Plk INHIBITORS FOR AML

Use of the experimental agent volasertib (Boehringer Ingelheim) more than doubled the response rate in previously untreated older patients with acute myeloid leukemia (AML), according to a phase 2 study.

The data were published online July 8 in Blood.

The study involved 87 patients (median age, 75 years) who were considered unsuitable for intensive induction therapy. The primary outcome was objective response rate, defined as complete remission or complete remission with incomplete blood count recovery.

The response rate was better in patients treated with volasertib plus low-dose cytarabine (LDAC) than in those treated with LDAC alone (31.0% vs 13.3%; P = .052).

LDAC is a standard therapy in older patients who often cannot tolerate intensive induction chemotherapy doses and have very limited treatment options, said lead researcher Hartmut Döhner, MD, from the Department of Internal Medicine at Ulm University in Germany.

As an alternative to intensive induction, LDAC is a treatment of choice in Europe, but its efficacy could be enhanced, the authors suggest.

"Attempts to improve upon this standard [with] novel drugs have so far failed," write Dr. Döhner and colleagues.

Volasertib is an investigational compound that inhibits enzymes called polo-like kinases (Plk), which can ultimately lead to apoptosis.

Plk1 has been shown to be overexpressed in a range of human cancers, including AML and non-small-cell lung, prostate, ovarian, breast, and colorectal cancers.

The researchers report that median overall survival was better with volasertib plus LDAC than with LDAC alone (8.0 vs 5.2 months; P = .047).

Median event-free survival was also better with volasertib plus LDAC than with LDAC alone (5.6 vs 2.3 months; P = .021), as was relapse-free survival (18.5 vs 10.0 months).

However, the study was not powered to show an improvement in survival end points, Dr. Döhner and colleagues point out.

Notably, responses to volasertib plus LDAC were observed in all genetic groups, including 5 of 14 patients with adverse cytogenetics.

"The response rate in this genetic high-risk group was remarkable," the researchers note.

In this study, volasertib 350 mg was administered intravenously over 1 hour on days 1 and 15 and LDAC 20 mg was administered twice daily subcutaneously on days 1 to 10. Cycles were scheduled every 4 weeks until progression, relapse, intolerance, or discontinuation.

There were more nonhematologic adverse events with volasertib plus LDAC than with LDAC alone, including grade 3 febrile neutropenia (38% vs 7%), grade 3 infections (38% vs 7%), and grade 3 gastrointestinal events (21% vs 7%).

The combination has a "clinically manageable safety profile," according to the researchers.

The results of this study have led to a phase 3 study; the global phase 3 POLO-AML-2 (NCT01721876) clinical trial is now enrolling patients. The trial compares volasertib plus LDAC with placebo plus LDAC in patients 65 years and older with previously untreated AML who are ineligible for intensive remission induction therapy.

The study was sponsored by Boehringer Ingelheim. Dr. Döhner and some of his coauthors report financial relationships with Boehringer Ingelheim and other companies, as detailed in the publication.

Blood. Published online July 8, 2014. Abstract