Oncology Live®
November 2012
Volume 13
Issue 11

In CML, Next-Generation TKIs Aim to Boost Outcomes


Researchers are continuing to investigate TKIs to help manage patients with CML who either do not respond to initial therapy or relapse after subsequent treatment.

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.

Bosutinib Approved as Later Therapy

“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.”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




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


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


Approved 10/2007

Approved 6/2010

Bosutinib (Bosulif)

CML in chronic, accelerated, or blast phase in patients resistant or intolerant to prior therapy


Approved 9/2012


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

Ponatinib Gains Priority Review

“Unfortunately, many of these patients who left the study because of adverse events did not have the opportunity to manage their adverse events,” Cortes said. “The investigators did not have the opportunity to give the patients treatment or dose adjustments of the drug, which is what we usually do in the clinic. That’s what I would do for a patient who has toxicity with any of the drugs.”The FDA recently announced that priority review status was granted to ponatinib, also in development as thirdline therapy. The designation was based on positive data yielded from the phase II PACE trial. The study found that 54% of patients with chronic-phase CML (144 of 267) achieved MCyR, 58% of patients (48 of 83) with acute-phase CML achieved a major hematologic response (MaHR), and 34% (32 of 94) of patients with blast-phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) achieved MaHR.4

In addition, more pronounced results were seen in patients who exhibited a mutation of T315I. For example, MCyR was achieved in 70% of patients with the T315I mutation (45 of 64) in the chronic-phase CML group. While positive results were seen regardless of mutation status, the response observed in patients with the mutation suggests that a specific group of patients with CML might gain a more pronounced benefit from ponatinib.

Choosing Among Options

“The mutation is not that common, but it is important because of this issue of the lack of any drug today that works in that setting,” Cortes said. “When you have that issue, and you have a drug like ponatinib that will work there, it covers a major gap that we have in the treatment, so even though it’s not a very common mutation, it is an important one for that reason.”With multiple available drugs to treat what is essentially the same group of patients, the answer might not be as clear as to which therapy is the right choice.

“I think that you have a good chance of doing well with any one of these drugs,” said Cortes. “Fortunately, having more drugs gives you the ability to choose based on other features.”

Cortes said one feature to consider is the toxicity profile; although all of these drugs are very well tolerated, they are also associated with a variety of side effects. For example, Cortes said that diarrhea is a common adverse event observed in patients who receive bosutinib, occurring in approximately 80% of patients who received the drug in clinical trials. The diarrhea is transient and can be managed, but it is still an adverse event, Cortes said. Conversely, in ponatinib, diarrhea is not as much of a problem, but pancreatitis was observed with greater regularity than with any of the other TKIs for CML.

“I think that in general, the toxicity profile of these drugs is as good as the others that we have,” Cortes said. “Obviously, these patients do need attention. They do need to be monitored closely and their adverse events managed carefully. That’s an important part of the management, that our patients get good treatment. But if you do that, I think the overwhelming majority of patients will be able to tolerate the treatment well.”

Beyond toxicity profile, Cortes said that there are other factors to consider. Mutational status is important. As previously indicated, patients exhibiting the T315I mutation appear to achieve a better response when they receive ponatinib. However, Cortes said that patients with a mutation of V299L have not responded to bosutinib in laboratory tests or clinical trials. Additionally, some of these drugs might be taken only once a day while others require two doses daily. Depending on the lifestyle of the patient, this might be an important factor in determining which therapy they receive.

These may appear to be minor differences, but Cortes said it is important to consider that as more patients are successfully managed, there will be more patients who live longer and therefore will eventually develop resistance to whichever TKI they receive in the frontline setting. As the efficacy of each of these drugs is observed clinically, oncologists will be able to determine the sequence that will yield the best results for individual patients.

“Little by little, these patients are going to be appearing more in the clinics of physicians,” Cortes said. “Some are doing well, but others are not, and we’re going to have to be able to recognize that and have things to do to try to make them feel better.”


  1. Bosulif [prescribing information]. New York, NY: Pfizer; 2012.
  2. Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib [published online ahead of print August 24, 2011]. Blood. 2011;118(17):4567-4576. doi: 10.1182/blood-2011-05-355594
  3. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial [published online ahead of print September 4, 2012]. J Clin Oncol. 2012;30(28):3486-92. doi: 10.1200/JCO.2011.38.7522.
  4. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. PACE: a pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. Presented at: 2012 ASCO Annual Meeting; June 1-5, 2012; Chicago, IL. Abstract 6503.

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