My Approach to Chronic Myeloid Leukemia Interview by L Scott Zoeller. 2012 Apr 3, Tim Hughes, MD

2012 Apr 3, Tim Hughes, MD

Timothy P. Hughes, MD, FRACP, FRCPA, is Head of the Department of Haematology at SA Pathology, RAH site, and Consultant Haematologist at the Royal Adelaide Hospital in Australia. He is also Clinical Professor of Medicine at the University of Adelaide and holds a Practitioner Fellowship from the National Health and Medical Research Council.

OncologySTAT: What is your approach to frontline therapy in patients with Chronic Myeloid Leukemia (CML) with imatinib? How and when do you employ strategies that involve imatinib dose escalation, combination therapy, or a second-generation tyrosine kinase inhibitor (TKI) and what about toxicity?

Dr. Hughes: The choice of first-line therapy now in many countries has increased. We have imatinib and we also have nilotinib and dasatinib. I think many people are struggling with the choice because they are three very good drugs and each has its own advantages. Some clinicians will probably decide to use one drug for all their patients perhaps because of familiarity with that drug. Others will try and tailor the therapy according to what they perceive as the needs of that patient and that may well be a very appropriate way to proceed.

In general, imatinib remains an excellent frontline therapy. It achieves long-term, stable control for 60% to 70% of patients. But, there is clearly a need for other therapy for around 30% of patients. The two broad approaches that are being tried by most people now is either to use imatinib and then to selectively use the more potent second-generation drugs, either nilotinib or dasatinib, for patients who don’t tolerate it, or who are judged to have failed to achieve adequate response on imatinib—or to go straight to a frontline nilotinib or dasatinib approach for their patients.

Now, the potential advantage of going straight to nilotinib or dasatinib is that they are substantially more potent than imatinib and the randomized trials that have been conducted over the last 2 to 3 years clearly demonstrate that they both achieve deeper molecular responses at earlier time points. So what we’re seeing is a more rapid reduction in the leukemia cell mass over the first 2 to 3 years with these more potent drugs. That means that more patients are achieving the key targets of therapy, including complete cytogenetic remission and major molecular remission.

The other advantage that has been evident from the randomized trials is that the newer drugs also reduce the risk of progression. One of the key targets of chronic myelogenous leukemia (CML) therapy is to prevent patients from going from the chronic phase into the acute phase. While we know that the risk of that is about 7% to 10% over the first 3 to 5 years with imatinib, the emerging data with the newer drugs suggests that the risk of progression will be substantially below that.

The figures with nilotinib are somewhere around 2% to 3%, similar to that with dasatinib. So, we’re probably reducing the number of patients who progress over the first few years and at this stage, there’s no evidence that this is just a delay and that those patients who would have progressed on imatinib are doing it at a later time point on nilotinib or dasatinib. The figures, even now at 3 years, are very encouraging. We’re still seeing a difference in the rates of progression.

Unfortunately, what we’re not seeing at this stage is a difference in survival. It’s a little bit surprising, given the difference in progression, that we’re not seeing that reflected in improved survival. One think we need to recognize is that there are an equal number of deaths related to CML as there is unrelated to CML. In fact, there’s been a slightly higher rate of so-called CML-nonrelated deaths in the studies. It’s very difficult to know whether some of those deaths are actually related in some way to the toxicities of the more potent drugs.

So, lacking that difference in survival, it’s hard to mount a compelling case that patients should receive the more potent—and in most countries, more expensive—drugs first up. Certainly, the approach in Australia, in the trial setting, has been to use imatinib as the frontline therapy and, then, rapidly identifying patients who are not achieving deep molecular responses over the first 12 months and switching them, in the current trial in Australia, to nilotinib and also allowing patients who are intolerant to imatinib to switch to nilotinib. We’ve been impressed by the overall success of that strategy in that around about 65% to 70% of patients are able to remain on imatinib, which has a very good, long-term safety track record and is going to be the cheapest drug, by far, once it comes off patent over the next few years. So the approach is to give imatinib to the patients in whom you’re confident you are going to achieve good responses and then focus the more potent, potentially more toxic, second-generation drugs on those patients who clearly need them, as declared by either intolerance to imatinib or failure to achieve sufficiently deep molecular responses.

Now, an important consideration when you’re confronted with a new patient with CML is that you have to decide what your primary aim of therapy will be, because if it’s eventually to take the patient off therapy (ie, you’re aiming to achieve a sustained complete molecular response), it looks as though the more potent drugs are going to be a better strategy to get to that endpoint. More patients are achieving complete molecular responses on the more potent drugs than are achieving it on imatinib.1,2

In addition, in the most recent trial that we are conducting, called the ENESTcmr study, where patients who were still PCR-positive after at least 2 years of imatinib therapy were randomized to either continue their imatinib or switch to nilotinib. We showed in the 12-month analysis presented at ASH that at least twice as many patients achieved deep levels of molecular responses when they switched to nilotinib compared to those patients who remained on imatinib.3

So the evidence is becoming fairly strong that if your focus is the achievement of complete molecular response, with a subsequent aim of stopping therapy if that becomes possible, then the more potent drugs are an appropriate frontline strategy.

By contrast, if you’re looking at an older patient where the focus is not likely to be cessation of therapy, but merely to control the disease adequately and to give them good quality of life, then a strong argument can be made that imatinib might be a more appropriate upfront approach in that setting. So I think these are the factors that need to be considered when deciding what drug to use for a particular patient.

The other important factor that we haven’t discussed yet is the prognostic score. The evidence coming out from these randomized trials is that progression, and mutations, are predominantly seen in those patients who have intermediate or high SOKAL prognostic scores. For those patients, the benefit of the more potent drug is clearly evident. For patients with low SOKAL scores, very few are likely to progress on imatinib, so it is more difficult to argue that the more potent drugs would be advantageous.

So, the factors that would weigh in favor of choosing the more potent drugs would be the younger patient, where you’re focusing on the eventual achievement of a complete molecular response, and, hopefully, cessation of therapy, and the patient with a high SOKAL, where you are particularly focused on the reduction in the risk of progression.

OncologySTAT: Which factors do you consider in terms of genetic and biomarker testing at various stages?

Dr. Hughes: There are some interesting assays that are being developed in the context of clinical trials, but not really developed to a stage where they are relevant for the hematologist who is making clinical decisions today.

OncologySTAT: What is the evidence, at this point, surrounding treatment discontinuation in patients who have achieved long-term, complete molecular responses?

Dr. Hughes: The French study as well as the Australian study has both looked at the safety and effectiveness of stopping therapy in patients who have achieved a stable complete molecular response for at least 2 years. In both studies, there is a requirement that all of the polymerase chain reaction (PCR) results were negative on every occasion for 2 years before they actually stopped their imatinib therapy. The approach was successful for approximately 40% of patients. By successful I mean that they remained PCR-negative in a complete molecular response and did not require restarting the imatinib.4,5

Many of those patients have now been off imatinib 4 or more years and are still not requiring any restart of their imatinib. So those patients may well have achieved long-term drug-free remission, However, 60% of the patients do have a rapid development of PCR-positivity, usually within 3 to 6 months, and they need to restart their imatinib. It is important to note that nearly all of those patients have successfully achieved CMR once again, on restarting imatinib. So overall, with experience in over 140 patients, we know from these two trials that this is a safe approach.

We haven’t seen resistance to imatinib developing in these patients and we haven’t seen progression to blast crisis in any of these patients. So, it’s a safe approach in the setting of a clinical trial where there is very close observation, highly sensitive and reliable real-time quantitative PCR monitoring, and strict adherence to the criteria. We’re not recommending this practice should be conducted in the community because it does need very rigid PCR monitoring and close observation. However, it’s certainly an interesting and very encouraging result that suggests that in the longer term, we may be able to achieve drug-free remission for many of our patients who are currently on TKI therapy to CML.

OncologySTAT: So does this approach cure?

Dr. Hughes: Cure is a difficult word to define in the setting of CML. Presumably, cure would imply that the patient never has recurrence of their CML and dies of other causes many years later. That, of course, can only be determined in retrospect. So, it’s much more practical and measurable to talk about sustained complete molecular response off-therapy. That we can measure. Additionally, because we know that the vast majority of patients, greater than 80%, who will need to restart therapy do so in the first 6 months, you can very rapidly assess whether your strategy of ceasing the drug has been successful or not.

Now, at the moment, we have medium follow-ups of only about 3 or 4 years, but we may see over the longer term that some of these patients eventually do have recurrence of PCR-positivity and even develop CML once again. However, that will require much longer follow-up. So, we don’t focus on the word cure, we focus on the possibility of sustained drug-free remission.

OncologySTAT: Would you talk about TKI-resistant CML? What are the available treatment options? How and when do you sequence them and when do you consider transplant?

Dr. Hughes: There are two types of resistance to the TKI therapies, either primary or acquired. With primary resistance, we see an inadequate response to therapy right from the start. Now, it can be confusing because some of those patients will also go on to develop acquired resistance. I will first focus on primary resistance, defined as failure to achieve a significant reduction in leukemia over the first 6 to 12 months of therapy. These patients still have greater than 10% BCR-ABL1 transcripts as measured by PCR tests on an international scale at 3 months, and still have greater than 1% at 12 months. Those patients we recognize as being primarily resistant, whether they’re on imatinib, nilotinib, or dasatinib, they have a substantially higher risk of progression and they have a low probability of achieving a major molecular response (MMR) or going on to a complete molecular response (CMR). So we can recognize those patients very early.

What we don’t know yet is whether we can salvage those patients by switching to another TKI. That is something we’re testing in Australia at the moment. However, at this stage, we don’t have clear evidence that switching those patients to another TKI can adequately improve their outcome in the long term. This will be a subject of intensive study over the next 5 years I suspect.

It’s somewhat discouraging that those patients, when they are switched to another TKI, in many circumstances, don’t achieve deep molecular responses. In the future, we may have to consider whether those patients should be candidates for allogeneic stem cell transplant. But at this stage, we need further studies to really define what the appropriate approach is for patients who fail to achieve a 10% BCR-ABL1 level in 3 months or fail to achieve 1% by 12 months.

The second type of resistance that we see is in patients who achieve a good response and then subsequently lose it. The majority of those patients have kinase domain mutations that are the presumed cause of their resistance. It is clearly important that the proper mutation is identified because if you’re switching those patients to another TKI, as long as you avoid using an inhibitor that is resistant to that particular mutation, you’ve actually got a very good chance of getting a response to that second-generation drug.

So, for instance, if a patient who is on imatinib and has a good response later loses their response and there is a F359 point-mutation in the BCR-ABL1 tyrosine kinase, we know that this patient will do poorly if put on nilotinib, but would likely respond well if put on dasatinib. So it’s critically important when a patient loses their response to imatinib, and you’re considering your second line of therapy, that you know the type of mutation that the patient has acquired. Approximately 55% of patients will have a mutation detectable at that time.

Now, there is one mutation, T315I, that none of the first- or second-generation drugs is capable of controlling. For patients who have a T315I mutation, the current recommendation for patients who are eligible would be an allogeneic stem cell transplant. We do now have a third-generation TKI, which is undergoing clinical assessment, called ponatinib, which is fully active against the T315I mutation and the results of using that particular TKI in that setting looked very promising. However, we need more data before we’re confident that ponatinib is going to be an effective long-term approach.

OncologySTAT: Which of the newer agents under development appear most promising and where might they fit in with currently available therapy?

Dr. Hughes: I just mentioned ponatinib, a third-generation TKI that has been shown to be highly effective, at least in the short term, against the T315I mutation. So that may well become an appropriate drug for patients with that mutation who are not candidates for allogeneic stem cell transplant. Ponatinib is also looking promising in patients who are resistant to more than one TKI. Generally, patients who develop resistance to more than one TKI have a poor prognosis, but we’re seeing quite encouraging results with this third-generation TKI, ponatinib. I think we need more studies with that drug and more long-term follow-up, but it looks encouraging that it may be an effective option even for those patients with the T315I mutation and patients who have resistance to multiple types of drugs.

OncologySTAT: What message would you send to physicians treating leukemia out in the community?

Dr. Hughes: I’d like to send a message that today we have a number of highly effective TKIs to control this disease and it’s more critical than ever that we institute close, sensitive molecular monitoring over the first 2 years of therapy. During this period risk of progression is high and it’s during this period that there’s the most value in early intervention for patients who aren’t achieving appropriate molecular responses. It’s also the time where you might recognize, at an early stage, a significant rise in the level of BCR-ABL1 which may indicate either poor drug adherence or early evidence of acquired resistance. In that setting a careful review of drug adherence with the patient and ongoing close monitoring will facilitate a switch in therapy where appropriate. So, it’s critically important that in treating CML today that the clinician has access to high quality PCR monitoring which should be conducted every 3 months to determine a patient’s response to therapy and to allow rapid switching to another therapy if appropriate response is not being achieved.

References

1. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251-9.

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

3. Hughes TP, Lipton JH, Leber BL, et al. Complete molecular response (CMR) rate with nilotinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) without CMR after ≥2 years on imatinib: preliminary results from the randomized ENESTcmr trial of nilotinib 400 mg twice daily (BID) vs imatinib. Blood. ASH Annual Meeting Abstracts. 2011;118(21): abstr 606.

4. Mahon FX, Réa D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029-35.

5. Ross DM, Branford S, Seymour JF, et al. Patients with chronic myeloid leukaemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukaemia by DNA PCR. Leukemia. 2010;24:1719-24.

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My Approach to Chronic Myeloid Leukemia Interview by L Scott Zoeller. 2012 Apr 3, Tim Hughes, MD