The hematopoietic system balances self-renewal and differentiation in response to various environmental cues. The nuclear hormone receptor superfamily consists of ligand-activated transcription factors that allow cells to integrate external stimuli with cellular programs regulating cell lineage, metabolism, proliferation, and survival. We and others have shown that members of this family play central roles in normal, stress and malignant hematopoiesis. Here, we report that expression of peroxisome proliferator activated receptor-alpha (PPARA) is elevated in patients with high-risk subtypes of acute myeloid leukemia (AML). On this basis, we hypothesized that genetic disruption of PPARA would impair AML maintenance. A significant survival advantage was observed in Ppara -/- AML as compared to wild-type AML. By contrast, steady-state myelopoiesis and hematopoietic reconstitution were largely undisrupted by Ppara loss with the exception of an increase in differentiated myeloid cells. Ppara-/- MLL-AF9 leukemia displayed gene expression patterns indicative of downregulation of lipid metabolism, monocytic cell type, innate cell inflammatory responses and increased granulocytic differentiation concomitant with up-regulation of antigen presentation and stimulation of the adaptive immune response. Transplantation into Rag2 -/- recipients substantially reduced the survival advantage in Ppara -/- leukemia, demonstrating dependence on the adaptive arm of the immune system. Taken together, our in vivo studies of Ppara in MLL-AF9 AML are consistent with a model in which PPARA promotes leukemia maintenance through concomitant regulation of cell-intrinsic programs and modulation of interactions with the leukemic immune microenvironment suggesting pharmacologic inhibition of PPARA could be an effective therapy in a high-risk subset of AML.
The FLT3 inhibitor quizartinib has been shown to improve overall survival when added to intensive induction chemotherapy ("7 + 3") in patients 18-75 years old with newly diagnosed AML harboring a FLT3-ITD mutation. However, the health economic implications of this approval are unknown. We evaluated the cost-effectiveness of quizartinib using a partitioned survival analysis model. One-way and probabilistic sensitivity analyses were conducted. In the base case scenario, the addition of quizartinib to 7 + 3 resulted in incremental costs of $289,932 compared with 7 + 3 alone. With an incremental gain of 0.84 quality-adjusted life years (QALYs) with quizartinib + 7 + 3 induction vs. 7 + 3 alone, the incremental cost-effectiveness ratio for the addition of quizartinib to standard 7 + 3 was $344,039/QALY. Only an 87% reduction in the average wholesale price of quizartinib or omitting quizartinib continuation therapy after completion of consolidation therapy and allogeneic hematopoietic cell transplant would make quizartinib a cost-effective option.
Clinical trials are crucial for improving patient outcomes. Although a significant number of trials are discontinued prematurely, our understanding of factors influencing early termination is limited. We conducted a comprehensive search of ClinicalTrials.gov to identify leukemia trials from 2000 to 2020, followed by data abstraction performed by two independent reviewers. Among 3522 leukemia clinical trials identified, 28.4% were terminated prematurely. Slow accrual was the leading cause of termination 38.2%. The termination rate increased significantly from 17.0% between 2000 and 2005 to 30.9% between 2010 and 2015 (p < .001). Large trials had a lower termination rate than small trials (p < .001). Academic-sponsored trials had the highest termination rates compared to other sponsors' trials (p < .001). Early-phase trials showed higher termination rates compared to late-phase (p < .001). Other significant factors included a sequential assignment, single-center, and non-randomized trials (p < .001). Much of leukemia trials are terminated prematurely, with slow accrual being the most common reason for early termination.
