Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
Menin inhibitor (investigational)
Ziftomenib
Komzifti · ZIFT
A menin inhibitor for NPM1-mutated AML whose chief renal hazard is differentiation syndrome and tumor lysis.
ModerateMenin inhibitor · approved 2025
Relapsed/refractory NPM1-mutated acute myeloid leukemiaKMT2A-rearranged acute leukemia (investigational)
Signature kidney injury
Prerenal / Hemodynamic AKI
Renal-specific data are not established. The class-defining serious toxicity is differentiation syndrome — reported in 12/83 (15%) of patients in the KOMET-001 phase 1 trial (with higher severity in KMT2A-rearranged patients, halting that cohort's enrolment) — which can cause capillary leak, fluid overload and AKI. Tumor-lysis risk accompanies rapid blast clearance. No drug-specific renal incidence is published.
Source: Wang et al., Lancet Oncol 2024 (KOMET-001)
Mechanism of kidney injury
Indirect: differentiation syndrome (analogous to that seen with IDH inhibitors and ATRA) produces a systemic inflammatory/cytokine state with capillary leak, fluid retention, weight gain, hypotension and prerenal/ischemic AKI; concurrent tumor lysis adds urate/phosphate intratubular injury. A direct tubular/glomerular lesion has not been described.
Clinical presentation
Dyspnea, pulmonary infiltrates, edema, weight gain, hypotension and rising creatinine during differentiation syndrome; metabolic derangements of tumor lysis (hyperuricemia, hyperphosphatemia, hyperkalemia) if present. Fever and leukocytosis often accompany differentiation syndrome.
Onset
Differentiation syndrome typically within the first weeks of therapy as blasts differentiate; QTc prolongation is also seen.
Reversibility
Reversible
Anticancer mechanism
Oral, selective inhibitor of the menin-KMT2A (MLL) protein-protein interaction. Disrupting the menin-MLL complex displaces it from target gene promoters (HOXA9/MEIS1), driving terminal differentiation of leukemic blasts. Approved (2025) as monotherapy for relapsed/refractory NPM1-mutated AML; under active development in combination and in KMT2A-rearranged leukemia.
Management
Treat differentiation syndrome promptly (corticosteroids, supportive care, consider drug interruption for severe cases); standard tumor-lysis management; supportive care for prerenal/ischemic AKI. Correct electrolytes (also for QT safety). No drug-specific renal antidote is defined.
Risk factors
- High leukemic burden / rapid response (differentiation syndrome and TLS)
- KMT2A-rearranged disease (higher differentiation-syndrome severity)
- Baseline CKD
- Concurrent nephrotoxins in the AML setting
Prevention
- Vigilance for and prompt corticosteroid (dexamethasone) treatment of differentiation syndrome; consider hydroxyurea for leukocytosis
- Tumor-lysis prophylaxis (hydration, allopurinol/rasburicase)
- Close monitoring of creatinine, electrolytes, weight and oxygenation early in therapy
Note · FDA-approved in 2025 for relapsed/refractory NPM1-mutated AML (first menin inhibitor). Renal-specific literature remains essentially absent; the differentiation-syndrome/TLS framing is class-based, drawn from KOMET-001 and analogy to IDH-inhibitor differentiation syndrome. Treat renal claims as low-certainty.
Clinical depth
Renal dose adjustment
No dedicated renal dose adjustment is established; ziftomenib is hepatically metabolized. Dose interruption is driven by differentiation syndrome, QTc and cytopenias rather than CrCl. Data in significant renal impairment/dialysis are absent.
Dialyzability & ESKD dosing
Not characterized; a protein-bound, hepatically cleared small molecule unlikely to be appreciably dialyzed. No ESKD dosing guidance.
Differential diagnosis
Distinguish differentiation-syndrome AKI (capillary leak, pulmonary infiltrates, edema, fever) from tumor-lysis AKI (urate/phosphate, early) and neutropenic-sepsis ATN; these often co-occur and the management overlaps (steroids for DS, TLS measures, supportive care).
Monitoring
- Daily symptom/weight/oxygenation review early on for differentiation syndrome
- Creatinine, electrolytes, uric acid, phosphate (TLS screen) at initiation and through response
- ECG/QTc and CBC
Key trials & series
- KOMET-001 (Wang, Lancet Oncol 2024) — phase 1/2 carrying the differentiation-syndrome safety signal
- KOMET-007 (Wang, Blood 2026) — combination with venetoclax/azacitidine
Clinical pearls
- Differentiation syndrome is the signature serious toxicity — fluid overload, hypoxia and AKI; treat early with dexamethasone, do not just blame volume.
- Like IDH inhibitors, the menin class differentiates blasts — expect both differentiation syndrome AND tumor lysis in the first weeks.
- Renal data are thin even post-approval; reason from the differentiation-syndrome/TLS analogy.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Prerenal / Hemodynamic AKIElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of menin inhibitor (investigational)s.
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Differentiation syndrome
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- QT prolongation
Evidence
5 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkZiftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial.Wang ES et al. · Lancet Oncol 2024 · PMID 39362248Pivotal phase 1 trial; differentiation syndrome in 15% (and more severe in KMT2A-rearranged patients) — the basis for the predicted capillary-leak/AKI renal risk.PMIDZiftomenib with venetoclax and azacitidine in relapsed/refractory NPM1-mutated acute myeloid leukemia.Wang ES et al. · Blood 2026 · PMID 42227701Combination trial confirming differentiation-syndrome and QTc as the key managed toxicities; documents the approved monotherapy context.PMIDMenin inhibitors in KMT2A-rearranged and NPM1-mutated acute leukemia: A scoping review of safety and efficacy.Dali SA et al. · Crit Rev Oncol Hematol 2025 · PMID 40441466Class scoping review summarizing differentiation-syndrome rates and efficacy across menin inhibitors including ziftomenib.PMIDOnconephrology.Kala J et al. · Crit Care Clin 2021 · PMID 33752861Onconephrology review covering treatment-related and tumor-lysis AKI mechanisms relevant to differentiating-agent therapy.PMIDTumour lysis syndrome.Howard SC et al. · Nat Rev Dis Primers 2024 · PMID 39174582Authoritative TLS primer supporting the tumor-lysis component of menin-inhibitor renal risk at blast clearance.
Related agents
Other agents sharing the same signature kidney injury.