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. |
