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PI3Kδ/γ inhibitor

Duvelisib

Copiktra · DUV

PI3Kδ/γ inhibitor · approved 2018 · 6 references

Dual PI3K-delta/gamma inhibitor with the same immune-colitis Achilles heel — diarrhea and volume loss are the path to prerenal AKI.

Signature injury
Prerenal / Hemodynamic AKI
Severity
Mild
Reversibility
Reversible
Onset
Diarrhea/colitis often after several months; rash and transaminitis can appear earlier.

Signature kidney injury & incidence

Prerenal / Hemodynamic AKI.

Diarrhea/colitis is common (any-grade ~50%, grade 3+ roughly 15-20% in DUO); the resulting volume-depletion prerenal AKI is not separately tabulated. Direct nephrotoxicity is uncommon.

Source: Flinn et al., Blood 2018 (DUO); Flinn et al., J Clin Oncol 2019 (DYNAMO)

Reported injury signatures: Prerenal / Hemodynamic AKI, Acute Interstitial Nephritis.

Renal toxicity profile

  1. Prerenal / Hemodynamic AKIPrimary
  2. Acute Interstitial NephritisSecondary

Onset timing & rechallenge

Delayed (>6 weeks / cumulative) — Diarrhea/colitis often appears after several months, whereas rash and transaminitis can appear earlier.

Mechanism of kidney injury

As with idelalisib, PI3K-delta/gamma inhibition impairs regulatory T-cell tolerance and produces immune-mediated colitis, hepatitis and pneumonitis. The PI3K-gamma component adds effects on myeloid/innate immunity. Renal injury is secondary — secretory diarrhea and reduced intake cause volume contraction and prerenal azotemia, with ischemic ATN possible if hypoperfusion is severe and prolonged; immune-mediated interstitial nephritis is plausible but not a defining feature.

Clinical presentation

Profuse, sometimes late-onset diarrhea or frank colitis, dehydration and orthostasis; creatinine rises with a prerenal urine profile (low FeNa, high urine osmolality). Transaminitis, rash and pneumonitis may coexist as part of the immune toxicity.

Management

Interrupt duvelisib for severe diarrhea/colitis, exclude infectious causes, rehydrate, and treat immune colitis with corticosteroids (budesonide or systemic steroids). Restore euvolemia to reverse prerenal AKI; consider AIN with steroid trial if creatinine fails to recover despite volume repletion. Permanently discontinue for life-threatening events.

Risk factors

  • Pre-existing CKD, diuretic therapy or baseline volume depletion
  • Concurrent nephrotoxins
  • Older age and frailty
  • Delayed recognition of severe diarrhea

Prevention

  • Early reporting and prompt management of diarrhea; exclude infection (including CMV)
  • Vigorous rehydration during diarrheal episodes
  • Infection prophylaxis (PJP) per label
  • Interrupt for grade 3+ diarrhea/colitis

Renal dose adjustment

No renal dose adjustment specified (hepatic CYP3A4 metabolism); use caution in CKD. Dose modifications are driven by colitis, hepatotoxicity, infection and cytopenias.

Dialyzability & ESKD dosing

Highly protein-bound; not expected to be dialyzable. No ESKD dosing established.

Differential diagnosis

Separate prerenal AKI (volume-responsive, low FeNa) from infectious colitis (C. difficile, CMV) driving the losses and from immune AIN; concurrent hepatotoxicity can confound with hepatorenal physiology.

Monitoring

  • Stool frequency and volume status; weight at each visit
  • LFTs every 2 weeks initially, then periodically
  • Serum creatinine/electrolytes during diarrheal episodes
  • CMV viral load and clinical infection surveillance

Key trials & series

  • DUO (Flinn, Blood 2018) — registrational RCT vs ofatumumab defining the colitis/diarrhea signal
  • DYNAMO (Flinn, J Clin Oncol 2019) — indolent NHL safety dataset

Clinical pearls

  • Mechanistically and clinically a sibling of idelalisib — anticipate immune colitis and dehydration.
  • Late-onset severe diarrhea is the classic and most dangerous toxicity; rehydrate early.
  • Exclude CMV before attributing colitis to the drug and starting steroids.
  • PJP prophylaxis and CMV vigilance are part of standard care.

Anticancer mechanism

Oral dual inhibitor of the delta and gamma isoforms of PI3K. PI3K-delta drives malignant B-cell proliferation while PI3K-gamma modulates the supportive tumor microenvironment; combined inhibition is active in CLL/SLL and follicular lymphoma.

Note

Renal involvement is indirect, mediated by immune colitis/diarrhea and volume depletion. Quantified AKI rates are lacking; the signal is inferred from the dominant GI toxicity.

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.The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL.Flinn IW et al. · Blood · 2018 · PMID 30287523
  2. 2.DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma.Flinn IW et al. · J Clin Oncol · 2019 · PMID 30742566
  3. 3.Managing toxicities of phosphatidylinositol-3-kinase (PI3K) inhibitors.Hanlon A et al. · Hematology Am Soc Hematol Educ Program · 2020 · PMID 33275709
  4. 4.Duvelisib: a new phosphoinositide-3-kinase inhibitor in chronic lymphocytic leukemia.Frustaci AM et al. · Future Oncol · 2019 · PMID 31137964
  5. 5.Current status of phosphoinotiside-3 kinase inhibitors in blood cancers.Shouse G et al. · Curr Opin Oncol · 2022 · PMID 35855508
  6. 6.The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib shows preclinical synergy with multiple targeted therapies in hematologic malignancies.Faia K et al. · PLoS One · 2018 · PMID 30067771

Case reports & series (1)

The weakest rung of clinical evidence — single-patient and small-series reports, strongest first. Each carries a heuristic strength grade (A Strong / B Moderate / C Limited) inferred from its abstract and journal, not a formal appraisal. Weigh well below the primary references above.

  1. C1.[B · Moderate]Cutaneous and Systemic Complications in Primary CD8+ Aggressive Epidermotropic Cytotoxic T-cell Lymphoma.Nikakis J et al. · Cureus · 2025 · PMID 41607964
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.