Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
Immunotoxin (IL-2–diphtheria)
Denileukin diftitox
Lymphir · DENI
An IL-2/diphtheria-toxin fusion whose capillary-leak syndrome drives prerenal AKI — check albumin before every cycle.
ModerateIL-2-diphtheria-toxin immunotoxin · approved 2024
Relapsed or refractory stage I-III cutaneous T-cell lymphoma after at least one prior systemic therapy (improved-purity formulation, denileukin diftitox-cxdl)
Signature kidney injury
Prerenal / Hemodynamic AKI
Capillary-leak syndrome (CLS) occurred in ~20.3% (grade >=3 ~5.8%) in the 2024 denileukin diftitox-cxdl trial. With the original formulation hypoalbuminemia was very common (~79%, ~15% grade 3/4) and a vascular-leak syndrome occurred in roughly a quarter of patients. AKI here is prerenal/hemodynamic rather than a quantified direct renal injury rate.
Source: Foss et al., J Clin Oncol 2024 (20.3% capillary-leak syndrome; attributable AKI rate not separately quantified)
Mechanism of kidney injury
Capillary/vascular-leak syndrome: IL-2- and toxin-mediated endothelial injury increases vascular permeability, causing fluid and protein extravasation, hypoalbuminemia and intravascular volume depletion, which produces prerenal (hemodynamic) AKI. It is not a direct tubular nephrotoxin.
Clinical presentation
Hypotension, edema, weight gain, hypoalbuminemia and a rising creatinine, often with infusion reactions and transaminase elevation. Onset is within days of infusion, mainly in the first 1-2 cycles.
Onset
Acute, peri-infusion (first 1-2 cycles); generally not cumulative.
Reversibility
Reversible
Anticancer mechanism
Engineered fusion protein joining interleukin-2 to the catalytic and translocation fragments of diphtheria toxin (DAB389IL-2). IL-2 binds the high-affinity IL-2 receptor (CD25/IL-2R-alpha) on malignant T cells; after internalization the diphtheria-toxin fragment ADP-ribosylates elongation factor 2, halting protein synthesis and causing apoptosis.
Management
For CLS: give IV fluids and albumin repletion, hold or discontinue for grade >=3, and provide supportive care for edema. For prerenal AKI: restore volume and perfusion. Most events reverse hemodynamically and are not cumulative.
Risk factors
- Low baseline serum albumin (key CLS risk — do not initiate if albumin below ~3.0 g/dL)
- Pre-existing edema or volume overload
- Cardiovascular compromise and baseline hypotension
Prevention
- Check and optimize serum albumin before each cycle; do not initiate if albumin <3.0 g/dL
- Premedicate (corticosteroids, antihistamines, antipyretics)
- Ensure euvolemia/hydration and monitor weight and blood pressure
Note · Frontier-era 2024 reapproval (improved-purity formulation); the original Ontak was approved in 1999 and withdrawn ~2014 for manufacturing/purity reasons. Renal mechanism is capillary leak / prerenal AKI, well described across formulations.
Clinical depth
Renal dose adjustment
Weight-based dosing (9 micrograms/kg/day for 5 days every 21 days); modification is driven by toxicity (albumin, organ function), not by CrCl. No CrCl-based dose thresholds are defined.
Dialyzability & ESKD dosing
Not established — a large fusion protein; AKI here is managed hemodynamically rather than by dialytic drug removal.
Differential diagnosis
Distinguish CLS-driven prerenal AKI from sepsis or GI-loss prerenal states, cardiorenal/volume overload, hepatorenal physiology, tumor nephropathy, and infusion-reaction hypotension — versus intrinsic ATN.
Monitoring
- Serum albumin before each cycle (gating parameter)
- Daily weight and blood pressure during cycles
- Creatinine and LFTs each cycle
- Edema and infusion-reaction assessment
Key trials & series
- Pivotal phase 3 of denileukin diftitox-cxdl (Foss, J Clin Oncol 2024) — CLS ~20.3% (grade >=3 ~5.8%)
- Original Ontak pivotal phase 3 (Olsen, J Clin Oncol 2001) — vascular-leak/hypoalbuminemia profile
Clinical pearls
- Check albumin before every cycle and do not start if it is below ~3.0 g/dL — the AKI is prerenal, not tubular.
- CLS clusters in the first cycles within days of infusion — front-load monitoring.
- The improved-purity cxdl (Lymphir) formulation has CLS ~20% (grade >=3 ~6%).
- Treat hemodynamically — volume plus albumin reverse most prerenal AKI; injury is generally reversible and non-cumulative.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Prerenal / Hemodynamic AKI
Evidence
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkEfficacy and Safety of Denileukin Diftitox-Cxdl, an Improved Purity Formulation of Denileukin Diftitox, in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma.Foss FM et al. · J Clin Oncol 2024 · PMID 39700456Registrational phase 3 trial for the 2024 reapproval; CLS ~20.3% (grade >=3 ~5.8%).PMIDPivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma.Olsen E et al. · J Clin Oncol 2001 · PMID 11208829Original pivotal trial documenting vascular-leak syndrome and hypoalbuminemia (~79%).PMIDE7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma: A phase I study.Ohmachi K et al. · Cancer Sci 2018 · PMID 29363235First study of the reformulated product; hypoalbuminemia/hyponatremia among dose-limiting toxicities.PMIDDenileukin diftitox for the treatment of steroid-resistant acute graft-versus-host disease.Shaughnessy PJ et al. · Biol Blood Marrow Transplant 2005 · PMID 15744237Dose-dependent grade 3/4 renal/hepatic toxicity and vascular-leak syndrome at 9 micrograms/kg.PMIDClinically approved immunotoxins targeting hematological cancers: "the best of both worlds".Rashad Y et al. · Front Pharmacol 2025 · PMID 41181593Review of FDA-approved immunotoxins including denileukin diftitox safety and risk management.PMIDOnconephrology: Core Curriculum 2023.Yarandi N et al. · Am J Kidney Dis 2023 · PMID 37855786Onconephrology review providing context for capillary-leak/prerenal AKI.PMIDA phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma.Foss F et al. · Blood 2005 · PMID 15811959Shows bexarotene upregulates CD25/IL-2R, enhancing cytotoxicity — illustrates the receptor target.
Related agents
Other agents sharing the same signature kidney injury.