline CKD
- Concurrent QT-prolonging drugs and electrolyte depletion
- Dehydration from nausea/mucositis or sepsis
- High tumor burden at initiation (tumor-lysis risk)
Prevention
- Correct potassium and magnesium and obtain baseline/serial ECGs
- Maintain hydration; manage nausea/mucositis proactively
- TLS prophylaxis (hydration +/- allopurinol/rasburicase) when tumor burden warrants
- Avoid additive QT-prolonging and nephrotoxic agents; caution in severe renal impairment
Note · The renal link is indirect — QT-relevant electrolyte derangements, dehydration, and leukemia/treatment-related tumor lysis rather than a direct renal lesion. The FDA labeled a limitation of use in severe renal impairment pending further study.
Clinical depth
Renal dose adjustment
No dose adjustment recommended for mild-moderate renal impairment; safety/PK in severe renal impairment were not established at approval (labeled limitation; post-marketing study required). Hepatic CYP3A4 metabolism predominates.
Dialyzability & ESKD dosing
Highly protein-bound small molecule; not expected to be appreciably dialyzable, and ESKD dosing is not established.
Differential diagnosis
Distinguish prerenal AKI (volume-responsive) from tumor-lysis crystalline nephropathy (hyperuricemia/hyperphosphatemia, often early), sepsis-associated ATN, and electrolyte-driven QT effects. The leukemic context makes multifactorial AKI the rule.
Monitoring
- ECG/QTc at baseline, ~1 week, then periodically
- Serum potassium and magnesium frequently (correct before/during therapy)
- Serum creatinine and TLS labs (uric acid, phosphate, potassium) early in treatment
- CBC each cycle; volume status
Key trials & series
- BRIGHT AML 1003 (Cortes, J Hematol Oncol 2020; Norsworthy FDA summary, Clin Cancer Res 2019) — registrational glasdegib + LDAC dataset
Clinical pearls
- Glasdegib's renal story is indirect — QT/electrolytes and dehydration in a frail AML population, not a primary nephropathy.
- Magnesium and potassium repletion does double duty: it protects the kidney's milieu and the QT interval.
- Heed the labeled caution in severe renal impairment — dedicated data were lacking at approval.
- Assess tumor-lysis risk at initiation even though glasdegib's cytoreduction is modest.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Injury signatures
Prerenal / Hemodynamic AKIElectrolyte Wasting
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkFDA Approval Summary: Glasdegib for Newly Diagnosed Acute Myeloid Leukemia.Norsworthy KJ et al. · Clin Cancer Res 2019 · PMID 31064779Approval summary detailing QT warning, musculoskeletal toxicity and the severe-renal-impairment use limitation.PMIDSurvival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy.Cortes JE et al. · J Hematol Oncol 2020 · PMID 32664995BRIGHT AML 1003 outcomes/safety in the frail AML population at renal risk.PMIDGlasdegib in the treatment of acute myeloid leukemia.Wolska-Washer A et al. · Future Oncol 2019 · PMID 31432695Review of efficacy, pharmacokinetics and the safety profile to monitor.PMIDEfficacy and Safety of Sonic Hedgehog Inhibitors in Basal Cell Carcinomas: An Updated Systematic Review and Meta-analysis (2009-2022).Nguyen A et al. · Am J Clin Dermatol 2023 · PMID 36795228Class context for Hedgehog-inhibitor muscle-spasm and metabolic toxicities.PMIDOnconephrology: The Intersections Between the Kidney and Cancer.Rosner MH et al. · CA Cancer J Clin 2021 · PMID 32998135Framework for tumor-lysis and hemodynamic AKI relevant to glasdegib-treated AML.PMIDGuidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review.Cairo MS et al. · J Clin Oncol 2010 · PMID 20331465Consensus TLS prevention/management applicable to AML induction.
Related agents
Other agents sharing the same signature kidney injury.