PH: Hello. We’re reporting from San Francisco from the current annual ASH meeting and we’re talking about the updates and exciting updates in chronic lymphocytic leukaemia, CLL. I’m joined by two very good friends, Clemens Wendtner from Munich and Uli Jäger from Vienna, who will discuss their thoughts about the meeting and CLL. So first of all, welcome. We’ve had a very interesting ASH so far. One important piece of data has been around the definition of new therapies and what chemo-immunotherapies we should use in CLL in fit patients. Certainly a German study has reported a follow-up to CLL10, what are your thoughts about CLL10? What’s the message from this trial?

CW: CLL10 was a randomised trial comparing FCR versus BR in front-line fit patients with CLL. So the main outcome was that the PFS for FCR is superior to BR so BR, if you want, was the loser. But there’s always a however. The toxicity was also much more increased with FCR, especially in the elderly, above the age of 65. So what would we conclude from this trial? I would say FCR is a very good option for very fit, especially young, patients with CLL but BR is a good option for elderly fit patients.

PH: Because that trial recruited patients who were considered fit for FCR and didn’t plan to look at the elderly group, the more elderly group, they’re still young for CLL, 65-70 in age, do you think we can conclude from that trial that the BR is suitable or acceptable for patients who are above 65?

UJ: I think so. I mean, many of these patients will have comorbidities and over the age of 65, to my mind, BR is the winner to be honest.

PH: I think it’s probably a little bit early to say because we’ve got a relatively early follow-up. Certainly from other parts of Europe where BR isn’t as prominent, perhaps, as in Germany and Austria, we probably would want to see a confirmatory study to look at that group of patients.

CW: You’re right from a very statistical point of view. The sub-group analysis was not powered for age so that’s correct but I agree with Uli that in the end we have to do, or draw, a practical conclusion and having in mind that you have more than a doubling of severe infections above the age of 65, let’s put it this way, I wouldn’t put my grandma on FCR.

PH: And there was another paper that was also presented by the German group looking at MRD from CLL8 and CLL10 suggesting that MRD may be an important marker, your thoughts about that study?

CW: Yes, that’s correct. MRD seems to be one of the most prominent and also independent markers based on these big phase III trials. It’s been shown that even in patients with PR, so partial remission, that had an MRD negative status, they were doing as well as patients with a CR. So in this case, for example, didn’t count.

PH: And looking at the data, the data that was presented was for blood MRD assessment and I think bone marrow is probably a more informative tissue and I think we need more data.

CW: I agree.

PH: But one of the questions is in patients who don’t have an optimal response to chemotherapy, who are MRD positive in partial remission, people are interested in consolidation and there have been two important studies, one from Austria, and a further study looking at maintenance with antibodies. Your thoughts about those two trials?

UJ: I think we can discuss them together because they were very similar in their outcome. One was with rituximab, the one led by the Austrian study group, and the other one with ofatumumab. It’s quite clear that by doing maintenance with antibodies you can prolong the progression free survival, you can prevent relapses, that was one of the major messages of the Austrian study, and you can probably deepen the remission, that’s what you were alluding to, I think. That’s a very valuable option because a prolonged, deeper remission will lead to a prolonged progression free survival, so that’s important. What’s lacking here is certainly the information on overall survival – will that impact finally on the overall survival?

PH: So it was a relatively short follow-up. There is a cost to pay, of course, in terms of toxicity and both of those randomised trials, rituximab or ofatumumab maintenance, did show an increased risk of infections.

UJ: That’s true, yes. In fact we were participating in this study and we’ve seen that but the risk-benefit ratio is still quite good and I would certainly see this as a very valuable option. If you think of the other molecules that are currently in use, they are also kind of maintenance treatment.

PH: This is true. I think one of the issues with the prolonged study, with the ofatumumab study, was that if you look at that data both the rituximab and ofatumumab maintenance studies had 24 months of maintenance and then stopped. The follow-up is relatively early but there seems to be a relatively quick relapse after stopping maintenance. Do you think two years is the right duration of maintenance? Should we be going longer?

UJ: Here toxicity may be important so I don’t think that we have enough experience to just prolong treatment and we should go with these studies in terms of evidence. We should say that finally we have randomised trials for this question, we were lacking this data and now we have this data, and I would think that we should go with… if we apply it to our patients we should go with the schedule that the two studies used.

PH: So I guess the question that we ask in those studies is is progression free survival the appropriate end point for such trials because these patients would not be on treatment otherwise and if we delay time to the next treatment we might be able to salvage them with treatment and therefore not intervene. Do you think we need to wait longer to see the outcomes of secondary responses and overall survival or do you think we have enough evidence on the current data to change practice?

CW: Honestly I think we have to wait for a very long time to see a really significant difference with respect to overall survival because we know nowadays, at least in many European countries, we do have access to these novel drugs like ibrutinib and idelalisib so it will take a long time until we would conclude on this endpoint. So I agree with Uli that these two maintenance trials are very important, even with the PFS endpoint. We do see that especially patients with some partial remission, still some tumour burden, they benefit probably most from this kind of intervention. I think this is a kind of alternative, even from the budget point of view, with the new novel drugs. We also have to think that we have to be very responsible with the money we are spending.

PH: So when we have, if you like, defined the best chemotherapy, or as much as we can, and we have consolidation on maintenance approaches, you mention and refer to the new era of drugs – it’s remarkable to think we’re only three or four years into this revolution of ibrutinib, idelalisib, ABT-199 and a number of other drugs we’ve heard about at the meeting today, this week. What are your thoughts about the new data, for example with ibrutinib we’ve seen some new data today?

CW: Yes, ibrutinib has shown impressive data even in high risk CLL so there was an impressive presentation by Susan O’Brien showing, especially in this high risk group, also very long PFS times, very impressive responses. The same is true for idelalisib.

PH: So the ibrutinib trial you refer to was 17p deleted so really the worst, relapsed 17p deleted and we were involved in that trial. I think 144 patients but relatively short follow-up still but really impressive responses. And we’ve heard data earlier regarding idelalisib and last year at ASH we saw the 116, the first randomised data, very immature follow-up at that point. Your impressions about the further information we’ve had on this occasion?

UJ: I think it’s in the same league as ibrutinib, I think we can say that. They are a bit different in side effects but only a bit, I would say. There is a difference because rituximab is used in conjunction with idelalisib so it will be hard to compare these treatments head to head. But, to my mind, it’s a very good alternative and the important questions for us will also be if a patient relapses on one of these agents can we use the other ones to rescue the patient?

PH: Yes, Jeff Sherman showed the results of the 0116 trial and also showed that in that trial patients with 17p or 11q deletion treated with the idela-rituximab arm did equally well as the patients who didn’t have those high risk markers, whereas the rituximab patients, actually the 17p still fared worse than the non-17p patients. So I think we agree that both of those two new agents are effective in the very high risk disease.

CW: If I may add one point, I think there’s still the question of what will we do with younger patients after they have been treated on these new agents, so the question of allogeneic transplantation comes up. There was also an interesting abstract how we might try to figure out this very specific patient group that’s also going to allogeneic transplantation after these novel drugs have been used and complex karyotype carriers with a cytogenetic abnormality besides the simple deletion of 17p. These might be the patients that should be also sent to allogenic transplantation even if they are still in a remission. So this might guide us a little bit to figure out the ultra-high risk within this group.

PH: So we saw from the MD Anderson the data with complex karyotype and 17p, I think we need to look at that in more detail. We don’t have prospective trial data for that and using cytogenetics will change, significantly change, the way we have to investigate patients. So I think we probably need to study it in our larger trials. You, Uli, alluded to the use of rituximab with idelalisib, do you think that we actually need to use rituximab with idela?

UJ: Well, the trial is there. We have done previous work in the laboratory that rituximab also signals through the PI3 kinase pathway. There is obviously, when you look at it, data that there is an improvement when you add rituximab but that may be mainly due to the ADCC action of rituximab and not to the direct signalling. What will be really interesting to see is how the other combinations, like with bendamustine, will do. It may be even better to have a chemotherapy attached to it and that is, by the way, one of the questions that we have to ask if we do these long-term treatments because the patients will be on those two drugs, ibrutinib and idelalisib, until they progress or relapse. Then, of course, will that be our new paradigm or should we go for combinations that bring deep remissions and then stop?

PH: Just regarding the idelalisib data, we will have some data without rituximab because of the crossover patients, we haven’t got that information yet. There are a significant number of patients who crossed over to single agent idela and one of the key questions which we still, in my opinion, aren’t certain of is is the apparent improvement with rituximab cosmetic? In reality we talk about combination therapy but the first six months is combination and after that it’s monotherapy with idelalisib. So it may be different with the other antibodies and we have more effective antibodies – ofatumumab, obinutuzumab – that we’ll have to see the combinations. Imagine the issue, really, of prolonged treatments and we mentioned also when we were talking about maintenance the antibodies. So there was a very interesting abstract looking at ABT-199 for the first time in combination, your thoughts?

UJ: Well, this agent, Venetoclax as it’s called now, may be different, it may be more effective, at least in this combination because there is quite a substantial number of complete remissions and even molecular remissions. That points, let’s say, to more activity and here we may have the chance to go for a stop trial while with the others probably not, at least not in the combinations they’ve been used so far.

PH: And in that trial we had 13 patients that achieved MRD negative remissions, as Uli alluded to, and also some patients had even stopped treatment. Your thoughts about, I think, five patients who came off therapy?

CW: This is a new paradigm with these new drugs because it seems that there’s not a popping up of the disease when we just interrupt therapy. So I agree that ABT might have another quality and might help to just cycle for a specific time with treatment but then we can stop and observe. This has been shown in combination with rituximab, there are early data also of the combination of ABT and GA101 and there’s a small trial, we also took part, with ABT plus BR, so also the chemo-immuno part has been added.

UJ: But, if I may add, this comes with a price and that’s toxicity up-front. I think we have to learn how to handle this agent, it’s a different weapon, I would call it a weapon, and you have to really make sure that tumour lysis does not occur. So we have to handle it carefully.

PH: So we change the way we start with ABT-199, we’ve much more slowly built up. We’ve got experience in my group and it seems to be manageable but it’s certainly not without its difficulty.

CW: Besides this ramping up dosing, we also try to reduce this kind of tumour lysis danger in the beginning. So in a new trial of the German CLL study group we will start just with GA101 and add the ABT on day 22, so after three weeks. So this might help also to get rid of this fear.

PH: So trying to debulk the patient first?

CW: Exactly.

PH: Of course we can use the other drugs, the ibrutinib and idelalisib in the same way because you see such a rapid reduction in lymph nodes very quickly with those agents. So we have a lot of new treatments and we’re starting to get combinations of therapies now, which combinations would excite you the most? Where do you think we’re going to be moving in the next year or two with the data you’ve seen at this meeting?

CW: My personal favourite is ABT plus a very potent anti-CD20 like GA101, this would be my favourite.

UJ: I would disagree a bit because the other two agents are certainly very safe for the comorbid and elderly population. We may see that ABT is substituting more for FCR than for anything else, could be, I’m just speculating. I see it more in the younger fit population. The other two, of course, in any respect I would still be interested in combinations and particularly with chemotherapy. The issue of having a chemo-free treatment is not resolved and if we believe in the concept of getting good remissions, maybe MRD negative remissions, and then keep the patients off treatment for a long time, we will have to combine them.

PH: Certainly the excitement of that approach and the fact we’re stopping, the same with ABT plus rituximab, stopping therapy and the remissions are longer than the people have been on treatment is very encouraging that that’s an approach. If we’re going to move these therapies, which I think we all are trying to do, into patients who aren’t refractory, the earlier patients, then we really have to abbreviate the therapy and get better remissions quickly. Whether that’s with chemotherapy, with combinations of small molecules, with antibodies or with all of those things, but we need to really get down to shorter durations for, not just cost for the patients, tolerability and the risk of resistance. So I think we’ve had a very exciting ASH, we’ve had a lot of new therapies that have been developed and combinations. We’ve seen the next generation of the trials coming along where we’re seeing MRD negative remissions, we’re seeing improvements on chemo-immunotherapy and it really augers well for the future. So from a not so sunny San Francisco, thank you for your attention and thank you Uli and Clemens.