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Dasatinib Moves Ahead of Imatinib as Front-line Therapy for Newly Diagnosed CML in Chronic Phase

BY FRAN LOWRY | December 7, 2010

ORLANDO, FLA—Dasatinib (Sprycel) should become the initial treatment option in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Follow-up data from the DASISION* trial continued to show dasatinib(Drug information on dasatinib)’s superior efficacy to imatinib(Drug information on imatinib) (Gleevec).

Neil Shah, MD, PhD, presented 18-month follow-up data from the DASISION trial that showed dasatinib, which is currently well-established as second-line treatment for patients with CML-CP, produced higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib.

Dr. Shah is an assistant professor at the University of California, San Francisco, and coleader of the Hematopoietic Malignancies Program at the UCSF Helen Diller Family Comprehensive Cancer Center.

Earlier results from the phase III DASISION study—conducted in 180 countries with 519 patients—were published in the New England Journal of Medicine earlier this year. In that study, newly diagnosed patients were randomized to receive dasatinib (100 mg once daily) or imatinib (400 mg once daily) as front-line therapy. The primary analysis, after a median follow-up of 14 months, demonstrated superior efficacy of dasatinib over imatinib and an acceptable safety profile. As a result, dasatinib 100 mg daily has been recently approved by the FDA for the front-line treatment of CML-CP (N Engl J Med 362:2260-2270, 2010).

Dr. Shah presented data from 81% of patients in the dasatinib arm and 80% of patients in the imatinib arm who remained in the trial. All analyses were based on intention-to-treat patients. Efficacy and safety results in the extended analysis were consistent with those reported after 12 months of follow-up, Dr. Shah said.

The confirmed CCyR at 12 months was 77% with dasatinib vs 67% with imatinib. With the longer follow-up, it was 78% with dasatinib vs 70% with imatinib (P = .0366). The likelihood of achieving CCyR at any time was 1.5 times higher with dasatinib than with imatinib, Dr. Shah said. The median time to CCyR was 3.1 months for dasatinib and 5.8 months for imatinib (ASH 2010 abstract 206).

Rates of MMR at 12 months were 46% for dasatinib and 28% for imatinib. With further follow-up, there was still a statistically significant benefit in this regard for dasatinib at any time: 57% vs 41% for imatinib (P = .0002), Dr. Shah reported. Based on time-to-response analysis, the likelihood of achieving MMR was 1.8-fold higher with dasatinib than with imatinib (P < .0001). Among patients who achieved MMR, the median time to achievement was 8.3 months with dasatinib and 11.8 months with imatinib. There was a greater likelihood of achieving MMR, regardless of Euro/Hasford risk group status, in dasatinib-treated patients than in those treated with imatinib.

Fifteen patients had transformed to accelerated or blast phase CML (six in the dasatinib arm and nine in the imatinib arm). One case in each group has been accelerated, and the remainder have been blast phase. Five patients who achieved a CCyR transformed to accelerated or blast phase (two in the dasatinib arm and three in the imatinib arm). No patient who achieved an MMR had transformed to accelerated or blast phase at the time of the ASH presentation, Dr. Shah noted.

At 18 months, the rates of progression-free survival were 94.9% for patients in the dasatinib arm and 93.7% for those in the imatinib arm. Eleven deaths occurred among the dasatinib-treated patients and six in the imatinib arm. The overall survival rates were 96% for dasatinib and 97.9% for imatinib.

Discontinuation of treatment due to drug-related adverse events was infrequent in both groups and there were very low grade 3 and 4 toxicities in either arm, Dr. Shah said.

“Dasatinib 100 mg once daily continues to demonstrate superior efficacy compared with imatinib, with higher and faster rates of complete cytogenetic response and major molecular response,” Dr. Shah said. “The longer follow-up continues to support the use of dasatinib as first-line therapy in newly diagnosed chronic phase patients. Based on the predictive value of early complete cytogenetic response, we anticipate that further follow-up may demonstrate better long-term outcomes for patients receiving dasatinib rather than imatinib.”

*DASISION = The Dasatinib versus Imatinib Study in Treatment-Naive CML Patients

Related Reading

Deeper molecular responses seen with dasatinib in new chronic myeloid leukemia

by Gregory Pawelski | December 08, 2010 7:47 PM EST

CML is one of the great success stories for targeted chemotherapy drugs and imatinib (Gleevec) has been a godsend for patients with CML since it came on the market a decade ago. But resistance is growing, and at least two similar drugs are now on the market, dasatinib (Sprycel) and nilotinib (Tasigna).

Some mutations of the BCR-ABL1 gene make the cancer resistant to imatinib (Gleevec), which is designed to block the action of the hyperactive tyrosine kinase receptors in people with CML. But don't look to any tests currently on the market to determine what they are.

The review of 31 studies found that the presence of any BCR-ABL1 mutation does not appear to predict differential response to treatment in CML patients treated with imatinib-, dasatinib- (Sprycel), or nilotinib- (Nilotinib) based regimens.

The study looked at whether the presence of specific mutations in people who had CML determine if patients would respond to expensive new drugs commonly used to fight the diseases.

Indeed, the report said there is "no evidence that presence of any BCR-ABL1 mutation can differentiate response to tyrosine kinase inhibitor therapies."

It is possible that pharmacogenetic testing and the subsequent use of targeted therapies will add cost without producing clinically meaningful improvements in patient outcomes.

Genomics is far too limited in scope to encompass the vagaries and complexities of human cancer biology when it comes to drug selection. Efforts to administer targeted therapies in randomly selected patients often result in low response rates at significant toxicity and cost.

All the mutation or amplification studies can tell us is whether or not the cells are "potentially" susceptible to this mechanism of attack. They don't tell you if one targeted drug or another targeted drug is worse or better than the other or some other drug which may target this.

The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions (processes). It would be a benefit to analyze the systems' response to drug treatments, not just one target or pathway.

While researchers continue to develop molecular probes to select candidates, the cell culture analysis platform serves as a functional profile capable of examining the nuances of cellular response to drugs. To exploit the full potential of targeted anticancer therapies, physicians will need laboratory tests that match patients to specific drugs.

Cell culture assays are able to accurately predict how an individual patient's cancer cells will respond to an array of drug combinations. It is able to quantify synergistic drug combinations and individually tailor treatment.

Dasatinib Moves Ahead of Imatinib as Front-line Therapy for Newly Diagnosed CML in Chronic Phase

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