Dr Andrew Davies and Dr Paul Fields 

PF: Hi, my name is Dr Paul Fields. I’m here at the British Society of Haematology in Edinburgh and I’m a consulting haemato-oncologist at Guy’s Hospital in London. I’ve really enjoyed the conference and there have been some really interesting new presentations on the treatment of lymphoma here at the conference. I’m here with a colleague, Dr Andrew Davies from the University of Southampton, who gave a presentation this morning in our lymphoma communications session where he described a new agent in the treatment of relapsed and follicular lymphoma. I’m going to ask Andy what his thoughts were about the new drugs, particularly in indolent non-Hodgkin’s lymphoma. Andy.
AD: So, Paul, I think it’s a really exciting time for follicular lymphoma and for new therapies. There’s a whole range of different agents, those that may be affecting cell surface molecules or those that affect disregulated pathways in follicular lymphoma and maybe those that affect the microenvironment, which as we know is absolutely critical as a driver in follicular lymphoma. So over the last years we’ve had data on the effectiveness of the lenalidomide.
PF: In the microenvironment?
AD: Yes, absolutely, and obviously the R-squared regimen where perhaps the rituximab augments the natural killer cells’ ability to perform ADCC.
PF: Yes, that’s a new combination.
AD: So that combination is exciting with very high response rates reported. You can see fantastic molecular responses, PET responses etc. So R-squared is very promising and obviously in the relevant study, which is a randomised study between R-squared and R chemotherapy, then that’s going to show some really important results. So I think lenalidomide is really interesting in follicular lymphoma.
PF: Yes.
AD: The story about ibrutinib, which is the BTK inhibitor, and how that’s evolving in follicular lymphoma is one that is probably an unanswered question yet. So we know that we get great data in mantle cell lymphoma and in CLL with ibrutinib but the studies with follicular lymphoma there’s one reported where the response rate is perhaps less than one would have seen with mantle cell lymphoma. So that’s evolving with ibrutinib but I think that’s going to be important. We see different monoclonal antibodies; we don’t know yet whether the effectiveness of the second generation anti-CD20s such as obinutuzumab, which has been shown to have superiority in CLL, whether that’s going to be useful in follicular lymphoma. So we’ll wait and see what GALLIUM study…
PF: It seems a lot of these drugs in CLL are being translated to non-Hodgkin’s lymphoma and the CLL field is slightly ahead in some of these compounds.
AD: Absolutely and we’ve got the PI3 kinase whole group of inhibitors and PI3 kinase is again disregulated in B-cell malignancies and has an effect on proliferation, cell survival…
PF: Apoptosis.
AD: Apoptosis, adhesion etc.
PF: Yes.
AD: So there are a number of PI3 kinase inhibitors and, of course, there are isoforms of PI3 kinase. So there’s the delta isoform which I was talking about today, but also there’s a number of other agents…
PF: Like the alpha.
AD: Alpha or pan-PI3 kinase, so copanlisib, there was a presentation about the effectiveness of copanlisib in a range of B-cell malignancies.
PF: So there are a lot of drugs that you can choose from. Just focussing more on the presentation that you gave this morning in which you specifically focussed on idelalisib in relapsed refractory non-Hodgkin’s, what are your thoughts? To me there are a lot of issues that when you see the novel agent the efficacy and the toxicity, what were your thoughts on the background to your presentation?
AD: Yes. I was talking about idelalisib, which is a highly specific delta inhibitor of PI3 kinase, so one of the isoforms. It’s orally active and I presented data on a single arm phase II study because in the phase I study there was some evidence to suggest that this agent, idelalisib, was going to have utility, hopefully, in indolent non-Hodgkin’s lymphoma.
PF: And this was a paper that was written up in the New England Journal?
AD: I presented an update of the data that was presented. So this study that I presented the update of it is a single arm phase II study of oral idelalisib which is given twice a day at a dose of 150mg. The key thing about this study is it was focussed entirely on patients who were refractory to rituximab and an alkylating agent. So every patient had either progressed whilst receiving rituximab and an alkylator or had relapsed within six months of having completed therapy.
PF: Which is key for this group. So a very difficult group of patients.
AD: Very difficult.
PF: And some of the patients had also had fludarabine and bendamustine as well.
AD: Absolutely.
PF: So the whole repertoire of drugs they’d seen.
AD: Yes, so I think 65% of people had had bendamustine previously; 11% had had a stem cell transplant previously. So we recruited 125 patients as part of an international collaboration; the last patient was recruited in October 2012 so I presented an update of the study. What we saw was that overall response rate was 57% with 10% of patients achieving a complete response which I think is a really impressive overall response rate.
PF: For this very heavily pre-treated group.
AD: Absolutely. Duration of response was some 13 months.
PF: So prolonged responses, yes.
AD: Fascinating.
PF: So you’ve mentioned overall response rate, which is highly significant for a heavily pre-treated group. So what about the other important endpoints of progression free and overall survival?
AD: The median time patients were on treatment for was about 6.6 months with a mean of about 10 months but some people had had 36 months’ worth of treatment. The progression free survival was 11 months. But what was really interesting is the progression free survival of their prior therapy. So that was a median of just 4.6 months whilst the progression free survival of the next regimen, of idelalisib, was 11 months. You remember that old data…
PF: So a fifth line treatment double.
AD: As it’s a median of 4 for previous therapies. But you remember that old data with chemotherapy that we’d seen from Barts and other places that the number of responses, the more times you’ve had treatment…
PF: The shorter your duration of response. So this is new changer, really. Prolonging.
AD: So it’s actually… to reverse that is really exciting.
PF: And would not be totally unexpected, given it’s working through a novel targeted biological pathway and not a chemo pathway. So that really is remarkable, really. And what about the overall survival in the group as a whole?
AD: I haven’t got a direct comparison, obviously, but the overall survival of the group as a whole was some 30 months. So it’s pretty impressive. And the deaths have been almost entirely due to progressive disease.
PF: Progressive disease. So they get good prolonged responses, have there been any toxicity quality of life issues with giving this, given that they’re very heavily pre-treated? Have you seen an increased incidence in infection or even side effects such as colitis, which has been described in this group?
AD: The major adverse event that has been reported was diarrhoea/colitis and actually 50% of patients at some point during their treatment did report an adverse event related to diarrhoea/colitis. The reason I use colitis in brackets is because actually not all of them had a formal diagnosis but had diarrhoea.
PF: They weren’t biopsied.
AD: But the number of patients who had severe colitis was obviously relatively small and it was about 24% of patients. We know that those patients responded to cessation of the drug and that actually, of those patients who came off drug, you could safely reintroduce the drug in the majority of patients with some dose modification when everything had settled down. What was key, though, about the diarrhoea is that actually we saw onset at a range of times. So, on average, the onset is about 7 months after initiation of treatment but actually we saw patients who developed colitis a year, even 18 months after initiating treatment. So I think it’s really important to remember that when you’re prescribing it, that actually it’s not an immediate effect like we may see with some other pathway inhibitors, actually it can be many, many months later.
PF: So it can be very late and the patients, critically, can still be on the drug. They can be just having the drug and suddenly this side effect can occur.
AD: So it’s education; it’s education to the patient, they need to know what they need to do if they get diarrhoea. And obviously us as physicians need to know how we should respond to the diarrhoea and always have it in our mind, even though the patient has been happy for the last 18 months.
PF: But critically you can re-challenge with a lower dose.
AD: You can re-challenge, yes.
PF: I guess it’s too early to tell but do you see a reoccurrence of the side effect?
AD: About half the patients who have been re-challenged have been re-challenged successfully.
PF: And what about other side effects?
AD: After having had, I should say, grade 3 or 4 toxicity. So after having had severe toxicity, yes.
PF: So we’ve mentioned the colitis but then the other commonly reported adverse effect here could be the abnormality in liver function tests. It’s commonly reported for this, particularly grade 1 and grade 2, what’s your view?
AD: Patients who develop grade 1 or grade 2 transaminitis, elevation of ALT and AST, those patients were safely continued on the drug. It was only those patients who developed grade 3 or grade 4 transaminitis that the drug was stopped and that was 18 patients in total. It settled down and with re-introduction of idelalisib, again at a dose reduction, three-quarters of the patients didn’t have any recurrence of this adverse event. So we are aware that it causes a degree of transaminitis, we need to keep an eye on it. We know how to deal with it and stop it but we can safely reintroduce if it occurs.
PF: So the take home message is that patients can still remain on the drug, even though they’re getting these adverse events and you can re-challenge the patients at a lower dose.
AD: We saw some haematological toxicity associated with it. There are numbers of patients who have a decrease in their neutrophil count and there are patients who have, a small number, who have a decrease in their platelet count.
PF: It’s interesting, in the entry criteria that quite a few patients… so they entered the study with their bone marrow function…
AD: Yes, I think this is really important. The neutrophil count cut-off was lower than one would expect; the platelet count cut-off was 50.
PF: To allow new entry and to take the drug?
AD: For a novel agent trial. And I think that just represented the fact that these were a heavily pre-treated patient population and therefore it’s great that they were able to go into the study.
PF: That’s very important for a group that have had four or five lines of treatment, particularly things like fludarabine and bendamustine. OK, that’s very interesting. So it really is showing promise, this agent, in the relapsed refractory setting. Obviously this is delta PI3 kinase isoform inhibitor but there are other class inhibitors in this group that are coming through. Having just been chairing a session, there’s also the alpha and delta inhibitor. What are your thoughts on the other class compounds in this group?
AD: Just to say, regarding idelalisib, the delta inhibitor, I think this is a group of patients where we don’t have very much in the way of conventional treatments to offer so I think the responses and the duration of responses that we’ve seen in this study that I’ve just presented are really important.
PF: I agree. I agree.
AD: But the whole field of PI3 kinase inhibitors is really one that’s exciting in B-cell malignancies. So there was a presentation about copanlisib which is a pan-PI3 kinase inhibitor but has particular activity in alpha and delta isoforms. It’s an IV preparation given day 1, 8, 15 of a 28 day cycle. George Follows presented data from the study looking at both indolent and aggressive lymphomas, demonstrating some very clear responses and a good safety profile. Interestingly, there was no colitis reported to date.
PF: They had a side effect with high glucose levels, didn’t they?
AD: That’s absolutely right. The alpha part of the pathway that’s involved in insulin homeostasis, glucose homeostasis I should say, and so there were some patients who had hyperglycaemia.
PF: But once again they could re-challenge them.
AD: Absolutely, well they treated them with insulin and it was a very early effect and didn’t recur.
PF: It wasn’t prolonged, no.
AD: So there were responses clearly in patients with follicular lymphoma but other subtypes, so that was very interesting. But also there are other PI3 kinase inhibitors coming through; there’s an agent called duvelisib, which instead of being selective for alpha or delta or pan, this is selective for gamma and delta. Again we’re seeing clear responses in patients with follicular lymphoma. So how all this is going to put together is going to be really fascinating.
PF: Yes. I was going to ask you that question because we’ve got these wonderful new drugs which previously many of these patients have had chemotherapy and these drugs have been used obviously in the relapsed refractory setting. But obviously the idea is to try and keep these patients going as long as possible with a quality of life. How do you see the field moving forward, given the evidence of all these different compounds? Where do you think it will move forward as a whole?
AD: I think we’ve got a lot of work to do in order to work out which patients will benefit from which type of PI3 kinase inhibitor or actually any of these new agents. I think that will come from us being able to better understand the biology and for us being able to better understand an individual patient’s tumour.
PF: Re-stratify the patients at diagnosis.
AD: Absolutely right. So I think we’ve got these fantastic response rates of idelalisib in a difficult patient to treat population. We’re now looking at that in combination with rituximab and bendamustine in a randomised phase III study and also in combination with rituximab in patients with relapsed indolent lymphomas. So I think we’re looking at the potential for combination with chemotherapy. There is clearly a lot of potential to put these together with other novel agents but what we’ve got to do is we’ve got to clearly understand the pre-clinical science so that we make sure that we make rational choices about our combinations.
PF: And balance it against toxicity.
AD: Yes, absolutely. And because these agents are going to have different toxicity profiles we’ve got to find the right toxicity.
PF: Another point would be a lot of the patients that we’re seeing who are down the road with their previous therapies will be elderly patients with comorbid conditions or on other drugs for other cardiovascular disease, pulmonary disease. So those side effects and toxicities which are unknown, really, the interactions will need to be studied.
AD: Absolutely and I think only through more careful clinical evaluation are we going to be able to work this out. But I think it’s a really fascinating and hopeful time.
PF: I think so as well. It’s very exciting, actually, to be a lymphoma doctor. We’re very lucky, we’re very fortunate. Thank you for joining us here at the BSH. We’ve had a wonderful conference and I hope you enjoyed our discussion about all these really exciting agents in non-Hodgkin’s lymphoma.