Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
FLT3 / multikinase inhibitor
Midostaurin
Rydapt · MID
First-generation FLT3/multikinase inhibitor added to induction in AML — its renal-relevant risks are treatment-related tumor lysis, edema and QT, not a direct nephrotoxicity.
MildTargeted FLT3-inhibitor era · approved 2017
Newly diagnosed FLT3-mutated acute myeloid leukemia (with standard induction/consolidation chemotherapy)Advanced systemic mastocytosis, systemic mastocytosis with associated hematologic neoplasm, and mast cell leukemia
Signature kidney injury
Prerenal / Hemodynamic AKI
Given with intensive chemotherapy, the dominant toxicities are cytopenias, nausea/vomiting, mucositis, edema and QT changes; tumor lysis is a treatment-related (largely chemotherapy-driven) hazard. A midostaurin-specific direct nephrotoxicity is not described, and AKI is multifactorial (volume loss, sepsis, TLS).
Source: Stone et al., N Engl J Med 2017 (RATIFY); Stone et al., Blood Adv 2018
Mechanism of kidney injury
Midostaurin has no characteristic direct renal lesion. Its renal relevance in AML is indirect: (1) nausea/vomiting/mucositis and febrile neutropenia reduce intake and cause volume depletion and prerenal azotemia; (2) cytoreduction during induction produces tumor lysis with uric-acid and calcium-phosphate crystal nephropathy and ATN; (3) edema/fluid shifts and QT prolongation (worsened by electrolyte loss) add hemodynamic and metabolic stress. In mastocytosis, mediator-release events can cause hypotension and prerenal injury.
Clinical presentation
Nausea/vomiting, mucositis, edema and cytopenias during induction; a prerenal creatinine rise with poor intake or sepsis, and TLS labs (hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia) early in treatment. QT prolongation on ECG with electrolyte depletion.
Onset
Tumor lysis early in induction; prerenal/electrolyte issues track intercurrent illness; edema across treatment.
Reversibility
Reversible
Anticancer mechanism
Oral multitargeted kinase inhibitor (a staurosporine derivative) that inhibits FLT3 (ITD and TKD), KIT, PDGFR, VEGFR2 and PKC. Added to 7+3 induction/consolidation it improves survival in newly diagnosed FLT3-mutated AML and is active in KIT-driven advanced systemic mastocytosis.
Management
Treat tumor lysis with hydration, rasburicase/allopurinol and electrolyte correction (dialysis if refractory). Restore volume for prerenal AKI and treat the precipitating sepsis/GI losses. Keep electrolytes replete and monitor QTc; hold/adjust for significant prolongation. The injury is generally reversible once the precipitant is controlled.
Risk factors
- High blast burden at induction (tumor-lysis risk)
- Volume depletion from vomiting/mucositis/sepsis
- Pre-existing CKD and concurrent nephrotoxins/QT-prolonging drugs
- Mast-cell mediator-release events in mastocytosis
Prevention
- TLS prophylaxis at induction: hydration plus allopurinol or rasburicase by risk
- Antiemetics and aggressive supportive hydration; manage mucositis
- Correct potassium/magnesium and monitor QTc
- Avoid additive nephrotoxins; manage mast-cell mediator release in mastocytosis
Note · The renal link is indirect — treatment-related tumor lysis, dehydration/edema and QT-relevant electrolyte shifts rather than a direct midostaurin nephrotoxicity. AKI in this setting is multifactorial.
Clinical depth
Renal dose adjustment
No specific renal dose adjustment for mild-moderate impairment; severe impairment/ESKD not well characterized (extensive hepatic CYP3A4 metabolism, highly protein-bound). Modifications driven by hematologic/GI toxicity and QT.
Dialyzability & ESKD dosing
Highly protein-bound; not expected to be dialyzable. Dialysis is used for TLS metabolic complications, not drug clearance.
Differential diagnosis
Separate tumor-lysis crystalline nephropathy (early, hyperuricemia/hyperphosphatemia) from prerenal azotemia (volume-responsive), sepsis-associated ATN and chemotherapy co-toxicity. In mastocytosis, consider mediator-release hypotension.
Monitoring
- TLS labs (uric acid, phosphate, potassium, calcium, creatinine) at induction
- Potassium and magnesium with ECG/QTc monitoring
- Volume status, weight and signs of edema
- CBC and renal function each cycle
Key trials & series
- RATIFY/CALGB 10603 (Stone, NEJM 2017) — registrational trial adding midostaurin to induction
- Stone et al. (Blood Adv 2018) — discovery-to-approval review including AML and mastocytosis safety
Clinical pearls
- Midostaurin's renal risk is essentially the AML-induction context — tumor lysis and dehydration, not a drug-specific nephropathy.
- It is given with cytotoxic chemotherapy, so attribute AKI multifactorially.
- Keep magnesium and potassium replete to protect both the kidneys' milieu and the QT interval.
- In mastocytosis, mediator-release events can produce transient hypotensive prerenal injury.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Tubular Lumen
The urine flow path
Injury signatures
Prerenal / Hemodynamic AKIElectrolyte Wasting
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkMidostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.Stone RM et al. · N Engl J Med 2017 · PMID 28644114RATIFY registrational trial defining efficacy and the supportive-care/toxicity context for renal risk.PMIDMidostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis.Stone RM et al. · Blood Adv 2018 · PMID 29487059Mechanism and approval narrative spanning AML and mastocytosis safety.PMIDMidostaurin plus daunorubicin or idarubicin for young and older adults with FLT3-mutated AML: a phase 3b trial.Sierra J et al. · Blood Adv 2023 · PMID 37581981Large phase 3b safety dataset across age groups confirming the supportive-care toxicity profile.PMIDOnconephrology: The Intersections Between the Kidney and Cancer.Rosner MH et al. · CA Cancer J Clin 2021 · PMID 32998135Onconephrology framework for tumor-lysis and hemodynamic AKI in AML induction.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 FLT3-AML induction.PMIDOnco-nephrology: Core Curriculum 2020.Rosner MH et al. · Am J Kidney Dis 2020 · PMID 33276867Core reference for crystalline/hemodynamic AKI mechanisms relevant to this setting.
Related agents
Other agents sharing the same signature kidney injury.