Expert Highlights Frontline Advancements in Treatment Landscape for CML

Neil P. Shah, MD, PhD

Neil P. Shah, MD, PhD

There are now 5 FDA-approved drugs for the treatment of patients with chronic myeloid leukemia (CML), including second-generation tyrosine kinase inhibitors (TKIs). These agents, including dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif), have revolutionized the treatment landscape.

Including the first-generation TKI imatinib (Gleevec), there are now 4 TKIs approved for the frontline treatment of CML. The second-generation TKIs, however, have proven more effective than first-generation imatinib. A 5-year analysis of the randomized phase III DASISION trial demonstrated that dasatinib is a more effective frontline treatment than imatinib for patients with newly diagnosed CML.

In the randomized phase III ENESTnd trial, 2 different doses of nilotinib were compared with imatinib treatment in patients with newly diagnosed chronic-phase CML. Over 50% of patients in the 2 nilotinib arms achieved a molecular response compared with 31% in the imatinib arm. Additionally, there was a lower risk of progression in the nilotinib arms as well.

Although TKIs are changing the treatment landscape for patients with CML, there are toxicities physicians should be aware of when selecting the right agent to give each patient. For instance, a patient with diabetes should consider a TKI that is not associated with hyperglycemia.

“Without question, TKIs have completely revolutionized the treatment landscape. They are, of course, associated with some day-to-day [adverse] effects that many patients experience,” said Neil P. Shah, MD, PhD. “There are concerns regarding potential long-term toxicities, but for the most part, most of the [toxicities] have been relatively minimal.”

In an interview withTargeted Oncology, Shah, a professor of medicine in the Division of Hematology and Oncology at the University of California, San Francisco, discussed the latest advancements in the treatment landscape of CML, including the introduction of TKIs. He also addressed some of the challenges both oncologists and patients face in this space.

TARGETED ONCOLOGY:What challenges still need to be addressed in the treatment of CML?

Shah:With respect to the management of CML, we now have 5 drugs approved, and the ability to treat drug-resistant mutations is quite good. However, there are some key issues that still plague a lot of patients: [adverse] effects, and/or resistance, or a combination of those 2 remain, so there remains a need to develop new therapies. In addition, there are growing concerns about long-term treatment with these agents. To date, we haven’t seen anything with most of the agents that is highly concerning. Now, several of them can be associated with vascular toxicities, increased incidence of coronary artery disease, and so on, but we would like to try to, if possible, stop treatment in a larger proportion of patients. How we get there is actually a challenge in the field.

We’d like to try to understand why some patients are able to get there in the first place and others are not. That’s an obvious first question because we know that about 50% of chronic-phase patients on a second-generation drug, we predict, will be able to get to the depth of remission required to allow them to stop treatment 1 day, but that means 50% will not. Of those that are fortunate enough to attempt discontinuation, the question is, why are only 50% of those successful and the other 50% have to resume treatment. There’s been a lot of effort to try to solve both of these questions. With respect to achieving deeper remissions, there are a number of adjunctive therapeutic approaches that may target CML stem cells, and so on. These have shown activity in laboratory studies to date, but very little has been translated to clinical studies.

The ability to safely manage women who want to have children is of increasing importance because we are projecting that most of these patients are going to live an otherwise normal lifespan. For a woman who is on the younger side and wants to have children, this can impose significant questions and concerns regarding the management. How do you optimally manage somebody through that without compromising their long-term outcome, and at the same time, without posing any undue risk to the unborn child?

TARGETED ONCOLOGY:How has the introduction of TKIs changed the treatment landscape of CML?

Shah:The advent of TKIs has, of course, been revolutionary for the management of CML. We, in most cases, can identify a dose of therapy that is both effective and well tolerated. By effective, I like to stress that we’d like to achieve a BCR-ABL transcript level of about 1% or less on the international scale because we know that is associated with superior outcomes. Obviously, the ability to get deeper remissions that can facilitate treatment discontinuation is of considerable importance to patients and when these drugs were first being tested 20 years ago, I don’t think anybody envisioned that there would come a time when as many as 25% of people may be able to successfully stop treatment 1 day.

Without question, TKIs have completely revolutionized the treatment landscape. They are, of course, associated with some day-to-day [adverse] effects that many patients experience. There are concerns regarding potential long-term toxicities, but for the most part, most of the [toxicities] have been relatively minimal. However, nonetheless, if you are looking at somebody with decades of life ahead of them, you would like that to be as close to 0% probability as possible.

TARGETED ONCOLOGY:What experience have you had with patients’ comorbidities affecting treatment with TKIs, and how have you managed them?

Shah:There may be many patients who have comorbidities that can dictate which treatment they should go on. For instance, we have 4 approved [TKIs] now for the frontline management of CML. While there are very few absolute contraindications to any of these drugs, some of these agents, for instance, can be associated with hyperglycemia, so somebody with diabetes, although that is not an absolute contraindication, somebody with diabetes may be better served with a different medication. There are some patients that may have compromised pulmonary status, so they may not tolerate pleural effusion very well. Again, it’s not an absolute contraindication to start something, but 1 does worry that such a patient may be better served with an agent that doesn’t have such a significant risk of pleural effusion. There are also lifestyle factors to bring in as well. Most of the drugs are once daily, while 1 of the drugs is twice daily with fasting, and for some patients, that’s a considerable barrier.

TARGETED ONCOLOGY:What do you recommend after a patient with CML relapses?

Shah:In patients who have documented relapse of CML, I think 1 of the first things to ensure is that it is true relapse while the patient has been consistently taking the drug. In many cases, patients may, for 1 reason or another, stop taking their drug, so non-adherence is something that should be carefully evaluated. There are also other drugs that can interfere with the metabolism of TKIs, things that induce cytochrome P450 3A4 can actually lower drug levels, and that can lead to an increase in the transcript level and in some cases, even hematologic relapse. It’s important to confirm that a patient is not on such a medication.

If there is true acquired resistance, the next step is to obtain a BRC-ABL domain mutation test. That can help dictate which therapy the patient goes on next. If the mutation present is not 1 of that small number [of mutations] that have a preferential next treatment, then I think 1 can use any of the drugs. If the patient does have, of course, the T315I mutation, then ponatinib (Iclusig) is the only effective therapy for that particular agent.

TARGETED ONCOLOGY:What are some of the emerging treatment options being investigated in CML?

Shah:There are a number of therapies that are being developed for CML, and these are basically in the same class of inferring with the function of BCR-ABL. The reason this seems to continue to be critically important is because we’ve learned that this is a valid therapeutic target. All of the TKIs have tremendous activity, but due to a combination of resistance and, in some cases, intolerance to these agents that patients may develop over a period of several years, they could actually run out of options, in which case, managing them can become quite challenging.

We have done transplants for people that are intolerant of multiple TKIs and if possible, we [will] identify other agents that may be as effective and better tolerated, such as things coming down the pipeline like ABL-001, there are a couple of drugs being developed in Asia as well as a drug being developed in Russia, these are kinase inhibitors. I think the more the merrier; the more options, the better because this population of patients is continuing to grow and the number of patients who are going to have issues is going to increase simply because there are going to be more people at risk for problems with these agents.

There are other therapies that are being evaluated that have different mechanisms of action. The challenge, of course, is when you have treatments that are already so effective, something has to be really effective and well tolerated for the CML community to become realistically excited about the possibility of using it.