Indication for a Pneumocystis Prophylaxis Therapy in Patients with Vascular Anomalies Treated with PIK3/AKT/mTOR Pathway Inhibitors: Experts' Opinion and Systematic Review from the Literature

by Selleckchem | Nov 27 2023

Background: Vascular anomalies (VAs) are increasingly being treated with PI3K/AKT/mTOR pathway inhibitors. These drugs have immunosuppressive properties and thus theoretically overexpose patients to opportunistic infections, especially Pneumocystis jirovecii pneumonia (PJP). PJP prophylaxis use lacks consensus. We aimed to investigate the prevalence of PJP in patients receiving mTOR/PI3K/AKT inhibitors for VAs and determine any indication for pneumocystis prophylaxis in this population.

Methods: The study was conducted in 2 parts: (1) we sent a survey to a panel of international experts of VAs asking about their use of pneumocystis prophylaxis drugs and (2) we performed a systematic review of the literature of all published cases of patients receiving these drugs for VA to estimate the prevalence of PJP in this population.

Results: Answers from 68 experts were analyzed: 21 (30.9%) answered they always add PJP prophylaxis when prescribing mTOR inhibitors, 20 (29.4%) case-by-case, and 27 (39.7%) never. For the systematic review, among 3,053 reports screened, 217 were included involving 1,189 patients (1,143 received sirolimus, 38 everolimus, 4 alpelisib, 4 miransertib). Among the 1,189 cases, 2 (0.2%) PJP were reported: one under sirolimus and one under everolimus. Thus, the prevalence of PJP was estimated at 0.88 cases/1,000 patients under sirolimus (95% CI: -0.84 to 2.59) and 26.31 cases/1,000 under everolimus (95% CI: -24.58 to 77.18). Patients with PJP never received prophylaxis drugs. We found no PJP cases under alpelisib and miransertib. PJP prophylaxis was given in 218 (18.3%) cases, more frequently for children (91.3 vs. 77.2% in the non-prophylaxis group, p = 0.012), mostly trimethoprim-sulfamethoxazole (186 patients, 85.3%).

Conclusion: Our study shows that even if PJP is a rare event, it may occur in patients with VAs treated with an mTOR inhibitor. Although our results cannot allow for revising guidelines, prophylaxis with TMP-SMX might be appropriate for a subgroup of patients with risk factors for PJP.

Comments:

The study you described provides valuable insights into the prevalence of Pneumocystis jirovecii pneumonia (PJP) in patients receiving mTOR/PI3K/AKT inhibitors for vascular anomalies (VAs). Based on the survey of international experts and the systematic review of published cases, the key findings can be summarized as follows:

1. **Prevalence of PJP**: The study found that PJP is a rare event in patients with VAs treated with mTOR inhibitors. Among 1,189 cases, only 2 (0.2%) PJP cases were reported, one under sirolimus and one under everolimus. This indicates that while the risk is low, it's not non-existent.

2. **Prophylaxis Practices**: The survey revealed that there is no consensus among experts regarding PJP prophylaxis in patients receiving these inhibitors. About 30.9% of experts always add PJP prophylaxis, 29.4% do it on a case-by-case basis, and 39.7% never add prophylaxis. This lack of consensus reflects the uncertainty in the medical community about the need for prophylaxis.

3. **Prophylaxis Effectiveness**: Interestingly, patients who developed PJP had not received prophylaxis drugs. This suggests that prophylaxis might be effective in preventing PJP in this population.

4. **Prophylaxis Administration**: In cases where prophylaxis was given, trimethoprim-sulfamethoxazole (TMP-SMX) was the most commonly administered drug. It was provided more frequently to children, possibly due to their higher vulnerability.

5. **Implications for Practice**: While the overall prevalence of PJP is low, the study suggests that prophylaxis with TMP-SMX might be appropriate for a subgroup of patients with specific risk factors for PJP, especially in children. The decision to administer prophylaxis should likely be made on a case-by-case basis, considering individual patient factors and risk profiles.

6. **Limitations**: It's important to note that the study has limitations, and the results may not be applicable to all patients. Additionally, the lack of consensus among experts indicates the need for further research and guidelines in this area.

In conclusion, the study highlights the need for careful consideration of PJP prophylaxis in patients receiving mTOR/PI3K/AKT inhibitors for VAs. While rare, the potential for PJP occurrence suggests that prophylaxis, particularly with TMP-SMX, might be beneficial for certain high-risk patient groups. Clinical decisions should be based on a thorough evaluation of individual patient factors and a balanced assessment of potential benefits and risks associated with prophylactic treatment.