Interferon alfa（干扰素）

Before imatinib, the only effective medical therapy available for patients with CML was interferon alfa, which when combined with cytarabine, was able to achieve cytogenetic and molecular responses in a small group of patients. But the cost was substantial toxicities.

（在伊马替尼之前，对CML患者唯一有效的药物治疗手段就是当和阿糖胞苷混合时能使一小部分患者有遗传细胞和分子反应的干扰素。但是代价是大量的毒性。）

But interferon is trying to make a comeback. A recent study published in NEJM has shown that when added to imatinib, pegylated interferon alfa-2a improved the molecular response rate in patients with CML.

（但是干扰素试图“东山再起”，

In the study, 636 patients with untreated chronic-phase CML were randomly assigned to imatinib 400 mg daily, imatinib 400 mg daily; with cytarabine; imatinib 400 mg daily with pegylated interferon alfa-2a; or imatinib 600 mg daily. They measured molecular and cytogenetic responses, time to treatment failure, OS, event-free survival and adverse events.

There was no difference in the rates of cytogenetic response among the four groups. The molecular response rate for the pegylated interferon alfa-2a plus imatinib group was 30% vs. 14% for the imatinib 400 mg daily group. But during the first year, 45% of patients receiving the pegylated interferon alfa-2a discontinued treatment, mainly due to adverse events. There were also more adverse events overall in the group that received pegylated interferon alfa-2a. There was no benefit in event-free survival or OS.

“Two additional studies have shown no benefit of adding interferon alfa to imatinib, so this evidence should be considered, at best, inconclusive or questionable,” Cortes said. “Interferon may have a role, but we have to find the right place for it. It is more likely to be used at the end of treatment, if patients still have residual disease after treatment with a tyrosine kinase inhibitor, to see if that will help the patient move to a complete response. But at the moment, there is no evidence of a benefit, and it is still clearly an experimental approach.”

Jorge Cortes

The studies of interferon continue. Some studies may be designed to test the imatinib/interferon combination against the second-generation drugs nilotinib and dasatinib. Some experts said the monotherapy will prevail and spare patients from the adverse effects associated with interferon.

“I am hopeful that the second-generation drugs are able to achieve a response that is equivalent or superior to that of the imatinib and interferon combination,” Shah said. “There are studies ongoing now that are combining the second-generation drugs with interferon. It will be several years before we can learn whether this would add anything substantial to monotherapy with a second-generation drug, but this is an area of significant ongoing research.”

Drugs in investigation

At the 2010 ASH Annual Meeting, data were presented on a new TKI, bosutinib (Pfizer), both in the third-line setting and the first-line setting.

In an open-label, phase 1/2 study, the safety and efficacy of bosutinib as a third-line treatment in CML was assessed. The study included 28 patients with CML who were resistant to nilotinib and 86 patients who were resistant or intolerant to dasatinib. All had failed initial treatment with imatinib. The patients received a starting does of 500 mg of bosutinib.

At week 24, 26% of the patients had achieved a major cytogenetic response and 13% had a complete cytogenetic response. The cumulative response rates were 34% for a major cytogenetic response and 22% for a complete cytogenetic response. Most patients (81%) who achieved a major cytogenetic response retained their response after a median duration of 23 months.

In a phase 3 study, 502 newly diagnosed patients were randomly assigned to bosutinib 500 mg/day or imatinib 400 mg/day. At week 48, 71.5% of the patients were in complete cytogenetic response and 74.8% of patients were in complete hematological response. The rates of complete cytogenetic response rates were similar between the two groups, but the median time to complete cytogenetic response was shorter in the bosutinib group. More patients in the bosutinib group discontinued treatment because of adverse effects.

Resistance to mutation

Bosutinib, along with imatinib, dasatinib and nilotinib, has one critical weakness: It is ineffective against the T315I mutation. But for patients with this particular mutation, there may be a new treatment option in the future. The drug ponatinib (Ariad Pharmaceuticals) is currently in phase 2 trials.

Data from a phase 1 trial of ponatinib were also presented at the 2010 ASH Annual Meeting. Sixty-seven patients were enrolled in this trial: 95% of these patients had failed treatment with two tyrosine kinase inhibitors, and 64% of these patients had failed treatment with three tyrosine kinase inhibitors. Patients were treated at doses up to 60 mg. Of the 30 patients with CML in the chronic phase, 94% had a complete hematologic response and 63% had a major cytogenetic response.

“An agent to overcome the T315I mutation would represent a quantum leap in the management of patients with chronic phase CML, following the quantum leaps that imatinib and the second-generation tyrosine kinase inhibitors have made in the past decade,” Shah said.

Another agent of interest is DCC-2036 (Deciphera Pharmaceuticals). This drug binds to and inhibits the BCR-ABL in a different manner than the approved tyrosine kinase inhibitors. According to Shah, the hope is that this agent will also be less vulnerable to the resistance-conferring mutations, such as T315I. The agent is currently in a phase 1 trial. – by Emily Shafer

Disclosures: Dr. Cortes is a consultant for Ariad, Novartis and Bristol-Myers Squibb, and receives research funding from Novartis, Bristol-Myers Squibb, Pfizer and Ariad. Dr. Mauro receives research funding from Bristol-Myers Squibb, Novartis and Ariad. Dr. Radich is a consultant for Novartis, Bristol-Myers Squibb, and Pfizer, and receives research funding from Novartis. Dr. Schiffer is a consultant for Bristol-Myers Squibb, Novartis and Pfizer, and receives research funding from Bristol-Myers Squibb, Novartis and Ariad. Dr. Shah has served as a consultant for Bristol-Myers Squibb, Novartis and Ariad.

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