Second-line CML Drug Evokes Faster Response, Fewer Side Effects, Pivotal Study Finds

MD Anderson News Release June 05, 2010

MD Anderson-led Phase III clinical study determines Sprycel superior to Gleevec as front-line therapy

MD Anderson News Release 06/05/10

Dasatanib, a medication currently approved as treatment for drug-resistant chronic myeloid leukemia (CML), provided patients with quicker, better responses as a first therapy than the existing front-line drug, according to researchers at The University of Texas MD Anderson Cancer Center.

The findings were presented at the 46th Annual Meeting of the American Society of Clinical Oncology today, and published in the New England Journal of Medicine. Hagop Kantarjian, M.D., professor and chair of MD Anderson's Department of Leukemia, presented the findings and is the corresponding author on the published study.

Currently, imatinib, or Gleevec®, is the approved initial therapy for CML, which has increased the five-year survival rate for the disease from 50 percent to 90 percent, said Kantarjian. However, 30-40 percent of imatinib patients do not achieve confirmed cytogenic complete response (CCyR), or the absence of the defective chromosome that causes the disease, within a year. This benchmark is clearly associated with improvements in long-term outcome, said Kantarjian.

"Previous research conducted at MD Anderson found that more patients taking dasatinib were achieving complete responses more quickly than they do on the current standard of care," said Kantarjian. "In this pivotal Phase III study, we confirmed that dasatinib gets more patients to high-quality remission faster than imatinib, making it a superior front-line therapy. Dasatinib, on average, also has a more favorable side-effect profile."

For the multinational Phase III study, known as DASSIN (Dasatinib versus Imatinib Study In treatment-naïve CML patients), 519 newly diagnosed CML patients who had received no prior treatment were randomized to receive either dasatinib, also known as Sprycel ®, 100 milligrams once daily (259 patients), or imatinib, 400 milligrams once daily (260 patients). CCyR, confirmed on two assessments, was the study's primary endpoint. Secondary endpoints included rate of and times to CCyR and major molecular response (MMR), defined as a level of .1 percent or lower of the defective chromosome, as well as safety.

After a minimum follow-up of 12 months, the researchers found that the rates of confirmed CCyR and MMR in those taking dasatinib were 77 percent and 46 percent, respectively, compared to 66 percent and 28 percent, on the imatinib arm.

Therapy failed in nine patients (3.5 percent) in those taking imatinib, compared to five patients (1.9 percent) taking dasatanib. The dasatanib arm reported fewer side effects - nausea, vomiting, muscle inflammation, rash, fluid retention - with most other toxicities being similar in both arms.

"We've learned that in cancer therapy, it's important to use your big guns up front. We know that achieving complete cytogenetic response within a year of starting treatment is associated with more favorable long-term survival; therefore, using this second-generation drug first will likely improve outcomes for patients with chronic myeloid leukemia," said Kantarjian.

CML is caused by an abnormality known as the Philadelphia chromosome that produces an aberrant protein, Bcr-Abl, which causes the overproduction of one type of white blood cell that drives the disease. Dasatinib, a tyrosine kinase inhibitor, blocks the action of Bcr-Abl; the drug is currently approved by the U.S. Food and Drug Administration for patients who can't tolerate imatinib or whose CML resists the drug.

The study was supported by Bristol-Myers Squibb, makers of dasatinib. Kantarjian receives research funding from the company.

In addition to Kantarjian, other authors on the ASCO study include: Jorge Cortes, M.D., Department of Leukemia, MD Anderson; Neil Shah, M.D., Ph.D., San Francisco School of Medicine; Andreas Hochhaus, M.D., Universitaetsklinikum Jena; Sandip Shah, M.D., Vedanta Institute of Medical Sciences; Manuel Ayala, M.D., Centro Medico Nacional La Raza; Beatriz Moiraghi, M.D., Hospital General De Agudos J.M. Ramos; Mejia M. Brigid Bradley-Garelik, M.D, Bristol-Myers Squibb; Chao Zhu, Ph.D., Bristol-Myers Squibb, and Michele Baccarani, M.D., University of Bologna. 06/05/10