Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
IDH1 inhibitor
Olutasidenib
Rezlidhi · OLU
Mutant-IDH1 inhibitor for AML whose differentiation syndrome and tumor lysis are the renal threats — a maturation-driven, not tubular, kidney risk.
ModerateMutant-IDH-inhibitor era · approved 2022
Relapsed or refractory acute myeloid leukemia with a susceptible IDH1 (R132) mutation
Signature kidney injury
Prerenal / Hemodynamic AKI
Differentiation syndrome (boxed warning) occurred in ~14% of patients (grade >=3 ~9%, with rare fatality) in the pivotal cohort; tumor lysis is a labeled risk. Discrete AKI incidence is not separately quantified and is largely consequent on these syndromes.
Source: de Botton et al., Blood Adv 2023 (pivotal R/R AML cohort; ~14% differentiation syndrome — the AKI is a downstream complication, not a primary rate)
Mechanism of kidney injury
Olutasidenib's renal threats are differentiation-driven, analogous to other IDH/FLT3 inhibitors. (1) Differentiation syndrome: rapid blast maturation releases inflammatory cytokines causing fever, capillary-leak edema, effusions, hypotension and acute kidney injury (mixed prerenal hypoperfusion and intrarenal inflammatory injury). (2) Tumor lysis syndrome: cytoreduction releases uric acid, phosphate and potassium, producing urate and calcium-phosphate intratubular crystal nephropathy and ATN. There is no characteristic direct tubular drug toxicity.
Clinical presentation
Differentiation syndrome: dyspnea, fever, weight gain/edema, pleural/pericardial effusions, hypotension and rising creatinine, typically within the first weeks-to-months. TLS: hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and AKI early in treatment.
Onset
Differentiation syndrome within days to a few months (often early); tumor lysis early in treatment.
Reversibility
Reversible
Anticancer mechanism
Oral selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1, R132). It blocks the neomorphic production of the oncometabolite 2-hydroxyglutarate, relieving the differentiation block so leukemic blasts mature, inducing remission in mIDH1 AML.
Management
For differentiation syndrome: start corticosteroids (dexamethasone) promptly, use diuretics for fluid overload, hold olutasidenib if severe, and support kidney function. For TLS: aggressive IV hydration, rasburicase for hyperuricemia, electrolyte correction and dialysis for refractory derangement. Renal injury generally reverses with timely treatment of the underlying syndrome.
Risk factors
- High leukemic burden/blast count (differentiation syndrome and TLS)
- Pre-existing CKD and concurrent nephrotoxins
- Rapid responders early in therapy
- Concurrent QT-prolonging drugs and electrolyte depletion
Prevention
- Vigilance for differentiation-syndrome symptoms; early corticosteroids and, if needed, drug interruption
- TLS prophylaxis: hydration plus allopurinol or rasburicase by risk
- Frequent blood-chemistry monitoring; correct potassium/magnesium
- Monitor for fluid overload and treat with diuretics
Note · The renal link is indirect but clinically important — AKI arises from differentiation syndrome and tumor lysis rather than a primary tubular drug toxicity. The differentiation-syndrome rate (~14%) is real and quantified from the pivotal cohort.
Clinical depth
Renal dose adjustment
No dose adjustment for mild-moderate renal impairment; severe impairment/ESKD not well characterized (hepatic metabolism). Interruptions are driven by differentiation syndrome/TLS rather than GFR.
Dialyzability & ESKD dosing
Highly protein-bound; not appreciably dialyzable. Dialysis is used for TLS metabolic complications, not drug removal.
Differential diagnosis
Distinguish differentiation-syndrome AKI (capillary leak, effusions, steroid-responsive) from sepsis/ATN, TLS crystalline nephropathy (early hyperuricemia/hyperphosphatemia), and prerenal azotemia. The maturation-driven systemic syndrome is the clue.
Monitoring
- Blood chemistries (potassium, phosphate, uric acid, creatinine) frequently, especially early
- Daily weight and assessment for edema/effusions (differentiation syndrome)
- Liver tests and ECG/QTc periodically
- Volume status and blood pressure
Key trials & series
- Pivotal phase 2 R/R AML cohort (de Botton, Blood Adv 2023) — registrational dataset with the differentiation-syndrome (~14%) signal
Clinical pearls
- Differentiation syndrome is the boxed warning — recognize early (dyspnea, edema, fever) and treat with dexamethasone before organ failure.
- Like other IDH/FLT3 inhibitors, the renal hazard is differentiation-driven, not a direct tubular toxicity.
- Tumor lysis is an early renal hazard in responders — risk-stratify and pre-treat.
- Frequent electrolyte monitoring guards both the kidney and the QT interval.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Tubular Lumen
The urine flow path
Injury signatures
Prerenal / Hemodynamic AKIElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of idh1 inhibitors.
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Differentiation syndrome
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- QT prolongation
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkOlutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML.de Botton S et al. · Blood Adv 2023 · PMID 36724515Pivotal registrational cohort quantifying differentiation syndrome (~14%) and the efficacy that drives tumor-lysis risk.PMIDOlutasidenib: a novel mutant IDH1 inhibitor for the treatment of relapsed or refractory acute myeloid leukemia.Cortes JE et al. · Expert Rev Hematol 2024 · PMID 38747392Drug review emphasizing differentiation syndrome and safety management.PMIDOlutasidenib alone or combined with azacitidine in patients with mutant IDH1 myelodysplastic syndrome.Cortes JE et al. · Blood Adv 2025 · PMID 40668616Extended dataset confirming differentiation syndrome and QT signals across mIDH1 disease.PMIDOnconephrology: The Intersections Between the Kidney and Cancer.Rosner MH et al. · CA Cancer J Clin 2021 · PMID 32998135Framework for differentiation-syndrome and tumor-lysis AKI in 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 prophylaxis/management applicable to IDH1-inhibitor-induced cytoreduction.PMIDOnco-nephrology: Core Curriculum 2020.Rosner MH et al. · Am J Kidney Dis 2020 · PMID 33276867Core onconephrology reference for crystalline and hemodynamic AKI mechanisms.
Related agents
Other agents sharing the same signature kidney injury.