Chimeric Antigen Receptor T-cell Immunotherapy and Need for Prophylaxis for Invasive Mold Infections

To the Editor—We read with interest the report by Haidar et al regarding invasive mold disease (IMD) in patients receiving chimeric antigen receptor modified T-cell therapy (CARTT) [1]. Because this revolutionary treatment is frequently associated with cytokine release syndrome (that requires intense glucocorticoid-based immunosuppression) and prolonged cytopenias, the concerns of excess risk for IMD are logical. However, the independent contribution of CARTT to IMD risk remains to be seen as refractory underlying lymphoid malignancy, currently the most common indication for CARTT, remains a major confounder in risk assessment. In particular, experience preceding CARTT shows that a comparably low subset of heavily pretreated adult and pediatric patients with refractory ALL, with associated cytopenias and cumulative corticosteroid use (both known IMD risk factors), developed IMD [2]. In addition, the increasing use of more intensive induction/consolidation chemotherapies for ALL make these patients acute myeloid leukemia–like in terms of IMD risk [3], even without CARTT, rekindling the discussion regarding the need for antifungal prophylaxis in these patients [4]. As CARTT is being introduced earlier in the course of these malignancies, carefully conducted case-control prospective studies/registries, paired with immunogenetic profiling [5], could give more precision of the CARTT-associated IMD risk. For now, we would recommend more caution as we do not have prediction rules to decide who would be the patients to benefit from preemptive screening vs mold-active prophylaxis following CARTT for refractory lymphoid malignancies. The authors assert that “preemptive screening,” with all the limitations listed in their discussion, is an option in institutions with < 6 % IMD rate and in patients not expected to have > 3 weeks of neutropenia (pre- or post-CARTT) or > 0.1 mg/kg/day of dexamethasone for > 7 days. The problem with those criteria is that modern hospitals have very low autopsy rates [6] and a significant proportion of IMD cases is still missed premortem [7, 8], even in the era of more sensitive fungal biomarkers. In addition, it would be hard to predict a priori who will develop prolonged cytopenia or requirement of significant corticosteroid use. Furthermore, important elements of immune responses against fungi (eg, monocytopenia, lymphopenia, even hypogammaglobinemia, a common condition post-CARTT) [9]—the type, dose, and frequency of CARTT—are not accounted for in the proposed algorithm. Until there is more experience about IMD risk, perhaps it would be prudent to start all patients with refractory lymphoid malignancy who are to receive CARTT on mold-active prophylaxis and to do a comprehensive baseline workup for occult IMD before starting on CARTT. The excess cost and risk associated with posaconazole prophylaxis are miniscule in relation to the costs of CARTT [10]. The decision of whether to use a broad-spectrum triazole or an echinocandin as prophylaxis in these patients should be influenced by the prevalence of Aspergillus and non-Aspergillus molds (eg, Mucorales) in each institution and patient-level characteristics such as comorbidities and receipt of leukemia drugs that affect QTc interval. Finally, efforts to increase autopsy rates in patients who die following CARTT would shed light on the IMD risk.

Notes

Financial support. D. P. K. acknowledges the Texas 4000 Distinguished Professorship for Cancer Research and the National Cancer Institute/National Institutes of Health Cancer Center CORE support grant (number 16672).

Potential conflicts of interest. D. P. K. has received research support from Astellas Pharma and honoraria for lectures from Merck & Co, Gilead, and United Medical; has served as a consultant for Astellas Pharma, Cidara, Amplyx, Astellas, Pulmocide, and Mayne; and is a member of the data review committee of Cidara. R. E. L. has received research funding from Merck and has served on advisory boards for Gilead, F2G, and Cidara. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.