Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
Type II RAF inhibitor
Tovorafenib
Ojemda · TOVO
A pediatric type II RAF inhibitor for BRAF-altered glioma — kidney signal limited to modest creatinine shifts.
MildType II RAF inhibitor · approved 2024
Pediatric relapsed/refractory low-grade glioma with BRAF alterations
Signature kidney injury
Prerenal / Hemodynamic AKI
No established intrinsic nephrotoxicity. In FIREFLY-1 the prominent toxicities were hair-color change, rash, anemia and fatigue; renal events were not a defining signal, and any creatinine elevation is described qualitatively rather than as a quantified AKI rate.
Source: Kilburn et al., Nat Med 2023
Mechanism of kidney injury
No characterized direct tubular or glomerular injury. A mild creatinine rise, if seen, is most consistent with hemodynamic/prerenal effects, MAPK-pathway-associated fluid shifts/edema, or non-renal creatinine fluctuation (muscle mass, growth) rather than structural nephron damage. In children, intercurrent vomiting/poor intake commonly drives transient prerenal azotemia.
Clinical presentation
When present, a small reversible creatinine increase without active urinary sediment; possible peripheral/periorbital edema; electrolytes generally stable. Pediatric creatinine must be interpreted against age- and size-adjusted norms.
Onset
Not well defined; any change emerges during ongoing therapy rather than at a fixed onset.
Reversibility
Reversible
Anticancer mechanism
Oral type II pan-RAF inhibitor that blocks both monomeric and dimeric RAF signaling in the MAPK/ERK pathway, overcoming paradoxical activation seen with type I RAF inhibitors. Approved for relapsed/refractory pediatric low-grade glioma harboring BRAF fusions/rearrangements or BRAF V600 mutation.
Management
Supportive; ensure euvolemia and review concomitant nephrotoxins before attributing AKI to the drug. Dose interruption/reduction per protocol for significant toxicity. Intrinsic renal injury has not been characterized.
Risk factors
- Intercurrent volume depletion (vomiting, poor intake) in children
- Concurrent nephrotoxins
- Pre-existing renal impairment
Prevention
- Routine creatinine and electrolyte monitoring on therapy
- Maintain hydration during intercurrent illness
- Interpret pediatric creatinine against growth-adjusted norms (consider cystatin C / eGFR equations)
Note · 2024 pediatric approval with minimal renal data. The prerenal/vascular framing is conservative and class/hemodynamic-based; no quantified renal incidence exists. Flag as low-certainty.
Clinical depth
Renal dose adjustment
No established renal dose adjustment; tovorafenib is hepatically metabolized with low renal elimination, so meaningful exposure change with reduced GFR is not expected. Pediatric dosing is body-surface-area based and unchanged for renal function in label-described populations.
Dialyzability & ESKD dosing
Not characterized; as a highly protein-bound small molecule with non-renal clearance it is unlikely to be appreciably dialyzed. No dialysis dosing data in this pediatric population.
Differential diagnosis
In a child on therapy, distinguish benign creatinine fluctuation / prerenal azotemia (intercurrent illness, dehydration) from true AKI using urinalysis, volume assessment and trend — structural drug nephrotoxicity has not been described.
Monitoring
- Serum creatinine and electrolytes periodically on therapy
- Hemoglobin (anemia is a common class effect)
- Weight/edema and growth parameters
- Hepatic function and CK per label
Key trials & series
- FIREFLY-1 (Kilburn, Nat Med 2023) — pivotal phase 2
- LOGGIC/FIREFLY-2 (van Tilburg, BMC Cancer 2024) — confirmatory phase 3
Clinical pearls
- Interpret pediatric creatinine carefully — muscle mass and growth move the number independent of true GFR.
- Hydrate through intercurrent vomiting/diarrhea; that, not the drug, is the usual cause of a creatinine bump.
- Renal claims for this 2024 pediatric agent are low-certainty and class/hemodynamic-based.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Prerenal / Hemodynamic AKIElectrolyte Wasting
Evidence
4 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkThe type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial.Kilburn LB et al. · Nat Med 2023 · PMID 37978284Pivotal efficacy/safety trial; toxicity profile is non-renal-dominant, supporting the low/qualitative renal assessment.PMIDLOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration.van Tilburg CM et al. · BMC Cancer 2024 · PMID 38291372Confirmatory phase 3 design/rationale documenting the safety-monitoring framework for the agent.PMIDAcute and chronic kidney injury during therapy for pediatric acute leukemia: A report from the Leukemia Electronic Abstraction of Records Network (LEARN).Hsiao W et al. · Pediatr Blood Cancer 2023 · PMID 37776085Pediatric oncology AKI cohort illustrating how definition (CTCAE vs KDIGO) and growth-related creatinine variability shape apparent renal-injury rates in children.PMIDOnconephrology: mitigation of renal injury in chemotherapy administration.Selamet U et al. · Curr Opin Nephrol Hypertens 2023 · PMID 38095483Onconephrology review of kinase-inhibitor renal effects framing low direct-tubular risk for MAPK-pathway agents.
Related agents
Other agents sharing the same signature kidney injury.