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IDH1 inhibitor

Olutasidenib

Rezlidhi · OLU

IDH1 inhibitor · approved 2022 · 6 references

Mutant-IDH1 inhibitor for AML whose differentiation syndrome and tumor lysis are the renal threats — a maturation-driven, not tubular, kidney risk.

Signature injury
Prerenal / Hemodynamic AKI
Severity
Moderate
Reversibility
Reversible
Onset
Differentiation syndrome within days to a few months (often early); tumor lysis early in treatment.

Signature kidney injury & incidence

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)

Reported injury signatures: Prerenal / Hemodynamic AKI, Electrolyte Disturbance.

Renal toxicity profile

  1. Prerenal / Hemodynamic AKIPrimary
  2. Electrolyte DisturbanceSecondary

Onset timing & rechallenge

Acute (~1–7 days) — Tumor lysis early in treatment.

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.

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
  • Treat fluid overload with diuretics

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.

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.

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.

Guidelines & consensus

Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.

  • ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.Nat Rev Nephrol · PMID 41361704
  • SIRM (2022) — SIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.Radiol Med · PMID 35303246
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.Kidney Int · PMID 33126977
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.Kidney Int · PMID 33276867
  • ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.EClinicalMedicine · PMID 40290844
  • ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.EClinicalMedicine · PMID 40290845
  • ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.EClinicalMedicine · PMID 40290846
  • KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.Crit Care · PMID 23394211
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsEvaluate and risk-stratify CKD, manage to delay progression and its complications, and practise explicit medication management and drug stewardship — the framework the atlas's G1–G5 eGFR banding and every renal dose-adjustment recommendation sit inside. Because the guideline excludes dialysis and transplant recipients by its own statement of scope, its recommendations do not carry to those settings, where this atlas's dialyzability and post-transplant guidance rests on other sources.Kidney Int · PMID 38519239
  • KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.Kidney Int · PMID 34556300
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.Kidney Int · PMID 38388147
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.Kidney Int · PMID 38182299
  • KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.Kidney Int · PMID 40975525

References

6 peer-reviewed references. Citation metadata via PubMed / NLM.

  1. 1.Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML.de Botton S et al. · Blood Adv · 2023 · PMID 36724515
  2. 2.Olutasidenib: a novel mutant IDH1 inhibitor for the treatment of relapsed or refractory acute myeloid leukemia.Cortes JE et al. · Expert Rev Hematol · 2024 · PMID 38747392
  3. 3.Olutasidenib alone or combined with azacitidine in patients with mutant IDH1 myelodysplastic syndrome.Cortes JE et al. · Blood Adv · 2025 · PMID 40668616
  4. 4.Prevention and Treatment of Tumor Lysis Syndrome in the Era of Onco-Nephrology Progress.Matuszkiewicz-Rowinska J et al. · Kidney Blood Press Res · 2020 · PMID 32998135
  5. 5.Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus.Cairo MS et al. · Br J Haematol · 2010 · PMID 20331465
  6. 6.KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantation.Malyszko J et al. · Kidney Int · 2020 · PMID 33276867
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.