Shah: Hello, thank you for joining us today. We are here at the American Society of Hematology’s annual meeting in New Orleans in 2013. I have the pleasure being joined today by Professor Giuseppe Saglio from University of Turin in Italy, and we want to touch upon a couple of important issues, one involving monitoring changes in recommendations for monitoring, and then the other being an abstract that Professor Saglio is going be presenting on updated information on one of the randomized studies of a second-generation kinase inhibitors, in this case nilotinib versus imatinib in previously untreated patients. But first as I mentioned, we want to touch upon this issue about monitoring because there have been changes lately. Certainly from the NCCN perspective where previously bone marrow assessments were recommended every 6 months until achievement of a complete cytogenetic response. However, more recently, in response to a wide range of data that has come from numerous sources, largely from European studies, that achievement of PCR level or BCR-ABL level of 10% or lower on the international scale is associated with superior overall survival in patients who are treated with imatinib, and we have now seen that also in patients who are treated with the second-generation agents, either in the second line or in the front line. In light of the fact that it is an early intervention time point, the NCCN Guidelines have been changed to reflect this, that if you start a patient for instance on imatinib and they fail to get to this level of molecular response, it is actually recommended to switch these patients to a second-generation agent because of course studies are showing that at least in the front-line setting, these second-generation agents get a higher proportion of patients to deep cytogenetic and molecular responses. So, as a result of that, a 3-month time point is an important time point. If you do not have access to a good PCR test, then you can perform bone marrow aspiration for cytogenetics and look for the presence of a major cytogenetic response, meaning 35% or fewer Philadelphia chromosome containing metaphases, and again, if patients fail to meet that, they should be switched. It is of course recommended to continue to monitor patients every 3 months and ensure that they are continuing to be stable or declining if they are responding, and then by 12 months the minimum acceptable level of response is generally a complete cytogenetic response. There are some instances whereby if patients are most of the way there, one can wait till 18 months. So that in essence is a snapshot of the NCCN Guidelines and what is recommended for initial monitoring and response data, but the ELN of course was the first organization to develop these sorts of guidelines which they did back in 2006 and they reevaluated them again in 2009, I believe, and now again in 2013. I thought Dr. Saglio you can tell us a little bit about what has changed from the ELN perspective.
Saglio: Yes, of course, also the ELN has established that the 3 months’ cutoff of 10% is a very important point to evaluate the different uses of the patients; however, whereas the NCCN, as you have mentioned, they suggest to switch, meeting the European LeukemiaNet recommendation decided that you can if you want to switch, but you can also wait because at the moment we do not have necessarily data suggesting that this can be very, very useful and still beneficial for the patients. So, this is a very conservative point of view; however, they simply recommended to monitor more carefully these patients because they know that they are at risk, but they cannot recommend an early switch because of lack of data. So essentially, this is the main difference. Of course, there are different positions, even within the members of the European LeukemiaNet panels, there are those who are in favor of switching and those who are in favor of waiting the 6 months’ time point, which is becoming also very important to establish at this point having failure for those who are above 10%.
Shah: So, the argument for switching, if I heard you correctly, would be largely based on the data that suggest second-generation inhibitors are in general superior to imatinib and that we have overall survival data that suggests or demonstrates that patients who do not have deep initial molecular response are less likely to be alive a few years down the road. You mentioned the argument against that is that we do not have any data that suggests that if you take patients who failed to meet that milestone and randomize them to either imatinib or a second-generation TKI, there have been no studies showing that the second-generation TKI is superior. To the best of my knowledge, I think those studies are ongoing, but could one also say that we do not have such evidence for failure to achieve a complete cytogenetic response. We do not have randomized studies, but we move ahead with switching patients because we know that the likelihood of doing well, if you do not have a complete cytogenetic response by 12 months or 18 months, your likelihood of doing well on imatinib is compromised substantially. Would you say that that is fair to say?
Saglio: I totally agree with you. I think that this is a very important point that, of course, at least in my personal opinion, it is very difficult to deny that switching patients that we know have an inferior prognosis and that could be, we are not sure, but that could be, improved by switching to a second-generation TKI. Even because this intervention is an intervention not particularly I would say demanding on the side of the patients, and therefore I think that in my personal opinion I am more in favor of the NCCN Guidelines with respect to European LeukemiaNet Guidelines.
Shah: Of course, both of these are available. There has been a publication from the ELN recently in Blood and NCCN Guidelines are available on NCCN website. I would like to switch gears now and ask you about this important update you are going to be presenting today with longer-term follow up of the second-generation agent, the ENESTnd study that compared nilotinib to imatinib in previously untreated patients. What can you tell us about this update?
Saglio: This is an important update because it is the 5-year update, and therefore, this was in origin the end of the study also, but now it has been decided to prolong the study for an additional 5 years, so we will have a 10-year long study, and this is mainly to look for deeper molecular responses which are particularly promising as I would say, and also for side effects, the toxic effect that the TKI assumption can cause on the long-term treatment of these patients. So, what at 5 years can we say on the comparison between imatinib and nilotinib 300 mg? That certainly nilotinib is able to cause more deeper molecular responses, not only really fast molecular responses but also very deep because in terms of MR 4, MR 4.5 in particular, we have now more than enough patients who are treated with nilotinib 300 mg or 400 mg who are already in MR 4.5, which previously was called a complete molecular response, and which is considered the correct procedure to enter to treatment-free remission or, if you like, discontinuation of studies, which means the possibility to remain in complete molecular response even without the drug continuing to consuming the drug. So, I think this is a very, very important point. It also changes a little bit the perspective of the goal that we should achieve in the treatment of CML because it is not simply, I would say, a prolonged overall survival. This probably has been achieved as it is difficult to further improve the results, but certainly one of the goals can be the discontinuation and the true cure of the disease. I think that this is an important point, also because little-by-little, in the long run, we are seeing that there are effects arising with the long-term treatment of CML patients with TKI. These have been observed for nilotinib, in particular cardiovascular events, and indeed in this update there are more cardiovascular events in both nilotinib arms but particularly in the 400 mg twice-a-day arm with respect to the 300 mg arm, with respect to imatinib, but also for harder types of side effects that can affect patients treated with dasatinib and/or with imatinib. So, the idea that probably what we can face is a situation in which a diagnosis, we enroll a patient in a treatment with imatinib and he can remain for the rest of his life in this treatment without any kind of discontinuation and without suffering, however, any kind of side effect is probably not completely substantiated. But what is coming out is an observation period, which is the length maximum is 12 to 13 years. So, I think that in little bit we are opening now a new chapter in the research of both biological and clinical associated CML. We should aim to the real cure of the disease.
Shah: I think you raised an important point about longer follow up because even though as you mentioned the imatinib has been approved for 12 or 13 years, the IRIS study I believe stopped following patients beyond 8 years. That is the longest follow up that has been presented. I am sure you, like I, have these younger patients and we can tell them what we know what 8 years of follow up. If you want to know about 15 years or 20 years, and obviously we do not have that much time yet, but I certainly applaud the decision to extend the follow up of this ENESTnd, this is very important study, from 5 years to 10 years because as you are alluded to, I completely agreed that with longer follow up one wants to know is the efficacy data holding up and more importantly is the toxicity data also holding up because as we have more and more patients, even with imatinib many patients do achieve complete molecular response, and so it is going to be very important to weigh these potential benefits for both these new drugs that are approved in the front-line setting, the nilotinib and dasatinib, with the other risks of potentially serious and irreversible toxicities and there are examples of both those types of things with both these new drugs. So, anything else you would like to tell us about your presentation today?
Saglio: I think that the data which is emerging is very, very striking, is simply represented by the deeper molecular responses, in particular those who are responding very fast are already below 1% after 3 months of therapy, in the ENESTnd study they achieved CMR in 70% of the cases, and this is an extremely important point if you consider that these patients are more than 50% of the total number of the patients. So, according to this number in this rather short period of time, we can enroll in discontinuation studies at least one-third of the similar patients.
Shah: Sounds very promising. I would like to thank Professor Saglio for joining us today, and I would like to thank all of you for taking time to watch this, and I would encourage you to visit the Managing CML website for further information. Thank you very much.
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Chronic Myelogenous Leukemia. (Version 2.2014) Release date 11/01/2013.
Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-84.
Saglio G, et al., ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes. [ASH Annual Meeting Abstracts] Blood. 2013;122(21):Abstract: 92.