Failure of Atovaquone Prophylaxis for Prevention of Toxoplasmosis in Hematopoietic Cell Transplant Recipients

Abstract

<h3>Introduction</h3> Toxoplasma gondii DNA can be detected by polymerase chain reaction (PCR) in up to 16% of hematopoietic cell transplant (HCT) patients post-transplant with attributable mortality of 44-66%. The majority (73-87%) of cases result from reactivation in previously exposed (i.e., Toxoplasma seropositive) recipients and most (67-87%) occur in patients not receiving effective prophylaxis. Clinical data on the efficacy of atovaquone for primary prophylaxis of toxoplasmosis following HCT is scarce. Reports of breakthrough toxoplasmosis in patients receiving atovaquone have raised concerns about its efficacy in high-risk patients such as donor positive (D+)/recipient negative (R-) heart transplant and R+ allogeneic HCT recipients. <h3>Objectives</h3> We describe three HCT patients with breakthrough toxoplasmosis while receiving atovaquone prophylaxis. <h3>Methods & Results</h3> We identified 126 (94 allogeneic and 23 autologous) HCT patients (August 2016-June 2019) who received atovaquone for Pneumocystis jirovecii pneumonia (PJP) prophylaxis. Seroprevalence among allogeneic HCT recipients with known Toxoplasmaserostatus (n=84) was 37%. Among 31 Toxoplasma seropositive allogeneic HCT recipients, 14 received atovaquone as initial prophylaxis and 17 received only after developing intolerance to trimethoprim-sulfamethoxazole (TMP-SMX). Three (10%) patients had breakthrough Toxoplasma reactivation, two of them with central nervous system (CNS) disease. Median time to reactivation was 66 (range, 52-67) days post-transplant. In the two cases with positive PCR in blood, Toxoplasma DNA became undetectable at 8 and 20 days of therapy, suggesting that parasitemia can be successfully managed with preemptive treatment. All three patients died. Death of patient #2 was suspected to be due to disseminated toxoplasmosis as PCR blood was positive at time of death. Median time to death from diagnosis of Toxoplasma reactivation was 83 (range, 57-311) days. CMV viremia preceded Toxoplasmareactivation in all cases; CMV may have impacted infection risk . All three patients underwent T cell depletion during conditioning. Absolute and CD4 lymphopenia at the time of diagnosis were a shared feature in these cases (median ALC: 176/mm3). <h3>Conclusion</h3> Breakthrough toxoplasmosis is a potentially fatal complication in HCT patients receiving atovaquone prophylaxis. TMP-SMX should remain the prophylactic agent of choice and PCR-based pre-emptive therapy should be considered in the pre-engraftment period and in patients at risk not receiving TMP-SMX. Such preventive strategies could improve outcomes in vulnerable Toxoplasma seropositive HCT recipients.