Glasdegib plus low-dose cytarabine for acute myeloid leukemia: Practical considerations from advanced practitioners and pharmacists

Abstract

Objective Acute myeloid leukemia (AML) is primarily a disease of older adults. These patients may not be candidates for intensive treatment, and there has been an ongoing need for treatment options for this group. We review the use of glasdegib, a hedgehog-pathway inhibitor available for use in combination with low-dose cytarabine (LDAC). Data Sources: PubMed and relevant congress abstracts were searched using the term “glasdegib”. In addition, based on our experience with glasdegib, we considered treatment aspects of particular relevance to pharmacists and advanced practitioners. Data Summary: In a randomized phase II study, the combination of glasdegib plus LDAC demonstrated superior overall survival versus LDAC alone (hazard ratio 0.51, 80% confidence interval 0.39–0.67, p = 0.0004). The trial reported adverse events (AEs) of special relevance for older patients, such as hematologic events, gastrointestinal toxicity, and fatigue, as well as AEs associated with Hh-pathway inhibitors (alopecia, muscle spasms, dysgeusia). Educating patients about typical AEs can facilitate adherence as well as early AE identification and proactive management. For LDAC, which is a long-established therapy in AML, various stages of delivery need consideration, with attention to individual circumstances. Practical measures such as dispensing a longer supply can reduce the number of return clinic visits, providing a meaningful difference for many patients. Conclusions Pharmacists and advanced practitioners play important roles in treatment with glasdegib plus LDAC. Ultimately, framing plans for treatment delivery within the individual circumstances of each patient may enable them to stay on therapy longer, giving them the greatest potential to achieve benefit.

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“…The above adverse events are within the controllable range. Glasdegib is suitable for long-term treatment (158). Also, glasdegib combined with low-dose cytarabine significantly prolonged the OS of patients, and the therapeutic effect of this combination therapy was more prominent in patients with secondary AML.…”

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“…Finally, drugs against acute myeloid leukemia, such as glasdegib, gilteritinib, midostaurin, cytarabine, and venetoclax, have high oral bioavailability and are widely used [ 255 , 256 , 257 , 258 , 259 , 260 ]. Most, such as glasdegib, gilteritinib, midostaurin, cytarabine, and venetoclax, are eliminated by oxidative metabolism, mainly CYP3A4 , with a minor contribution from glucuronidation by uridine diphosphate glucuronosyltransferase 1A [ 258 , 259 , 260 , 261 ].…”

“…Finally, drugs against acute myeloid leukemia, such as glasdegib, gilteritinib, midostaurin, cytarabine, and venetoclax, have high oral bioavailability and are widely used [ 255 , 256 , 257 , 258 , 259 , 260 ]. Most, such as glasdegib, gilteritinib, midostaurin, cytarabine, and venetoclax, are eliminated by oxidative metabolism, mainly CYP3A4 , with a minor contribution from glucuronidation by uridine diphosphate glucuronosyltransferase 1A [ 258 , 259 , 260 , 261 ]. However, because glasdegib, gilteritinib, midostaurin, cytarabine, and venetoclax are a substrate of CYP3A4 enzyme-mediated metabolism, plasma levels of glasdegib tend to decline; CYP3A inhibitors such as ketoconazole should be administered to increase glasdegib levels [ 256 , 257 , 258 , 259 , 260 , 262 ].…”

“…Most, such as glasdegib, gilteritinib, midostaurin, cytarabine, and venetoclax, are eliminated by oxidative metabolism, mainly CYP3A4 , with a minor contribution from glucuronidation by uridine diphosphate glucuronosyltransferase 1A [ 258 , 259 , 260 , 261 ]. However, because glasdegib, gilteritinib, midostaurin, cytarabine, and venetoclax are a substrate of CYP3A4 enzyme-mediated metabolism, plasma levels of glasdegib tend to decline; CYP3A inhibitors such as ketoconazole should be administered to increase glasdegib levels [ 256 , 257 , 258 , 259 , 260 , 262 ]. Table 3 shows one-year survival for each drug approved for the treatment of acute myeloid leukemia.…”