In CML, Next-Generation TKIs Aim to Boost Outcomes

Ben Leach
Published: Friday, Nov 30, 2012
Dr. Jorge E. Cortes

Jorge E. Cortes, MD

While many patients with chronic myeloid leukemia (CML) have benefited tremendously from imatinib (Gleevec) and other tyrosine kinase inhibitors (TKIs), that benefit only occurs if the drugs work initially and continue to work for years without the patient developing resistance. As a result, researchers are continuing to investigate TKIs to help manage patients who either do not respond to initial therapy or relapse after subsequent treatment.

Two new drugs, bosutinib (Bosulif) and ponatinib, are promising candidates for third-line use in patients who fail on second-line TKI therapy, and are being explored as second-line therapies in their own right.

While both drugs are designed to treat the same group of patients, the expanding armamentarium of therapies for this particular tumor type is allowing oncologists to consider adverse events, mutational status, and dose scheduling to select the best treatment possible, even among a group of drugs that each most likely would be able to provide some degree of benefit to the patient.

Jorge E. Cortes, MD, deputy chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, operates the largest CML research center in the world and served as lead investigator on the key clinical trials for both bosutinib and ponatinib. The results of these trials led to the recent FDA approval of bosutinib and the priority review that the FDA granted to ponatinib.

Cortes explained that about 60% to 65% of patients with CML have a positive outcome when they receive initial treatment with imatinib. While that number is encouraging, it means that more than a third of patients do not respond to the drug. Likewise, among the patients who fail on imatinib and receive second-line therapy with dasatinib (Sprycel) and nilotinib (Tasigna), fewer than half of those patients respond well to the second-line therapy, Cortes said.

“If you put those two lines of therapy together, most patients do well,” Cortes said. “However, that’s no consolation to all of those who are not doing well, and we need to improve on those things. That’s where these new drugs come in. You can, for now, at least offer them another option so you can get them to have a good outcome. Even when they fail the prior therapy, they still have the possibility of a good response and a durable response.”

Bosutinib Approved as Later Therapy

In September, the FDA approved bosutinib for the treatment of patients with chronic-, accelerated-, or blast-phase Philadelphia chromosome-positive CML who have developed resistance or intolerance to prior therapy.

The approval was based on the Study 200 trial, in which the number of patients, who had been previously treated only with imatinib, achieving a major cytogenetic response after bosutinib increased as the study continued. According to drug manufacturer Pfizer, updated results from a study originally published in Blood in 2011 showed that, after a minimum follow-up of 23 months, 53.4% of patients achieved a major cytogenetic response (MCyR). Of those patients, 52.8% experienced a MCyR lasting at least 18 months.1-2

However, results from the BELA trial were not as encouraging when bosutinib was compared head-to-head with imatinib in the front-line setting. Among patients with newly diagnosed, chronic-phase CML, the rate of complete cytogenetic response (CCyR) at 12 months among patients who received bosutinib 500 mg daily (70%; 95% CI, 64%–76%) was not statistically significantly superior when compared with imatinib 400 mg daily (68%; 95% CI, 62%–74%; two-sided P =.601).3

Cortes said that there are a number of reasons that may account for a lack of superiority demonstrated with bosutinib in this trial. He noted that one possible explanation is that the BELA trial consisted of an intentto- treat population, so that if patients achieved a CCyR nine months into the study, they would no longer be enrolled in the study at 12 months, when data from the trial were collected. Therefore, such patients would be considered as having failed the therapy even though they achieved the primary endpoint earlier.

Another possible explanation is that patients may not have been managed properly because investigators did not have a lot of experience with the drug, said Cortes. Nearly 19% of the 248 patients who initially received treatment in the BELA study discontinued the drug due to adverse events.

Table. Drugs for Adult Patients With CMLa

Agent Indications Sponsor FDA Status
Imatinib (Gleevec) Newly diagnosed CML in chronic phase

CML in blast crisis, accelerated phase, or chronic phase after failure of interferon-alpha therapy
Novartis Approved 5/2001

Approved 4/2003
Dasatinib (Sprycel) CML in chronic, accelerated, or blast phase in patients resistant or intolerant to prior therapy that included imatinib

Newly diagnosed CML in chronic phase
Bristol-Myers Squibb Approved 6/2006

Approved 10/2010
Nilotinib (Tasigna) CML in chronic and accelerated phases in patients resistant or intolerant to prior therapy that included imatinib

Newly diagnosed CML in chronic phase
Novartis Approved 10/2007

Approved 6/2010
Bosutinib (Bosulif) CML in chronic, accelerated, or blast phase in patients resistant or intolerant to prior therapy Pfizer Approved 9/2012
Ponatinib Resistant or intolerant CML Ariad Pharmaceuticals PDUFA Date 3/27/2013

aIn all cases, drugs are approved to treat patients with Philadelphia chromosome-positive CML.
CML indicates chronic myeloid leukemia; PDUFA, Prescription Drug User Fee Act.

FDA website ,, prescribing information for individual drugs, Ariad Pharmaceuticals news releases

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