Oncologystat- CML The Changing Landscape: Interview with Prof. Apperley-Parts 1 and 2

Jane Apperley

OncologySTAT Editorial Team. 2010 Nov 23, Interview by L Scott Zoeller

Dr. Jane Apperley is Professor of Hemato-oncology, Imperial College London.

Part I: First-Line Therapy

Imatinib vs newer agents

OncologySTAT: Dr. Apperley, would you talk about the changing landscape of front-line therapy for treatment of newly diagnosed chronic-phase chronic myeloid leukemia (CML)? Is the treatment paradigm changing? If so, how will imatinib fit in with the introduction of secondary tyrosine kinase inhibitors (TKIs)?

Dr. Apperley: There is no doubt that the front-line therapy for newly diagnosed CML will change but at different times, depending on where you are practicing. For instance, we in the United Kingdom are probably not going to be able to use second-generation TKIs up front for another 2 or 3 years, because we require NICE approval. In some ways, however, you could argue that it is a little bit too early to change from a drug, such as imatinib, that we know very well, that is highly effective in 65% to 75% of cases, and has side effects that are well known and understood. We also have extremely good and proven guidelines now for the timing of the responses that we expect with imatinib. I am obviously referring to the European LeukmiaNet (ELN) guidelines. These guidelines initially suggested that there should be a complete hematological response (CHR) by 3 months and a complete cytogenetic response (CCyR) by 18 months. Subsequent papers and independent cohorts have suggested that this does actually predict very accurately which patients will do well and which will do poorly. Although we might be able to think that we can guess at similar milestones for second-generation drugs, actually we have no proof of those milestones at all. Imatinib is clearly less expensive, better known, and better understood; and it works for the majority of patients.

The reasons to change to another agent are the data from, initially, single-center studies from MD Anderson, a multi-center study from Italy and subsequent randomized studies with nilotinib1 and with dasatinib.2 Results of both randomized studies suggested that the proportion of patients who achieve a CCyR at 12 months is higher with the second-generation drugs than with imatinib and also that the proportion of patients achieving a major molecular response (mMR) is higher. There is a lot of interest because the data from the IRIS (International Randomized Study of Interferon and STI571) study showed that the majority of patients given imatinib who then develop advanced-phase disease do so within the first couple of years of treatment.3 The target for the clinician has always been to try and maximize results from therapy as early as possible, in hope of avoiding transformation in those few patients whose disease is destined to progress to advanced-phase early on. This was, in a way, supported by ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) and the DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients ) studies because the rate of progression to advanced-phase disease in the first year was higher in patients randomized to imatinib 400 mg (4.0%) than with nilotinib or dasatinib.1,2 This looks very convincing except that in the ENESTnd study the proportion of patients progressing in the first year is far higher in the imatinib arm than it was in the original IRIS study. I think there is still some debate as to whether the new drugs are really catching those patients who were destined to do poorly early on.

Personally, I think we need more follow-up. Most hematology treatment (in any disease) is directed towards giving the most aggressive and best therapy first. Dasatinib and nilotinib are probably both more potent than imatinib. On that basis, if you had a free hand, you probably would use one of those.

OncologySTAT: Are there factors related to toxicity or administration that need to be considered when choosing a first-line agent?

Dr. Apperley: Another big problem, of course, is that we do not know much about the long-term toxicity of nilotinib and dasatinib. Again, the trials suggested that the proportion of patients who had to discontinue therapy in the first year was identical for those taking the new agents and for those taking 400 mg of imatinib. This is quite difficult to interpret because far more patients discontinued imatinib in these studies than they did in the first year of the IRIS study. This is very logical because when imatinib first became available, patients had no other satisfactory option, so they were prepared to put up with quite severe degrees of toxicity. Now that there are alternative agents, patients may be less inclined to accept the toxicity. Again, much longer follow-up is needed to see whether the toxicity of nilotinib and dasatinib are truly equivalent or less than that of imatinib, such that patients will be able to stay on these drugs long term.

High-dose imatinib

OncologySTAT: Is there still a role for high-dose imatinib in light of the fact that there is better efficacy with nilotinib and dasatinib?

Dr. Apperley: That is a very good question to which we do not really have a clear answer. We have always felt in the CML community that imatinib was probably licensed at too low a dose and that the ideal dose was probably 600 mg daily for chronic-phase disease. If the comparison for chronic-phase patients in the DASISION or ENESTnd studies had been with imatinib 600 mg, the results may not have shown such an advantage for these newer agents.

One reason I say this is based on the data that are coming from the Australian TIDEL (Therapeutic Intensification in DE-novo Leukemia) II trial. This was not necessarily a complicated trial, but it required absolutely rigorous monitoring. All patients were given 600 mg of imatinib and then were changed to a higher dose of 800 mg or even 1000 mg, depending on their responses at certain time points. The patients had to have good plasma levels of imatinib at about 3 weeks after starting treatment, and then at 3 months, 6 months, 9 months, and 12 months they had to have reached the optimal response according to the 2009 ELN guidelines. Patients who did not achieve an optimal response had their imatinib dose escalated and were reassessed 3 months later. If they had not achieved an optimal response at this point, they were switched to nilotinib.

The trial has been running for approximately 18 to 24 months now. Only seven patients in the study have switched to nilotinib. Perhaps, if we were much more aggressive with imatinib, starting with a higher dose early on and rigorous monitoring, including plasma levels at three weeks, then the difference between imatinib and the new agents might not be so obvious.

This rigorous monitoring is not something most centers have enough confidence to undertake because the polymerase chain reaction (PCR) assay is not standardized yet, so it is quite difficult to do. Then you have to consider the reason to do this; even though 600 mg of imatinib might be better, we know that nilotinib and dasatinib are more potent. The answer is that the side effects of imatinib and how to handle them are well-known from the TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) study data.4 The other point that came from the TOPS study (a randomization between 400 mg and 800 mg of imatinib), is that there was no difference between the two arms in terms of achievement of CCyR. Again, this is a difficult trial to interpret because 800 mg of imatinib is associated with a lot of side effects, such that more than 50% of the patients were unable to maintain that dose in the first year. The median dose in the first year was approximately 600 mg. The subset of patients who were able to remain on more than 600 mg a day achieved their major molecular response much faster than those who could not.

How you look at this question depends on whether you are talking about individualized personalized medicine, whereby you treat individuals based on their ability to cope with a higher dose and their response or whether you consider, in much wider terms, the outcome of a randomized study. Equal numbers of patients were started on either drug and 24 months later 70% of them in each arm had the same outcomes.5 That might be fine from the trial point of view, but any individual patient might have done better or worse on one or other arm of the study. There is no clear answer to this question at the moment.

OncologySTAT: It sounds as if there is the potential for individualized therapy based on toxicity because there are now a number of agents from which to choose.

Dr. Apperley: Yes, absolutely. This would also be based on response to therapy, as long as the patient is tolerating the drug. The easy situation is when the patient is tolerating 400 mg of imatinib and responding extremely well. That is about 65% of patients. In a patient who is tolerating imatinib but not responding very well, the choice becomes increasing the imatinib or switching to another drug. In that situation, I would probably switch to another drug because nobody has really shown a fantastic benefit from simply increasing the imatinib dose in a nonresponder. If you have a patient who is not responding and not tolerating the drug, then clearly you would go to a different drug. These situations can all be individualized.

Switching to another agent

OncologySTAT: How long should a first-line agent be continued before switching to another drug if no complete response is achieved? What type of monitoring in needed?

Dr. Apperley: The ELN guidelines are pretty good here in as much as when they were first drawn up it was really a bit of a best guess in terms of the responses we thought ought to have been achieved at each time point. They were based on evidence, from the IRIS study and in other national studies, but nobody knew at that time that the responses were going to be durable. Here at Hammersmith Hospital, my colleague David Marin took a cohort of about 200 patients who had not been treated in the context of a trial but had received imatinib from a diagnosis. He was able to exactly replicate the IRIS study in terms of the proportion of patients who responded. Also, achievement of a response within a certain time point was an extremely good indicator of future response. This work validated the ELN guidelines.

The updated guidelines did what the first set did not, which was to define clearly an optimal responder. Preferably, I would like a patient to be an optimal responder, meaning that he or she achieves a CCyR within 12 months instead of 18 months and would be in major molecular remission at 18 months. In this case, I would keep the patient on imatinib. Otherwise, I would move to another drug. The earlier time points, such as being in hematological response at 3 months and having some form of cytogenetic response and or a partial response at 6 months are also extremely important. For any time point where you have got a definition of an optimal responder, I would keep the patient on imatinib. If the patient does not achieve those milestones at the expected time points, I would change to another drug. I would be a little more rigorous than the current guidelines.

Pegylated interferon therapy

OncologySTAT: Where does pegylated interferon fit in? I had also read a recent study where they had a drug holiday from imatinib and gave pegylated interferon in between. Is that a viable strategy also?

Dr. Apperley: The French SPIRIT (STI571 Prospective International Randomised Trial) study showed a benefit at 2 years in a randomized study for the arm in which patients were treated with imatinib and pegylated interferon over imatinib 400 mg and imatinib 600 mg alone.6 This study gave pegylated interferon a new lease of life. The French group is continuing the study with a reduced number of arms to see whether it is a durable effect. One concern that the community tends to have about the study is that a great majority of patients randomized in the pegylated interferon arm were no longer taking interferon by 12 months or were taking a grossly reduced dose. It is hard biologically to come up with an explanation as to why 4 or 5 months of interferon therapy had such a profound effect 2 years later. Further follow-up of that study is needed. There is no doubt that giving pegylated interferon together with imatinib increased the toxicity, which means you have to be very careful about monitoring the patients, who have to come back to the hospital more regularly for blood counts and who also have more side effects.

Drug holidays

OncologySTAT: Are drug holidays useful with imatinib?

Dr. Apperley: Here one really has to consider why you would want to give a holiday for a drug to which the patient is responding well. David Marin has shown quite dramatic results for patients who are not adherent to imatinib.7 In some cases lack of adherence to therapy is akin to a drug holiday. Dr. Marin evaluated close to 100 patients who were in CCyR—to all intents and purposes, good responders. He asked them to participate in a 3-month study of compliance with medication and side effects. The patients were fully consented.

The patients were not told exactly how compliance would be measured. What they did not know was there was an electronic chip in the top of the bottle that recorded when the patient opened it and, therefore, had a reasonable chance of taking the drug. The alarming result from this study was that only 40% of the patients were completely compliant. Of the noncompliant patients, those who missed more than 10% of their doses, were much less likely to have achieved a major molecular remission than patients who took more than 90% of their doses.

All patients were followed up for 2 more years without their adherence being monitored. In the intervening 2 years, some of the patients who were not completely compliant lost their cytogenetic responses.

We have become very anti–drug holidays. First, because I think it does affect the response. Second, because I think it gives patients the wrong message. If we happily tell them it is okay to take a holiday from the drug, then we cannot blame the patients if they then interpret to an excess and say, “The doctor says it does not matter if I have a 1-week holiday a month, so I guess it does not matter if I have a 10-day holiday or a 2-week holiday. Next time I go away on my vacation, and I do not want to feel tired, I will just stop taking the drug because that is what I do anyway in my drug holiday.” I am sure that the people running the drug holiday interspersed with interferon were trying to do something different. They were trying to presumably target stem cells in the period that the patients were off the imatinib. I think at the moment that approach does not sit with me very comfortably.

In part II of this interview, Dr. Apperley discusses imatinib resistance, when to consider stem cell transplantation, and new drugs on the horizon.

References

1. Kantarjian H, Shah NP, Hochhaus A, et al. M. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Eng J Med. 2010 Jun 17;362(24):2260-70.

2. Saglio G, Kim D-W, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. June 17, 2010; 362:2251-2259.

3. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. December 7, 2006; 355:2408-2417.

4. Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol. January 20, 2010; 28(3):424-430.

5. Baccarani M, Druker BJ, Cortes-Franco J, et al. 24 Months update of the TOPS study: a phase III, randomized, open-label study of 400 mg/d (SD-IM) versus 800mg/d (HD-IM) of imatinib mesylate (IM) in patients (Pts) with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP). Blood. Nov 2009;114(22)(suppl):337. Abstract. Blood (ASH Annual Meeting Abstracts) 2009 114: Abstract 337.

6. Guilhot et al. N Eng J Med. Article in press.

7. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 12 Apr 2010 [Epub ahead of print].

Related Link:

View Part II: CML—What to do About Imatinib Resistance; When to Consider Transplant: Interview With Dr. Jane Apperley »

Copyright © Elsevier Inc. All rights reserved.

CML—What to do About Imatinib Resistance; When to Consider Transplant: Part II: Interview With Dr. Jane Apperley

OncologySTAT Editorial Team. 2010 Nov 23, Interview by L Scott Zoeller

Dr. Jane Apperley is Professor of Hemato-oncology, Imperial College London.

In part I of this interview, Dr. Apperley discusses treatment options for patients with newly diagnosed CML.

Part II: Imatinib Resistance

OncologySTAT: What is the recommended approach for second-line therapy in patients with imatinib-resistant disease?

Dr. Apperley: Of course, one would want to absolutely identify that the patient is resistant. We from time to time see patients who are doing fine on imatinib and then suddenly have a PCR result that does not make much sense. In the past, we have been guilty of changing the patient to a second-generation drug too soon, but the PCR on the day that we have prescribed the second-generation drug for the first time has subsequently come back as very satisfactory. If we had had that result in front of us at the time that the prescription was written we would not have changed therapy.

Therefore, one is always a little bit suspicious about patient adherence. If I see a rise in the PCR, before I change the patient, I would certainly repeat it. I would sit down with the patient and explain that there has been a change in their bcr-abl transcript level that might necessitate a change of drug, but I want to give them a little bit longer on the imatinib just to make sure. In patients who have been a little bit careless with taking their medication this can encourage them to take the imatinib every day and, therefore, the PCR results will come under control again. I want to be very sure that the patient’s disease was really resistant.

The concerns are usually around quite minor changes in tumor load. It would be a rise in the PCR level or change in the major molecular response to simply a cytogenetic response. However, if you see more dramatic changes, for instance, if the PCR level rises dramatically or the blood count is suddenly uncontrollable, it is highly unlikely that it is because the patient is not compliant with therapy and much more likely that he or she has developed resistance to imatinib. We always, in any case of expected resistance, do a mutation analysis because, just occasionally, if we identify one, it helps us choose a second-line drug.

For me, I would make absolutely sure in my own mind that the patient’s disease was indeed resistant. I would do a mutation analysis just in case it gave me a clue which drug to recommend. If I was going to change, I would make sure I had a proper medical history, so, if there was any history of diabetes, I would probably avoid nilotinib. If there was a history of respiratory disease, I would probably avoid dasatinib. If the patient had ever had a history of pancreatitis or perhaps if the patient was a heavy drinker, I might avoid nilotinib.

The proportion of patients in whom you have got some reason to choose one drug over the other is certainly less than 10%. It might be less than 5%. I would then talk to the patient about the two drugs that are readily available, dasatinib and nilotinib. From my point of view, there is no difference in efficacy of these two drugs. On many occasions, it comes down to talking about the side effects and the restrictions that taking the drug places on that individual patient; and by that I mean the dietary restrictions around taking nilotinib, which some patients do actually find quite difficult to comply with. The patient and I probably come to a decision, which in 50% of the cases is nilotinib and 50% of the cases is dasatinib. That is probably fair because it reflects the equal efficacy of the two drugs.

OncologySTAT: Is there an optimal length of time that you wait before deciding to switch? How long should we give the first agent to see if it works?

Dr. Apperley: Yes. There is now some useful data from both the MD Anderson investigators and our own group. We have both identified certain factors that seem to predict or not a response to the second-generation drug. This strongest predictor is the patient having had a prior cytogenetic response to imatinib. Those patients seem to do extremely well on the second-line drug. Patients who never had a cytogenetic response and who have some other risk factor seem to do very poorly on a second-generation drug. In the MD Anderson data, that risk factor was a poor performance score. In our data, it was previous cytopenias or high Sokal score at diagnosis.

Actually, in those patients, although I would give a trial of a second-generation drug, I would also be already looking for a stem cell transplant donor. This leaves a big group of patients in the middle who have either a poor prognostic feature, like a poor performance score or prior cytopenias, but who did have a prior cytogenetic response, or vice versa—they had no prior cytogenetic response but have none of the poor prognostic features. Of course, that middle group usually forms the biggest group. They would obviously get a trial of another drug.

We feel here at Imperial College that if the patient has not achieved a cytogenetic response, certainly by 6 months but most of them by 3 months, then you are probably never going to get a good response. Those data were first suggested by MD Anderson, but, in their recent analysis, they have interpreted these results to suggest giving a trial of not more than 12 months for a second-generation drug.1 I think you can personalize and individualize the treatment a little bit because the patient, who perhaps was in a molecular response and has just lost it or the PCR level has risen a bit, who goes to a second-generation drug, can probably be kept on that drug a little bit longer, as long as the PCR level is not rising, to see if it will eventually drop.

When to consider stem-cell transplant

If you have a patient who has frank resistance and has clearly lost his or her cytogenetic response or has lost hematological response, then I would not wait 12 months to see if that patient is going to respond to therapy. In this group of patients you will probably know in 3 months whether they will respond to therapy. Again, in a suitable patient, I begin to think about transplant at the point of considering changing their treatment to a second-generation drug because if they do not have a donor in the family, then we are going to have to initiate a search for an unrelated donor. It could take 3 or 6 months to find a suitable donor. You want to be ready to go when you have to go with a transplant.

OncologySTAT: What are the options for patients who have bcr-abl– independent resistance?

Dr. Apperley: This is not such an easy question – because I am not entirely sure we know what "bcr-abl–independent resistance" means. In patients who have advanced-phase disease and who are resistant to the TKIs, one assumes that whatever is driving their leukemia is not bcr-abl–dependent. In these patients, we would use acute myeloid leukemia–like chemotherapy. If we could restore remission, or return to chronic phase is probably a more accurate description, then we would perform transplant, if possible. It is not always possible, but we would certainly try. For the individual who is still in the chronic phase, it is very rare to have loss of hematological response to all of the agents, which is probably what you would have to have to be absolutely sure that the patient had some bcr-abl–independent mechanism driving the majority of the leukemia. If we still have good control of the patient’s blood counts and/or cytogenetic response, but not molecular response, a very high proportion of the disease is still bcr-abl dependent. It is quite a complex question, I think. In the end, the answer is that if the TKIs are not working, then you have to think about transplant.

What’s on the horizon?

OncologySTAT: What promising research is underway for those patients whose disease is resistant to most of these agents?

Dr. Apperley: There are a lot of new drugs coming through the pipeline. The drive to develop lot of these drugs was, of course, the presence of this T315I mutation, which renders any patient resistant to imatinib, dasatinib, nilotinib, and bosutinib. The most promising new therapy, or at least the one that seems to be furthest on in development, is the compound from ARIAD, which is called ponatinib. Ponatinib is being evaluated in a phase II trial and will be available in the United Kingdom, probably, towards the end of this year. It is already being used in the United States. Ponatinib seems to have efficacy, not only in the presence of the T315I mutation, but also in patients whose disease has already failed to improve with two or more TKIs. We are also pretty excited that homoharringtonine, which is a drug that has been around for a very long time and never really got developed (because imatinib was so much better), has shown some efficacy in patients who have refractory disease after two or more TKIs and even in patients with T315I mutations. This is not surprising because it is not a kinase inhibitor, so you would not expect it to be affected by a kinase mutation.

There are a number of other agents. Deciphera Pharmaceuticals’ compound (DCC-2036) and one from Exelixis, Inc. (XL228), which are in phase I. We are expecting to get updated results on the outcomes of these studies at the American Society of Hematology meeting. Certainly, there are a number of agents, whether they be TKIs or aurora kinase inhibitors, that are coming along that may be helpful in a small proportion of patients. My guess is that around 75% to 80% of patients will do well on first-line nilotinib or dasatinib. Of the remainder who are resistant to therapy, these other drugs might work in a small proportion, another quarter of them, if we are lucky. There will still be a proportion of patients in whom transplant is still going to be the best option.

OncologySTAT: Are there certain patients who you would recommend being enrolled in a clinical trial?

Dr. Apperley: I would recommend that all patients be enrolled in a clinical trial, if possible; but we do not always have the clinical trials available at the time the patient comes along. Of course, for the new agents, patients are only going to get them if they enroll in a clinical trial because none of them are licensed. I still think there are important questions to be answered regarding front-line imatinib therapy at an optimal dose with adequate monitoring versus second-line agents. One study that we would all like to see, but is very difficult statistically, would be a head-to-head comparison of nilotinib and dasatinib. I think there are loads of clinical trials we could do. I would encourage all my patients if possible to enter a clinical trial.

Reference

1. Tam CS, Kantarjian H, Garcia-Manero G, et l. Failure to achieve a major cytogenetic responseby 12 months defines inadequate response in patients receiving nilotinib or dasatinib as second or subsequent line therapy for chronic myeloid leukemia. Blood. 2008 Aug 1;112(3):516-8. Epub 2008 May 20.

Related Link:

View Part I: CML—News Drugs: Interview With Dr. Jane Apperley »

Copyright © Elsevier Inc. All rights reserved.