Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies
Abstract
:Simple Summary
Abstract
1. Introduction
2. Material and Methods
2.1. Literature Review
2.2. Review of the WHO Global Safety Database
2.3. Single-Center Experience
2.4. Review of the French Pharmacovigilance Database
2.5. Ethics Approval
2.6. Statistics
3. Results
3.1. History of Pi3 Kinase Inhibitor Development
3.2. New Pi3K Inhibitors and the Risk of Colitis
3.2.1. Literature Review
3.2.2. Pharmacovigilance Database
3.3. French Experience of Idelalisib-Induced Colitis
3.3.1. Single-Center Experience
3.3.2. Analysis of the French Pharmacovigilance Database
3.3.3. Histological Description
- -
- Increased lamina propria inflammation with lymphocytes, plasma cells, neutrophils and eosinophils;
- -
- Acute or chronic ischemic-like lesions with an atrophic or withered crypt appearance, including hyalinization of the lamina propria;
- -
- Apoptosis at the bases of the crypts with lymphocyte infiltration of the crypt epithelium, similar to what is seen in a graft vs. host disease but surrounded by more inflammatory cells.
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Pi3Kinhibitor | Target | Colitis Cases | Non-Cases | Reporting OR (95% CI) |
---|---|---|---|---|
- | 342 | 10,801 | 9.5 (8.6–10.6) | |
Idelalisib | PI3Kδ | 296 | 6093 | 14.6 (13.0–16.4) |
Alpelisib | PI3Kα | 27 | 4092 | 2.0 (1.4–2.9) |
Duvelisib | PI3Kγ/PI3Kδ | 16 | 365 | 13.2 (8.0–21.7) |
Copanlisib | All PI3K | 3 | 172 | 5.2 (1.7–16.4) |
Umbralisib | PI3Kδ | 1 | 82 | - |
Patient Characteristics | Idelalisib-Induced Colitis Characteristics | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Case | Age (Years) | Sex | Disease | Prior Tts | Concomitant Therapy | Grade | Intensive Care Admission | Delay (Months) | Colonoscopy | Treatment Stopped | Management | Recovery | Rechallenge | Death Occurred |
1 | 76 | M | WM | 6 | ofatumumab | 4 | Yes (hypokalemia) | 3 | Normal colonic mucosa | Yes | Symptomatic treatment | Yes | No | Yes (disease) |
2 | 71 | M | WM | 4 | ⁄ | 3 | No | 3 | Erythema and absence of vascular pattern in the colon | Yes | Prednisone 0.8 mg/kg | Yes | Yes | / |
3 | 76 | M | CLL | 6 | ofatumumab | 4 | Yes (hypovolemic shock) | 4 | Erythema, absence of vascular pattern and superficial ulcerations in the rectum and colon | Yes | Prednisone 1 mg/kg | Yes | No | Yes (disease) |
4 | 66 | M | WM | 1 | ofatumumab | 4 | Yes (hypovolemic shock) | 4 | Erythema and absence of vascular pattern in the rectum and colon | Yes | Prednisone 0.8 mg/kg | Yes | No | Yes (disease) |
5 | 84 | F | WM | 2 | ⁄ | 3 | No | 6 | Erythema and absence of vascular pattern in the colon | Yes | Enteric budesonide | Yes | Yes (fatal colitis) | Yes (colitis) |
6 | 89 | F | CLL | 2 | rituximab | 3 | No | 3 | Absence of vascular pattern in the sigmoid segment | Yes | Symptomatic treatment | Yes | Yes (no colitis occurrence) | / |
Patient Characteristics | n (%) |
---|---|
Age—years mediane (range) | 71 (65–78) |
Sex—male: female | 32:14 |
Type of hemopathy | |
| 26 (56.5%) 20 (43.5%) |
Anticancer drug treatments | |
| 27 (58.7%) 19 (41.3%) |
Time to first digestive symptoms—days | 122 (74–212) |
Time to specific management—days | 20 (6-30) |
Colitis seriousness | |
| 43 (83.5%) 35 (76.1%) 4 (8.7%) |
Colonoscopy findings | |
| 30 9 4 3 3 |
Idelalisib management | |
| 43 2 1 |
Therapeutic management | |
| 23 14 5 3 1 |
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Breal, C.; Beuvon, F.; de Witasse-Thezy, T.; Dermine, S.; Franchi-Rezgui, P.; Deau-Fisher, B.; Willems, L.; Grignano, E.; Contejean, A.; Bouscary, D.; et al. Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies. Cancers 2023, 15, 2279. https://doi.org/10.3390/cancers15082279
Breal C, Beuvon F, de Witasse-Thezy T, Dermine S, Franchi-Rezgui P, Deau-Fisher B, Willems L, Grignano E, Contejean A, Bouscary D, et al. Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies. Cancers. 2023; 15(8):2279. https://doi.org/10.3390/cancers15082279
Chicago/Turabian StyleBreal, Claire, Frederic Beuvon, Thibault de Witasse-Thezy, Solene Dermine, Patricia Franchi-Rezgui, Benedicte Deau-Fisher, Lise Willems, Eric Grignano, Adrien Contejean, Didier Bouscary, and et al. 2023. "Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies" Cancers 15, no. 8: 2279. https://doi.org/10.3390/cancers15082279