Managing CML:
Updated European LeukemiaNet Recommendations 2020

An exclusive two-part podcast with
Professor Richard Clark, MA, MD, MRCP, FRCPath
Royal Liverpool University Hospital, UK

This feature has been sponsored by Pfizer and contains promotional information.
PP-BOS-GBR-1043 | October 2020

Click here to view the prescribing information for Bosulif® (bosutinib)

BOSULIF® has been authorized under a conditional approval scheme. Since BOSULIF® has been granted a conditional approval, the company that markets BOSULIF® will carry out and submit the results of a larger study with BOSULIF® in patients with Ph+ CML previously treated with one or more tyrosine kinase inhibitors and for whom dasatinib, imatinib and nilotinib are not considered appropriate treatment options.

Bosulif is indicated for the treatment of adult patients with:

• Newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML).
• CP, accelerated phase (AP), and blast phase (BP) Ph+ CML previously treated with one or more tyrosine kinase inhibitor(s) [TKI(s)] and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.

The therapeutic landscape for treating chronic myeloid leukemia (CML) has gone through many changes in the past few years. These changes include the approval of several kinase inhibitors (TKIs) and the subsequent evolution of treatment goals for patients.

In 2020, an update to the European LeukemiaNet (ELN) recommendations for treating CML was published in Leukemia – seven years since the last update in 2013. These updated recommendations were compiled by a panel of 34 experts from across the globe who critically reviewed the published literature since 2013, as well as abstracts presented at recent international meetings.

These recommendations include updates on the use of baseline prognostic factors, definitions of response, first/second-line treatment options including patients with resistance mutations and more.1

In the first podcast below, Professor Richard Clark gives a summary of the main updates to the recommendations, and then more specifically on what the implications are for bosutinib following this update in the second podcast.

Part 1: 2020 updates in ELN recommendations for managing CML

“These are recommendations on the modern management of Chronic Myeloid Leukemia and the latest, the fourth in fact, in the series of ELN recommendations on CML, the last one being in 2013”

“They’re really reflecting updates in practice rather than a major shift in what one should and shouldn’t do in CML”

Transcript
Welcome to this podcast on the European Leukemia net recommendations that were recently published in March this year, 2020, in the journal Leukemia. These are recommendations on the modern management of Chronic Myeloid Leukemia and the latest, the fourth in fact, in the series of ELN recommendations on CML, the last one being in 2013. So, there's been a seven-year gap between these new recommendations and the last ones. My name is Richard Clark. I'm Professor of Hematology in Liverpool in the United Kingdom and I was one of 34 people who were on the panel that drew up these recommendations.

Of the 34 there's, I think, 10 people outside Europe. So, the majority are Europeans, some others from North America, one Australian, one from South Korea - so a real worldwide representation of CML expertise. Just a few general comments about the recommendations before getting into the meat of them, just to explain how the process works is that this is a kind of iterative process where it starts off with a series of questions, many of which are non-controversial. For example, do you feel you need to have molecular monitoring involved in modern CML management? Well clearly, the answer is a unanimous yes. So, there are many questions like that, and then, one passes onto the more contentious things where there's a series of questions that try to drill down to those problems. That's been the situation in past versions of these recommendations but this time, there was a little bit more face-to-face discussion of the more contentious problems at the main meetings EHA, ASH and the big CML meeting in September each year.

But the other general point I wanted to make is that it does state in these recommendations that they're primarily aimed at adult patients. And in fact, the NCCN guidelines, which came out a couple of years earlier from North American colleagues, don't address any pediatric issues at all.

Ok, so now, if I could go on to emphasize what's been changed from the 2013 guidelines, I think the first thing to say is they're really reflecting updates in practice rather than a major shift in what one should and shouldn't do in CML. So, let me highlight some of those. Firstly, there's more emphasis on the EUTOS long-term survival score as being perhaps a better tool of predicting CML outcome than the Sokal score, and there are data in there. But although ELTS may be better than Sokal, it's important to remember that even a high-risk group within the ELTS scoring system is still only conferring something like a 12% risk of dying of CML at six years. So, put that the other way up, 88% of the patients even in the high-risk group will be just fine, from the perspective of their CML after six years. So, it's still very difficult even in the high ELTS group to recommend a more aggressive approach, perhaps including a transplant, perhaps including a more risky drug for those patients.

And the other thing to say in relation to that idea is that there's quite a bit of space devoted to the presence of additional abnormal chromosomes beyond Philadelphia, at original diagnosis. That's based on published German data but the unpublished data from the SPIRIT 2 study, which is a British study which we've been looking at recently, suggests essentially pretty well the same findings as the German study on a group of patients that's almost as numerous. So, the findings that are in the ELN recommendations about abnormal chromosomes do seem to stack up more generally. There is some more detail in the new recommendations about additional diagnostic tests and this was to some extent, controversial. The first thing is the recommendation to do hepatitis B serology on everybody but that really comes about because of evidence that TKIs can reactivate hepatitis B in such individuals that are already positive. So, I'm not sure in practice what one does about that because if someone's positive, they still need their CML treatment because otherwise, things will go badly. I think it's really just to make awareness that hepatitis B can be an issue.

And almost similarly with doing cholesterol levels, lipase levels and ECGs, I think the decision about treating patients with drugs other than imatinib upfront is probably going to be made on other grounds from whether the cholesterol is high or not, but that's a contentious point, and you'll see that there aren't any firm recommendations in the recommendations as to what to do in the presence of a high cholesterol or lipase. There was a lot of discussion in drawing up the recommendations as to what to do for patients whose PCR remains above 10% after three months treatment. And that would be essentially, a failed early molecular response. And the discussion centered around where the patients who don't meet that, should be deemed failures and therefore a treatment change is recommended for those patients. As you may recall, if patients are in that situation at six months of treatment, in other words, the PCR is still above 10%, that is a failure. But the question was whether to bring that threshold forward as it were to three months. And there was quite a bit of discussion about that. Some of us felt that that was not necessary, you could safely wait for six months. Others felt strongly that if it wasn't right at three months, it was almost certainly not going to be right at six months so therefore, one should change straight away.

And so, there's a sort of compromised position which recommends rechecking the PCR level and if that's still above 10%, then the patient should change. And I think that's probably reasonable because if you think through the timeline of how a three-month test works, it might take let's say, a fortnight to get that result back, it would take another fortnight to get the patient back to the hospital or the center and do another blood test and it will then take another fortnight still to get that result back. So, one's not far off six months by the time a repeat sample is going to be there. And if that's still above 10%, then it may be perfectly reasonable to recommend change. But that's again, nuance with the individual's circumstances.

Another thing that was quite contentious was, whether treatment-free remission, in other words, stopping treatment for the patient who's been on treatment for a while, should be a goal. And I think it revolves around the semantics of what you think a goal is. If you think that the goal of treatment is to stop treatment – I think many of us felt that was wrong – but it certainly is in the modern era, something that one is aspiring. And one has to contrast the group of patients who perhaps are older, who get into a very good position with their CML on treatment and would really feel quite uncomfortable about stopping treatment because the drug is their security. And contrast that with perhaps a younger patient who has some side effect, which may not be that serious in the greater scheme of things but does interfere with lifestyle and that sort of patient may be very keen and almost desperate to stop treatment. So, it is nuanced to the individual patient.

The recommendations of 2020 do include some requirements for a treatment-free remission and most of those are fairly sensible on the side of things. There are some changes to the first-line recommendations that the bosutinib is now included as one of four possible drugs that can be given first-line. And for the second-line recommendation, bosutinib is added. In the previous recommendations, there were certain scenarios which had to apply for bosutinib to be supported. And those are now removed, bosutinib can be used just in second-line use just as any of the other drugs can be. Also, ponatinib has been removed from the second-line setting because unless the patient has T315I, there are probably better or at least safer alternatives to ponatinib. So, that's no longer supported in second-line use for the non-T315I patients.

One thing that's important, it was there in a different format in earlier recommendations, is the importance of checking BCR-ABL kinase domain mutations in patients who are failing their first-line drug. That's set out in table five in the recommendations and that's important because it's often forgotten. There's a small study from the UK looking at how compliant colleagues are in actually doing those mutation screens at failure and we're actually not very good. We might think we are and we might write it in guidelines, but the practical implications is that we're not actually good at remembering to check for kinase domain mutation. And that's an important point. Having checked for kinase domain mutations and not found any, the question is what drug to use. And really, the recommendations don't tell you. What they do say is that any of the four drugs, other than ponatinib, and any of the four available tyrosine kinase inhibitors, are fine. And the choice between them is depending on so-called patient-related factors, which include age, comorbidities, how the patient got on with their first-line TKI.

Very briefly, I think in patients with significant renal impairment, particularly where that's at risk of deterioration, it may be wise to avoid imatinib. Secondly, in patients with significant lung disease, it may be wise to avoid dasatinib because that is associated with about with pleural effusions in about 30 to 40% of patients. And although these might be trivial, that can make all the difference to somebody with severe, for example, pulmonary fibrosis or chronic obstructive airways disease, but clearly in someone with mild asthma, this would not be such a significant issue.

Thirdly, in patients with significant arterial disease that scenario would be, other things being equal, a situation where we would want to avoid nilotinib as first choice of drug and appropriate if we're talking about third-line setting, also avoid ponatinib simply because both of those drugs have a small but clinically important excess risk of further arterial disease. In the case of bosutinib, there appear to be no extra risk of cardiovascular events or of pulmonary events with the use of bosutinib and that's looking at the long-term follow-up of the use of bosutinib in earlier trials, as well as the BFORE2 study, which is less mature.

One additional issue that's not actually in the recommendations is diabetes, particularly type two diabetes, where nilotinib may well alter the blood sugar and tip the patients who are well-controlled on diet alone to needing oral hypoglycemics or indeed those who are already on oral hypoglycemics may be converted to needing insulin. So, these are issues to bear in mind. But again, there could be very good reasons to use nilotinib at certain patients perhaps because of a mutation pattern that would favor that drug rather than others.

And finally, I just wanted to mention the recent British Society of Haematology guidelines, which on the face of it might appear rather unnecessary because the ELN guidelines have been published in March and the BSH guidelines came out, I think in July. So, why do we need another set of guidelines? Well, I think there are some issues partly because of space, were not as well-covered in the ELN recommendations as they might be. One of those issues is, how to manage side effects from these drugs because the presence of a side effect doesn't always mean that you have to stop the drug. Sometimes a side effect, perhaps a rash, will go away after a short period of stopping the drug and doesn't reappear in a clinically troubling way to the patient. When you restart that drug, you might need to restart at a lower dose and build it up. So, a side effect of itself doesn't mean that the drug has to be stopped or changed.

And there are some scenarios which are discussed in the British guidelines, which perhaps are useful to clinicians. And a further point about the ELN recommendations is that they don't cover the practice in children that well, and the BSH guidelines do cover children and make some recommendations. And they also extend the ELN recommendations on parenting and CML, coping with the scenarios firstly of women who want to start a family and what do they do about their TKI and they come down reasonably on the position that all TKIs are potentially dangerous in pregnancy and should be avoided despite the move amongst some in Europe to advocate imatinib in later pregnancy, I think the British position is not to do that. And also to cope with the scenario of women who inadvertently do conceive whilst on the tyrosine kinase inhibitor, how to manage the CML in that scenario and how to manage the pregnancy as there would be a potential risk to the unborn child.

So in summary, I think armed with the new 2020 recommendations from ELN, perhaps supplemented by the British Society guidelines published just three or four months later, that this may be a very good armamentarium to go into the CML clinic with, forthwith.

Part 2: Updated recommendations specific to bosutinib

“Recent changes to the recommendations do support the use of bosutinib in either the first or the second line settings and in a group of patients who may have other comorbidities for which bosutinib is not a contraindication”

Transcript
Welcome to this podcast on the European Leukemia Net recommendations that were recently published in March this year, 2020, in the Journal Leukemia. My name is Richard Clark. I'm Professor of Hematology in Liverpool in the United Kingdom and I was one of 34 people who were on the panel that drew up these recommendations. These are the fourth iteration of the ELN recommendations, and it's seven years since the previous ones which came out in 2013. And what I'll be specifically focusing on here are the implications of these new guidelines for the use of the bosutinib within CML. So just to give a little background as to how these recommendations evolve, they come from a series of iterative questions that are circulated to the 34 members of the panel.

And many of these questions are very straightforward and there's rapidly unanimity, but some are more controversial, and these require further, more specific rounds of questions to drill down on what people think about more detailed aspects of some of those more controversial points. One thing that's changed, and I'm not going to discuss all the changes in the 2020 version compared with 2013, but one of the things that has changed are the recommendations for first- and second-line therapy. And in relation to first-line therapy, bosutinib is now added, and that's in the light of data emerging from the BFORE2 trial, which is ongoing, but for which there are one year and 18 months and, I think, two-year data available. The two-year data's not published, but it has been presented so it's in the public domain, and the 18-month data, likewise.

So bosutinib is now available as one of four TKIs that could be used for newly diagnosed patients. The other change in relation to bosutinib is in relation to second-line treatment. There were some caveats to using bosutinib as a second-line agent in the early recommendations, which are essentially now removed. So, the choice of second-line agent is really, again, free between the same four agents that were available for first-line use like imatinib, dasatinib, nilotinib and bosutinib. Ponatinib has been relegated from routine recommendation for use in second-line treatment to third-line and beyond and that is because of the significant risk of arterial events, especially in patients who already have had arterial events. So, it's best avoided, even in the second-line setting with the exception of patients who have the T315I mutation, which is not really accessed at all by any of the other four drugs. So it's Ponatinib or other TKI in essence, but outside the T315I setting, then Ponatinib is contraindicated in the second-line setting.

The reason for changing the recommendations, particularly for bosutinib is because of changes in product labels and the new clinical data that have emerged since the 2013 recommendations, particularly in the BFORE2 study and that's ongoing and it may well be in the next year or two, there'll be additional data from that study. That poses a problem for the clinician in making a decision both in first-line and indeed in second-line between these four drugs and the recommendations do set out a variety of clinical scenarios because of comorbidities, particularly where one drug may be a better choice than another.

Very briefly, I think in patients with significant renal impairment, particularly where that's at risk of deterioration, it may be wise to avoid imatinib. Secondly, in patients with significant lung disease, it may be wise to avoid dasatinib because that is associated with about with pleural effusions in about 30 to 40% of patients. And although these might be trivial, that can make all the difference to somebody with severe, for example, pulmonary fibrosis or chronic obstructive airways disease, but clearly in someone with mild asthma, this would not be such a significant issue.

Thirdly, in patients with significant arterial disease that scenario would be, other things being equal, a situation where we would want to avoid nilotinib as first choice of drug and appropriate if we're talking about third-line setting, also avoid ponatinib simply because both of those drugs have a small but clinically important excess risk of further arterial disease. In the case of bosutinib, there appear to be no extra risk of cardiovascular events or of pulmonary events with the use of bosutinib and that's looking at the long-term follow-up of the use of bosutinib in earlier trials, as well as the BFORE2 study, which is less mature.

So what are the overall implications for bosutinib in terms of these new recommendations? I think these recent changes to the recommendations do support the use of bosutinib in either the first or the second line settings and in a group of patients who may have other comorbidities for which bosutinib is not a contraindication.

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