Date of Award

January 2025

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Rory M. Shallis

Abstract

Acute myeloid leukemia (AML) care underwent a paradigm shift in 2017 with the development of a number of targeted therapies and less-intensive treatments. This changed expectations for survival and treatment course, particularly for those who are inappropriate candidates for intensive therapy due to frailty, comorbidities or disease-specific features. This period has also seen an evolution of healthcare system models that ultimately deliver sub-specialty care for patients with AML, including the rise of the academic center-affiliated community practices that may care for patients with this uncommon and high-stakes disease. These novel therapies and healthcare models also beget a lack of standardization amongst practices surrounding the delivery of integral supportive care. We explored changes made by our center to help supportive care accommodate the kinetics of AML care. Specifically, we aimed to determine the efficacy and safety of an early discharge program (EDP) used at our center to permit patients who undergo frontline intensive induction chemotherapy meeting specific criteria to be discharged before they reach count recovery, the threshold beyond which prevailing wisdom has dictated an acceptable mitigation of infection and bleeding risk has been reached. We also explored the use of isavuconazole as antifungal prophylaxis (AFP) for patients with AML as an alternative to voriconazole, which has long been used but has a number of intolerable side-effects preventing many patients from remaining on themedication. Thus, patients with AML undergoing frontline intensive induction chemotherapy at Yale Cancer Center (YCC) between December 2016 and January 2024 were evaluated for complications, survival, and predictors of outcomes based on whether they were discharged traditionally or through the EDP. Patients with AML started on voriconazole or isavuconazole AFP were also evaluated for complications while on AFP and for invasive fungal infection (IFI) incidence and survival. Amongst 185 patients receiving intensive induction, 99 (53.5%) were discharged with absolute neutrophil count (ANC) of ≤0.5 x10^3/μL via the EDP. An ANC of ≤0.1 x10^3/μL at discharge (n=54) was then used to identify EDP patients furthest from hematologic recovery for comparative analyses. EDP patients had fewer inpatient days even accounting for EDP patient re-admissions (23%) before count recovery (23.5 vs 28.0 days, p=0.0003), with no differences in 90-day mortality or median OS. Among 278 patients starting on voriconazole (n=215) or isavuconazole (n=63) AFP, patients on voriconazole experienced significantly more complications (55% vs 32%, p=0.002) requiring AFP withdrawal. Specifically, voriconazole withdrawal was more likely for transaminase elevations, hallucinations, and DDIs, while isavuconazole withdrawal was more likely for insurance/cost prohibition. Analyzing 129 patients who remained on just isavuconazole (n=41) or voriconazole (n=88), there were no differences in rates of IFI, early mortality, or median OS. Our study shows that patients with AML meeting certain criteria can be discharged via an EDP to spend up to a week less time in the hospital without impact on outcomes. We also show that isavuconazole is an AFP agent with a far more favorable side-effect profile than voriconazole that maintains efficacy at preventing IFIs and has no impact on early or median survival.

Comments

This is an Open Access Thesis.

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