Efficacy and safety of nilotinib therapy in patients with newly diagnosed chronic myeloid leukemia in the chronic phase

Abstract

ABL1-tyrosine kinase inhibitors (TKIs) have led to dramatic changes in treatment strategies for chronic myeloid leukemia in the chronic phase (CML-CP). However, clinical studies have highlighted increasing numbers of adverse events (AE) with TKIs. Although TKI modification plays a key role in AE management, this process is poorly understood, particularly in terms of the TKI nilotinib. In the present study, we retrospectively analyzed the records of 70 patients with newly diagnosed (ND)-CML-CP who were treated with nilotinib to investigate the drug potency of nilotinib and treatment management. During a median observation period of 3.4 years, 76% of patients continued nilotinib as a first-line treatment. The 1-year and overall major molecular response (MMR) rates and the overall molecular response (MR) 4.5 rate for all patients receiving first-line nilotinib therapy were 70, 84.2, and 50%, respectively. No case progressed to the accelerated or blast phase during the study. To avoid AEs during the early phase, nilotinib doses were reduced to < 600 mg/day in a third of patients (Reduced group); these patients experienced better therapeutic efficacy and a lower rate of AEs relative to those in Standard group (300 mg twice daily). Ten patients who received < 600 mg/day of nilotinib throughout the study had a 1-year MMR rate and overall MR4.5 rate of 90 and 60%, respectively. In summary, our findings indicate that careful management, including dose reduction, can yield better outcomes in patients with ND-CML-CP.

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

“…Limited data from small cohorts of patients suggest that lower doses of nilotinib (,600 mg per day) may be associated with better safety and efficacy than nilotinib 300 mg twice daily. 97 However, as with dasatinib, the minimum effective dose of nilotinib has not been established in randomized clinical trials.…”

A Repurposed Drug Screen Identifies Compounds That Inhibit the Binding of the COVID-19 Spike Protein to ACE2

“…The next four best candidates were actually two closely related pairs of drugs, which demonstrates the robustness of our screen in identifying each compound twice. Nilotinib, which was identified as both a free base (IC 50 4.21 ± 0.36 × 10 −6 M) and an HCl salt (IC 50 8.43 ± 1.18 × 10 −6 M), is a selective tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (Tokuhira et al, 2018). Hydroxycamptothecine (IC 50 6.87 ± 0.77 × 10 −6 M) and its stereoisomer S-10-Hydroxycamptothecine (IC 50 7.22 ± 0.06 × 10 −6 M) are DNA topoisomerase I inhibitors with anti-cancer activity (Fei et al, 2013).…”

“…First, many of the drugs are chemotherapy agents, and have toxic side-effects that would not be tolerable in COVID-19 patients. For example, Nilotinib inhibits a kinase important in B cell signaling (Tian et al, 2018;Tokuhira et al, 2018), and may prevent normal immune function, while Picropodophyllin (Ekman et al, 2016) and Docetaxel (Gustafson et al, 2003) both produce moderate to severe side effects when used in the context of chemotherapy. Secondly, several of the drugs have peak plasma concentrations that are orders of magnitude lower than the concentration required to inhibit spike-Ace2 binding in the in vitro assay, for example Oxytocin (Gossen et al, 2012) and Doramectin (Gayrard et al, 1999) (0.005 vs 4.2 µM and 0.014 vs 12.8 µM, respectively).…”

A repurposed drug screen identifies compounds that inhibit the binding of the COVID-19 spike protein to ACE2

“…The next four best candidates were actually two closely related pairs of drugs, which demonstrates the robustness of our screen in identifying each compound twice. Nilotinib (EC50 = 4.20 x 10 -6 M), which was identified as both a free base and an HCl salt, is a selective tyrosine kinase inhibitor used to treat chronic myelogenous leukemia 19 .…”

“…First, many of the drugs are chemotherapy agents, and have toxic side-effects that would not be tolerable in COVID-19 patients. For example, Nilotinib inhibits a kinase important in B cell signaling 19,24 , and may prevent normal immune function, while Picropodophyllin 25 and Docetaxel 26 both produce moderate to severe side effects when used in the context of chemotherapy. Secondly, several of the drugs have peak plasma concentrations that are orders of magnitude lower than the concentration required to inhibit spike-Ace2 binding in the in vitro assay, for example Oxytocin 27 and Doramectin 28 (0.005 vs 4.2 uM and 0.014 vs 12.8 uM, respectively).…”