The role of pentamidine for pneumocystis jirovecii prophylaxis in allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis

Abstract Background: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening opportunistic infection in allogeneic hematopoietic cell transplantation (allo-HCT) recipients, with significant comorbidity. While trimethoprim-sulfamethoxazole (TMP-SMX) remains the gold standard, its use is often limited by adverse effects such as cytopenias, nephrotoxicity, and severe hypersensitivity reactions, leading to higher discontinuation rate. In this systematic review and meta-analysis, we aimed to evaluate the efficacy and safety of pentamidine as an alternative PJP prophylactic agent in allo-HCT recipients. Methods: Following PRISMA guidelines, a systematic search of six databases (PubMed, EMBASE, Scopus, Cochrane, ClinicalTrials.gov, Google Scholar) was conducted through May 2025 using keywords and MeSH terms related to ‘pentamidine’ and ‘allo-HCT’. Out of 487 reports, we identified six eligible studies comparing pentamidine (IV or aerosolized) with TMP-SMX. Data were independently extracted for baseline characteristics, and outcomes. Efficacy outcomes included the incidence of PJP, PJP-related mortality, and overall survival, while safety outcomes encompassed adverse events (AEs), treatment discontinuation, and specific drug-related toxicities. Analysis was done using Review Manager (v5.4) and R (v4.5.1) with a random-effects model. Statistical heterogeneity was assessed via I² and τ²; sensitivity and influence analyses were conducted to explore the robustness of the findings. Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). Results: Six observational cohort studies involving 1,256 patients were included, 42.7% of them were female. The median age was 42 years (IQR 30–50) in adults and 5.6 years (IQR 1.8–11.7) in pediatric patients. PCP prophylaxis was administered with pentamidine (300 mg IV or nebulized every 2–4 weeks) or TMP/SMX (160/800 mg twice daily on nonconsecutive days), with pediatric doses adjusted for age and weight. Prophylaxis was continued for 6–12 months post-transplant or until immune reconstitution was achieved. Indications for allo-HCT included hematologic malignancies, solid tumors, sarcomas, and primary immunodeficiencies. Conditioning regimens included myeloablative (72%) and reduced intensity/non-myeloablative (28%) protocols. Donor types included 28.8% matched related, 21.4% matched unrelated, 2.8% haploidentical, 19.0% autologous, and 0.7% syngeneic transplants. Among allogeneic recipients, 13.9% received T cell-depleted and 36.3% received non-T-cell depleted grafts. In pooled analysis, pentamidine showed a non-significant trend toward higher PJP incidence (OR = 2.60; 95% CI, 0.17–39.43; I² = 69.4%) and significantly higher PJP-related mortality (OR = 14.88; 95% CI, 1.86–119.01; I² = 0%). TMP-SMX showed a non-significant advantage in overall survival (OR = 0.29; 95% CI, 0.07–1.30; I² = 86.8%). Pentamidine was associated with significantly fewer treatment-related adverse events (OR = 0.02; 95% CI, 0.00–0.33; I² = 96%) and fewer discontinuations due to toxicity (OR = 0.03; 95% CI, 0.01–0.11; I² = 0%). No significant differences were seen in nausea/vomiting (OR = 1.89; 95% CI, 0.34–10.53; I² = 61.3%) or rash (OR = 1.02; 95% CI, 0.01–145.60; I² = 92.9%). Conclusion: Pentamidine demonstrates comparable overall survival at 6-12 months post-transplant and offers While TMP-SMX may be more effective in preventing PJP-related mortality, pentamidine shows comparable short-term survival and significantly better tolerability. Its favorable safety profile supports its use as an alternative in patients who cannot tolerate TMP-SMX, pending confirmation from prospective comparative studies.