ASH 2013

Exciting new developments in the treatment of multicentric Castleman disease

Prof Nikhil Munshi - Harvard Medical School, Massachussets, USA
Dr Raymond Wong - The Chinese University of Hong Kong

Hello, I’m Nikhil Munshi from the Dana Farber Cancer Institute in Boston and I’m with my colleague here, Dr Raymond Wong from The Chinese University of Hong Kong, and we both are here to be part of the ecancer medicine discussion on multicentric Castleman disease which end up calling MCD. We’re going to discuss, Raymond, about this very uncommon disease, do you want to tell our viewers what MCD is, it’s so uncommon?

Yes, multicentric Castleman disease is actually a very rare lymphoproliferative disorder and patients will present with enlarged lymph nodes, they present with a variety of inflammatory symptoms, fatigue, weight loss, night sweats, fever and they also have a number of problems such as anaemia which have a severe impact on their quality of life. This disease is also potentially fatal.

So it’s a very uncommon disease so our colleagues are not going to see it as frequently. Maybe we should tell also how do we investigate the patient when somebody comes with a lymph node that’s not really lymphoma; a biopsy, of course, is the first step or the main diagnostic thing but some blood tests that maybe they should do?

Yes, you’re right that a lymph node biopsy is very important to exclude lymphoma and also which helps establish a diagnosis. We should also do a quite comprehensive work-up because this patient will have a number of problems, anaemia, they will have some elevated inflammatory markers, CRP, ESR, etc. etc. So we also need to look for any other associated problems. For example, Castleman’s disease is certainly associated with POEMS syndrome so therefore we also need to work up these patients and to look for any other problems.

Doing CRP and, if available, and we’ll talk about challenges, interleukin-6 levels are quite important as markers. It may or may not drive the disease or the treatment but it needs to be done. Also immunoglobulin levels, their polyclonal gammopathy, so doing quantitative immunoglobulin sometimes is helpful. They usually don’t have M-spikes so you can do SPEP but that will be negative.

Yes.

So that brings about what are the challenges for physicians who would see very occasionally a patient with Castleman, what can we tell them the challenges would be?

As we have mentioned, this is a very rare disorder so therefore the physicians and the patients are not familiar with this. Also up to now there is no standard of care for this disease so therefore treatment is also another challenge.

That’s very, very true and also the tests might not be available everywhere so you and I can do interleukin-6 levels but people in the community may not have access to it as easily although in the US it is becoming more easier done in private labs. I think CRP is a good surrogate which probably could be done in most of the places and, as you mentioned, anaemia, thrombocytosis could be something that they can follow quite easily. I think the biggest challenge, I feel and I would love to see what you think, but the biggest challenge is good pathological diagnosis.

Exactly.

Because pathologists, like physicians, don’t see it very often and so they make mistakes. Do you think people should get a second opinion on the pathology?

Yes, certainly. Because even the pathologists may not have experience of reading so many lymph node biopsies with Castleman’s disease so sometimes they may not be certain about whether this is a case of Castleman’s or not. So in that case they should actually send the specimen to actually seek a second opinion to confirm the diagnosis.

That’s very important and part of what we are doing is trying to increase awareness of this disease. There was an analysis being done that maybe Castleman’s disease is not so very, very uncommon as we think; it may be more common. So we have to think of some ways of increasing their awareness and one is what we are doing right now. Any other ideas we can think of of how to increase their awareness?

The education is still the most important point. We have to educate not only the physicians but also we have to tell the patients that, yes, this Castleman’s disease can actually exist and it can cause these kinds of symptoms and it can cause enlarged lymph nodes. So if they’ve got these sorts of symptoms and enlarged lymph nodes they should seek advice from their doctor. And if the doctor is also aware of this condition then if their problem is making the diagnosis then they should certainly refer it to specialists to get the proper diagnosis made.

Yes, that’s the main thing, to suspect the disease - once you think about the disease you might diagnose it. Quite often people don’t look at it because they don’t think about it. So once the diagnosis is made I would think a CT scan, doing from neck to pelvis CT scan, is important to see where the lymph nodes are, where are the disease-related lymph nodes that we may follow? But then treatment option is the next thing we should discuss – what are the treatment options? And we’ll go to the main new treatment option, siltuximab, in a minute, but what other treatment options are currently available?

Up to now there’s no approved treatment for the MCDs but conventionally people have been using corticosteroids or other treatments for lymphoma such as chemotherapy or rituximab for treating these patients.

So rituximab and [?? 5:46] are the two good ones; the chemotherapy, people have used it and there are cases where there’s shrinkage but I don’t think there’s a long-term impact of those treatments. So that’s where the evaluation came up with the anti-IL6 antibody; would you want to tell our viewers something about the antibody and maybe what the results of this study are?

In the ASH meeting 2013 we are going to present the abstract of the study which is a multicentre randomised controlled trial trying to evaluate the use of siltuximab, which is a monoclonal antibody targeting interleukin-6, for the treatment of these patients with multicentric Castleman’s disease. Now in these studies we have randomised patients who have got symptomatic disease, who are HIV negative, HHV-8 negative, to receive either siltuximab or placebo. These patients are also allowed to receive the best supportive care. Now in this study we have found that about one third of our patients who received siltuximab actually achieved durable tumour and symptom response. The symptom and also the tumour response actually last for at least eighteen weeks but this kind of response has not been seen in patients randomised to the placebo arm. So this is a very exciting result. In addition, we have also seen that one out of four patients allocated to the siltuximab arm actually achieved a complete resolution of all the symptoms related to MCD for at least eighteen weeks. So, again, this is very exciting. We have also shown an increase in the haemoglobin level and also rapid and significant reduction of all the inflammatory parameters. So we have seen a lot of these patients actually benefit from the treatment. On the other hand, the safety profile of this new drug is also very good because we have not seen any excessive side effects when compared with the placebo arm, although the patients who have been treated with siltuximab have actually received the treatment for much longer duration compared with the placebo so illustrating that this drug is actually pretty safe. In terms of infusion reaction we have less than 10% of patients having this reaction and we only had one patient who got a grade 3 anaphylactic reaction. So overall the safety profile of siltuximab is actually pretty good.

So what you described and what we both were part of for this exciting study in such an uncommon disease, we were able to put the patients on, randomise them, this is the first ever and probably the last randomised study to be done in Castleman’s disease, and it clearly showed that compared to best clinical practice, current practice where there was no response, there were significant responses in patients who got anti-IL6 antibody. What you brought up which should be highlighted is that patients have declined in their lymph node size but, very importantly, what really causes problems for patients is their symptoms and there was a very significant symptom improvement. The study included a lot of symptom evaluation criteria in it.

Yes, we have a very detailed assessment of the symptoms including 34 different symptoms, including some general symptoms, some related to neuropathy, oedema, the skin changes etc. So this is a very comprehensive evaluation of these patients.

So how do you think… what would be the best way to put patients on this treatment now? Which patients should be included for treatment with siltuximab as we move forward, as and when this drug becomes commercially available?

In this study we have actually recruited patients who were treatment naïve and also we have patients who have been pre-treated before. In the sub-group analysis we have seen that both groups of patients actually show a similar response to siltuximab so when this drug is available in the market those patients who have got a symptomatic disease, who’ve got enlarged lymph nodes, they are candidates for receiving siltuximab.

Very good. The final question comes up, with this new, very positive, result and the drug becoming available, how do you think the treatment practices will change in this disease?

I think there will certainly be a major change in the treatment approach to patients with MCD since this will be the first licensed approved treatment for MCD. A lot of patients will benefit from this drug. Of course, there are certainly some patients who may not respond that well so, again, we should try to investigate further how we should manage these patients. So probably we should have more clinical trials and we should put these patients into clinical trials to see how we should treat these patients appropriately.

You summarised it quite well because this study now changes the clinical practice in this disease. This is now a really validated randomised study-proven drug that works in multicentric Castleman’s disease so when patients are diagnosed with it one would consider, you and I would consider, using siltuximab as part of the treatment and, depending on if they respond or not, can decide how to follow up. Any final thoughts on follow-up of these patients?

The patients that have been recruited into the randomised controlled trial must still continue on the treatment and we are now putting them into extended treatment, so protocol. So hopefully we will get more data about the durability, how sustained the response will be and the follow-up data.

Thank you very much for watching and thank you very much to ecancer.tv for providing this educational effort. Thank you, Raymond, for joining me in discussing Castleman’s disease, its treatment and how siltuximab will play a role in this disease.