乌鸦传媒

ORLANDO -- An oral tyrosine kinase inhibitor outperformed standard therapy in older patients (ages 65 and up) with untreated chronic lymphocytic leukemia (CLL), researchers reported here.

In a phase III, open label randomized trial, ibrutinib (Imbruvica), an oral inhibitor of Bruton's tyrosine kinase, reduced the risk of death by 84% compared with , according to , of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

The drug was also superior to chlorambucil in progression-free survival (PFS), Burger and colleagues reported at the American Society of Hematology meeting, and online in the .

Ibrutinib was approved in early 2014 as second-line therapy in CLL, and the indication was expanded later in the year to include first-line treatment for patients with the difficult-to-treat chromosome 17p13.1 deletion.

CLL mainly affects older people, the researchers noted, with a median age at diagnosis of 72. Chlorambucil has been a standard first-line therapy.

The new findings seem likely to change clinical practice, commented of Columbia University Medical Center in New York City.

Life-extending treatment for CLL is relatively toxic and difficult for older patients, he said. "This study really opens up a new form of therapy for the older patient with CLL that's unable to tolerate more intensive treatment," he told 乌鸦传媒. "It's a game-changer."

In the RESONATE-2 study, the investigators enrolled 269 treatment-naïve people with a median age of 73 and either CLL or small lymphocytic lymphoma. Patients with the chromosome 17p13.1 deletion were excluded.

They were randomly assigned to either 420 mg a day of ibrutinib until progression or chlorambucil at 0.5 mg/kg body weight on days 1 and 15 of a 28-day cycle for up to 12 cycles. The chlorambucil dose could be increased to 0.8 mg depending on toxicity.

The primary endpoint of the study was PFS, as assessed by an independent review committee, but the investigators also reported on overall survival (OS), overall response, sustained improvement in hematologic variables, and safety.

After a median follow-up period of 18.4 months, they reported:

• Median PFS was 18.9 months for chlorambucil but had not been reached for ibrutinib
• The hazard ratio for progression or death was 0.16, or 84% lower with ibrutinib (P<0.001)
• The rate of PFS at 18 months was 90% in the ibrutinib group and 52% in the chlorambucil group
• Ibrutinib significantly prolonged OS although the median was not reached in either group at the time of the analysis
• The OS rate at 24 months was 98% with ibrutinib and 85% with chlorambucil
• Three patients in the ibrutinib group died compared with 17 in the chlorambucil group
• The relative risk of death was 0.16, favoring ibrutinib (P=0.001)

Of the three ibrutinib patients who died, one succumbed to a Klebsiella infection and the cause of death was not known for the others, the investigators reported. None of the ibrutinib patients whose disease progressed died.

On the other hand, among the 17 chlorambucil patients who died, the most common causes were progressive disease and infection, the researchers said.

Some 86% of ibrutinib patients responded to treatment, including 4% with a complete response, compared with 35% and 2% respectively, among those treated with chlorambucil.

Ibrutinib also outperformed chlorambucil in improving hematological variables, they found.

Among patients with anemia at baseline, 84% in the ibrutinib group and 45% in the chlorambucil group had sustained improvement in hemoglobin levels, while among those with baseline thrombocytopenia, 77% in the ibrutinib group and 43% in the chlorambucil group had sustained improvement in platelet count. The differences were significant (P<0.001 and P=0.005, respectively).

Chlorambucil patients were more than twice as likely to stop therapy owing to adverse events as those taking ibrutinib, so that exposure to treatment and adverse-event follow-up was nearly 2.5 times as long with the newer drug.

The researchers said they saw major hemorrhage in 4% of ibrutinib patients, without fatalities, and atrial fibrillation in 6%, with most events grade 2. Hypertension was more frequent with ibrutinib, but was grade 3 or lower and did not lead to dose modification. Rates of fatigue, nausea, vomiting, and myelosuppression were higher with chlorambucil.

Comment