Dihydroartemisinin inhibits the Bcr/Abl oncogene at the mRNA level in chronic myeloid leukemia sensitive or resistant to imatinib.
Due to the mutations of the Bcr/Abl oncogene that obstacle the binding of the protein with imatinib, the resistance to imatinib has developed in a significant portion of chronic myeloid leukemia (CML) patients. It stimulated the search for novel molecules for treatment of imatinib-resistance CML. Inhibiting the amplification of Bcr/Abl oncogene is believed to be a new effective strategy to override the imatinib resistance on CML cells. In present research, we demonstrated that dihydroartemisinin (DHA), a safe and effective antimalarial analog of artemisinin, could significantly inhibit the Bcr/Abl fusion gene at the mRNA level in CML cells sensitive or resistant to imatinib (including the primary CML cells with T315I mutation) and induce cell death. Moreover, dihydroartemisinin could also lead to the inhibition of the Bcr/Abl protein expression and tyrosine kinase activity, and strongly suppress on the downstream signals of Bcr/Abl, which included inhibition of tyrosine kinase activity of AKT and ERK, promotion of cytochrome c release from the mitochondria and the consequential activation of caspase-9/3 in imatinib-resistant CML cells. These results suggest for the first time that Dihydroartemisinin might be a potential novel drug candidate for treatment of imatinib-resistant CML and worthy of further study.
Lee J
，Shen P
，Zhang G
，Wu X
，Zhang X
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Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial.
Nilotinib has shown greater efficacy than imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase after a minimum follow-up of 12 months. We present data from the Evaluating Nilotinib Efficacy and Safety in clinical Trials-newly diagnosed patients (ENESTnd) study after a minimum follow-up of 24 months.
ENESTnd was a phase 3, multicentre, open-label, randomised study. Adult patients were eligible if they had been diagnosed with chronic phase, Philadelphia chromosome-positive CML within the previous 6 months. Patients were randomly assigned (1:1:1) to receive nilotinib 300 mg twice a day, nilotinib 400 mg twice a day, or imatinib 400 mg once a day, all administered orally, by use of a computer-generated randomisation schedule, using permuted blocks, and stratified according to Sokal score. Efficacy results are reported for the intention-to-treat population. The primary endpoint was major molecular response at 12 months, defined as BCR-ABL transcript levels on the International Scale (BCR-ABL(IS)) of 0·1% or less by real-time quantitative PCR in peripheral blood. This study is registered with ClinicalTrials.gov, number NCT00471497.
282 patients were randomly assigned to receive nilotinib 300 mg twice daily, 281 to receive nilotinib 400 mg twice daily, and 283 to receive imatinib. By 24 months, significantly more patients had a major molecular response with nilotinib than with imatinib (201 [71%] with nilotinib 300 mg twice daily, 187 [67%] with nilotinib 400 mg twice daily, and 124 [44%] with imatinib; p<0·0001 for both comparisons). Significantly more patients in the nilotinib groups achieved a complete molecular response (defined as a reduction of BCR-ABL(IS) levels to ≤0·0032%) at any time than did those in the imatinib group (74 [26%] with nilotinib 300 mg twice daily, 59 [21%] with nilotinib 400 mg twice daily, and 29 [10%] with imatinib; p<0·0001 for nilotinib 300 mg twice daily vs imatinib, p=0·0004 for nilotinib 400 mg twice daily vs imatinib). There were fewer progressions to accelerated or blast phase on treatment, including clonal evolution, in the nilotinib groups than in the imatinib group (two with nilotinib 300 mg twice daily, five with nilotinib 400 mg twice daily, and 17 with imatinib; p=0·0003 for nilotinib 300 mg twice daily vs imatinib, p=0·0089 for nilotinib 400 mg twice daily vs imatinib). At 24 months, survival was comparable in all treatment groups, but fewer CML-related deaths had occurred in both the nilotinib groups than in the imatinib group (five with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and ten with imatinib). Overall, the only grade 3 or 4 non-haematological adverse events that occurred in at least 2·5% of patients were headache (eight [3%] with nilotinib 300 mg twice daily, four [1%] with nilotinib 400 mg twice daily, and two [<1%] with imatinib) and rash (two [<1%], seven [3%], and five [2%], respectively). Grade 3 or 4 neutropenia was more common with imatinib than with either dose of nilotinib (33 [12%] with nilotinib 300 mg twice daily, 30 [11%] with nilotinib 400 mg twice daily, and 59 [21%] with imatinib). Serious adverse events were reported in eight additional patients in the second year of the study (four with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and one with imatinib).
Nilotinib continues to show better efficacy than imatinib for the treatment of patients with newly diagnosed CML in chronic phase. These results support nilotinib as a first-line treatment option for patients with newly diagnosed disease.
Novartis.
Kantarjian HM
，Hochhaus A
，Saglio G
，De Souza C
，Flinn IW
，Stenke L
，Goh YT
，Rosti G
，Nakamae H
，Gallagher NJ
，Hoenekopp A
，Blakesley RE
，Larson RA
，Hughes TP
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