The trade-offs between efficacy and toxicity: Real-world outcomes of dapsone vs atovaquone for pneumocystis prophylaxis in hematologic malignancies.

e18549 Background: Patients with Hematologic malignancies and multiple myeloma are at increased risk for Pneumocystis jirovecii pneumonia (PJP), necessitating prophylaxis. Dapsone and atovaquone are commonly used alternatives when trimethoprim-sulfamethoxazole is contraindicated; however, comparative real-world data on efficacy and safety remain limited. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network, including adults with hematologic malignancies or multiple myeloma who received either dapsone or atovaquone for PJP prophylaxis. Patients with HIV were excluded. Propensity score matching (1:1) was performed to balance demographics, comorbidities among others, yielding 6,187 patients in each cohort. Outcomes assessed over a 180-day follow-up included mortality, PJP, intubation, elevated LDH (≥450 U/L), and treatment-related adverse events including hemolytic anemia, GI upset, rash, transaminitis, and hyperbilirubinemia. Results: After propensity score matching, patients receiving dapsone experienced a significantly lower incidence of PJP compared with those receiving atovaquone. Kaplan–Meier analysis demonstrated a significantly lower hazard of PJP in the dapsone cohort over the 180-day follow-up period (hazard ratio [HR] 0.67, 95% CI 0.52–0.86, log-rank p=0.002). All-cause mortality was significantly lower in the dapsone cohort (HR 0.80, 95% CI 0.74–0.88, log-rank p<0.001). No statistically significant differences were observed between cohorts in the risk of intubation (HR 0.84, 95% CI 0.68–1.03, log-rank p=0.089) or elevated lactate dehydrogenase levels (LDH ≥450 U/L) (HR 0.90, 95% CI 0.78–1.03, log-rank p=0.119).Despite improved efficacy outcomes, our analyses demonstrated higher hazards of several treatment-related adverse events in the dapsone cohort, including gastrointestinal upset (HR 1.32, 95% CI 1.17–1.49; log-rank p<0.001), drug-related rash (HR 1.13, 95% CI 0.99–1.30; log-rank p=0.065), hemolytic anemia (HR 1.30, 95% CI 0.99–1.70; log-rank p=0.055), and hyperbilirubinemia (HR 1.18, 95% CI 1.05–1.33; log-rank p=0.005). In contrast, atovaquone was associated with a significantly higher hazard of transaminitis compared with dapsone (HR 0.54, 95% CI 0.42–0.69; log-rank p<0.001). Conclusions: In this study of patients with hematologic malignancies, dapsone was associated with a significantly lower risk of Pneumocystis jirovecii pneumonia and reduced all-cause mortality compared with atovaquone. However, these benefits were accompanied by higher rates of hematologic, gastrointestinal, and hepatic adverse events. These findings highlight a clinically meaningful trade-off between prophylactic efficacy and tolerability and support individualized selection of PJP prophylaxis.