Hematologic Oncology Update, Issue 1, 2016 (Video Program)Choice of first-line tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML) and role of generic imatinib
6:19 minutes.
TRANSCRIPTION:
DR SMITH: There are 3 drugs approved up front for CML: imatinib, dasatinib and nilotinib. They’re all very, very effective. There are a few facts we know. One is that a second-generation drug causes responses more quickly than imatinib. It causes responses to be deeper at each time point than imatinib. And these second-generation drugs are associated with fewer, we’ll call them, transforming events — death, accelerated or blast crisis phase. So we know that those drugs do a better job up front in those settings. What we also know is that there has not been a change or an improvement in overall survival based on using a second-generation versus a first-generation drug. So we know that we’re getting better responses, quality wise, but it’s not translating yet into a survival advantage. What this means to the practitioner is that each of these drugs is really fair game for up-front therapy. They work really, really well. There have been some retrospective looks at the Phase III data that pitted nilotinib versus imatinib as well as the Phase III data pitting dasatinib against imatinib. And they’ve seen that where the biggest benefit in response rate and possibly survival happens is in the high-risk patients. So patients that present early with a high Sokal score or a high Hasford score, those patients seem to derive more benefit from starting a second-generation drug than a low-risk patient. If we flip this around and make this patient a high-risk presentation, superbig spleen size, superhigh platelet count, a patient with possibly B symptoms, weight loss and feeling poorly for a few weeks before the diagnosis, I would suggest that, in that class or that group of patients I favor the second-generation drugs up front, because I think that’s where we see the greatest amount of benefit that might translate into survival. DR LOVE: So your algorithm there, do you see that being affected by price? DR SMITH: I do. And I only know this from answering the phone calls from the insurance companies who are asking me to represcribe the drug and asking me to clarify, is brand medically necessary, or can we use a generic? So those, at the annual renewal of these prescriptions for my patients, I’m getting a lot of queries and wanting me to follow up in a different way. We want to believe that the generic formulations are going to be just as effective. It’s quite likely they will be. We’re lucky in CML that we have got a marker called the Philadelphia chromosome that we can measure. And if we have patients that are persistently at very, very, very low levels and we switch to a generic formulation and we see something changing, we need to be able to collect those data moving forward so that we can really understand and be confident that patients are doing really, really well with the generic version. DR LOVE: That’s amazing. I feel like I ask people a million times about the issue of generic imatinib. And this is the first time any investigator brought up the question of whether or not a generic would be as effective. DR SMITH: Let me just tell you. We’ve been treating people with thyroid medications for years. And we know that all thyroid medications aren’t the same, for a lot of reasons. Many patients do beautifully well. And the answer for thyroid medicine is that a generic drug may work as well as a brand name, but, in fact, you may have to adjust the dose. It may not be absorbed as readily. You might need a slightly higher dose with the generic form. And we’ve been able to do that. We don’t quite have that luxury with our TKIs. There are certainly multiple different doses, but if a patient wasn’t absorbing the generic form of the drug very well, that may change what their response looks like moving forward. So I think it behooves us to be mindful. And I’m not at all suggesting that we can’t use generic drugs. I just want us to be mindful and thoughtful of how we monitor people when we make the change to a generic from a brand name drug. DR LOVE: That’s really fascinating. I never thought about the idea of absorption. You would think that the chemical itself, that should be pretty straightforward. But again, the absorption, that’s very interesting. DR SMITH: And again, this little vignette may or may not make sense. But one of the interesting things that came out at ASH in the last couple of years is this idea of compliance. And there’s been some really nice studies looking at compliance on clinical trials. And early on with treatment, compliance of less than 90% compared to those patients who comply more than 90% of their dosing has a very different outcome. The likelihood of getting a good response is lower. And in some studies, there’s been a hint that maybe survival is affected. If you think of 90% of doses in a month for patients with imatinib, that’s missing 3 doses, right? So if you miss more than 3 doses, you’re less than 90% compliant. Your response rate changes. Let’s translate that to a drug that’s absorbed 80% as effectively as another drug. And you say to yourself, “Jeez. What would my compliance be like there?” And so I really believe that we do need to monitor pCRs carefully. And small fluctuations are accepted across the board no problem. But if we see trends in our patients where their responses don’t feel as deep or as stable on generics, we’re probably going to have to further investigate that. |