Standing from the crowd in refractory CLL?
Last year the two FDA approvals of tisagenlecleucel (Novartis) and axicabtagene ciloleucel (Kite/Gilead) CAR T cell therapy for hematologic malignancies such as pediatric acute lymphoblastic leukemia (pALL) and non-Hodgkins lymphoma (NHL) have captured a lot of attention.
It’s worth remembering, however, that back in 2010 the first patient who had a dramatic response to CD19 targeted CAR T cell therapy was actually a gentleman with advanced chronic lymphocytic leukemia (CLL), the case study of which was subsequently published by Porter et al., (2011) in the New England Journal of Medicine.
We’ve been following CAR T cell therapy and its potential in CLL for some time now, with all the successes, trials and tribulations along the way.
Dr David Porter (Penn) told BSB earlier this month:
“The very first patients we treated are now eight years out from their infusion, a little over eight years, and still in remission, still doing extremely well with no evidence of disease or progression, never had any other therapy. So, I think it’s become very clear that for some patients this is effective in the far advanced setting.”
It’s now two years since we last spoke and it was a great pleasure to reconnect with Dr Porter. As he told BSB at ASH in San Diego:
“One way you make it better is to understand why it’s working and why it’s not.”
What have we since learnt about the potential for adoptive cellular therapy in CLL and what new insights did we gain from new data presented at ASH18? The answers may well surprise you.
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Buried amongst the intense hurly burly of a major medical meeting such as the American Society of Hematology (ASH) are the unsung preclinical researchers whose work largely makes clinical development possible. After all, few sensible companies would bet on an expensive clinical trial program, especially in combination, without first knowing whether such an approach is rational or not and has a decent shot of working efficaciously.
At stake here is the potential for building a blockbuster cancer drug niche by niche.
Venetoclax (BCL-2 inhibitor) got off to a somewhat slow start compared to say, ibrutinib (BTK inhibitor), which had a much broader initial indication and a lower risk of tumour lysis syndrome (TLS), yet it may actually have a wider application across multiple hematologic malignancies. This could well end up as one of those classic tortoise versus hare stories in the long run.
Back in 2013, we posted five interviews conducted with a range of experts including:
- Dr Oliver Sartor (prostate cancer)
- Dr Susan O’Brien (CLL)
- Dr Deepak Sampath (BCL-2 and ABT-199)
- Dr John Jenkins (then deputy director at the FDA)
- Dr Renier Brentjens (CAR-T cell therapy)
To put this in context, consider that we just recorded 15 interviews at ASH this year alone!
As regular readers know, we like to follow people and R&D stories over time, so while in Atlanta at ASH17 we took the opportunity to move a particular story forward – we wanted to learn where Dr Sampath and his colleagues are now and also where they are headed next. This gives readers a head start on anticipating what future clinical developments might be mentioned at JPM18 by either Genentech/Roche or AbbVie.
In our latest expert interview, we pick up and continue the discussion with Deepak Sampath to find out what’s happening with venetoclax four years on… it turns out quite a lot and makes for very interesting reading indeed.
Dr Deepak Sampath (Genentech)
Curious to now more about what this scientist and his work in BCL-2 targeting is all about? Check out this short excerpt:
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As we continue rolling out our ASH coverage, we now move on to the in-depth analyses and thought leader interviews post meeting… What do experts really think about the critical questions that arise from new data? What is practice changing versus a nice to have in a small subset of people?
Someone said to me recently, “You seem very picky about who you interview. Why’s that?”
You betcha we are!
ASH17 in Atlanta
There are hem/oncs, thought leaders, and true experts whose opinions we value and know are solid and fair balanced in their commentary. There are also others who have major COI and will say whatever needs to be said about a particular individual study they are involved in, but are not reliable in a strategic perspective of the broader landscape or the impact of a study in terms of future trends.
I’d rather talk to people in the first category and learn from them – they don’t have to know everything or even agree with our own viewpoint, but they do need to be independent and fair balanced.
In the first of our ASH interview series, we posed some tough questions to a CLL expert and here’s a snippet on what he had to say:
Hah, at least we are thinking along the same lines!
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Over the last five years the face of the chronic lymphocytic leukemia (CLL) landscape has changed quite dramatically with the advent of new approvals in several categories. These include anti-CD20 antibodies, BTK inhibitors, PI3K inhibitors and apoptotic Bcl–2 inhibitors.
In yesterday’s wide ranging interview we explored in-depth how these therapies are impacting the broader landscape, as well as emerging trends in how these regimens might be used.
In Part 2 of the ongoing series, we spoke with another CLL expert and explored promising new and earlier agents in development for a different perspective on how outcomes might be improved further.
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Targeted therapy and Chemo-Immunotherapy in CLL
At last December’s 2016 annual meeting of the American Society of Hematology, one of the areas that attracted attention was the latest clinical data on the treatment of chronic lymphocytic leukemia (CLL).
ASH 2016 in San Diego
In recent years, we’ve seen tremendous advances in the field with several new agents approved such as obintuzumab, ibrutinib, idelalisib, and venetoclax. There are also new treatment options available for CLL patients with high risk disease such as 17p deletions (Del17p).
Other new targeted therapies such as acalabrutinib are now in clinical development, plus we have CAR T cell therapies and combination strategies also being evaluated in the clinic.
So what was the hot news from #ASH16 in CLL?
- Does chemotherapy still have a role or is it a targeted therapy world?
- Are we further forward towards a cure?
- Have we worked out how to identify those at risk of relapse?
- Will CAR T cell therapy be a game changer in CLL?
- Is financial toxicity going to be an issue with combination strategies?
BSB interviewed two experts in CLL while in San Diego who kindly shared their thoughts on which CLL data impressed them at the ASH annual meeting and discussed some of the big strategic issues facing the field right now. These interviews are being posted in a two-part series.
Part 1 today answers some of the questions highlighted above and explores the changing face of the broader CLL landscape.
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One of the hot topics at the forthcoming 2016 annual meeting of the American Association for Cancer Research (AACR) in New Orleans is likely to be CAR T cell therapy (Twitter: #AACR16).
Several research groups have shown impressive results in acute lymphoblastic leukaemia (ALL), but challenges remain in using adoptive cell therapy to treat other leukemias such as CLL, as we heard from Dr Porter at the recent BMT Tandem meeting. See post: Challenges and Opportunities of CAR T cell therapy in CLL. Perhaps more significantly, there’s a long way to go before CAR T cell therapies hit prime time in solid tumours.
What is fascinating is the pace of scientific research in the field. By the time the first CAR-T cell therapy is FDA approved, the second generation constructs used in them will most likely be obsolete.
This post reviews completely new research, which we’ve not written about before, that I expect we’ll hear more about at AACR, and discusses novel concepts about how to make CAR T cell therapy more effective in both leukemia and solid tumours. It’s a good pre-AACR preparation for those interested in cancer immunotherapy and the emerging CAR T cell therapy landscape.
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ASH 2015 LBA Session
The annual meeting of the American Society of Hematology (ASH) has a few quirks compared to other meetings. One of these is that all the “Late Breakers” are presented together on the last morning of the meeting.
It’s a rather unfortunate time given many have already headed back to their busy clinics or left for SABCS in San Antonio and ‘late breakers’ by definition, often offer new data that’s really noteworthy.
The result can also be a bit of a hodgepodge session that you have sit to listen through to get to those presentations you really want to hear.
At ASH this year there were two late breakers on new treatment options for CLL patients with a 17p deletion (Del17p). This is a pretty challenging group to treat. Although ibrutinib is indicated for this patient group, many sadly relapse. There’s an unmet medical need for new treatment options. At ASH we heard data for idelalisib (PI3K-delta) and venetoclax (Bcl2).
After the session, I briefly spoke with Dr Kanti Rai (New York) for his reaction to the data. Dr Rai (pictured below) received the 2014 Wallace H. Coulter Award for Lifetime Achievement in Hematology.
Dr Kanti Rai receives 2014 ASH Lifetime Achievement Award
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The #ASH15 wall of people marching to the poster hall just after 5pm
Orlando – it’s Monday at the annual meeting of the American Society of Hematology (ASH) annual meeting, a day I call “Manic Monday” because there are so many simultaneous sessions, you end up running around frazzled, in/out of sessions, in the hope of catching all the presentations of interest.
It’s particularly challenging if you are in a full session — you won’t be able to get back in if you leave — which results in having to make difficult choices on what to see and where to run to. Some of the myeloma thought leaders were urging colleagues to tweet sessions they couldn’t be in, so “Manic Monday” may be a good time to contribute to the collective ASH Twittersphere.
We’re starting today’s rolling post with my notes from the lymphoma New Drugs session yesterday, then we’ll be updating the blog as the day goes by, as the opportunity permits.
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Earlier this month, Janssen/Pharmacyclics announced they had submitted a New Drug Application (NDA) for Food & Drug Administration (FDA) approval of ibrutinib, an oral Bruton’s tyrosine kinase inhibitor (BTK) in chronic lymphocytic leukemia (CLL) for the treatment of patients with a deletion of the short arm of chromosome 17 (del17p). Here’s a link to July 10 press release.
The company have requested Priority review; approval later this year or in early 2014 is highly likely given that the agent has also been designated a Breakthrough Therapy by the FDA.
This is great news for CLL patients!
CLL is an incurable disease. It is the most common leukemia in the United States with 15,500 new diagnoses a year.
Chromosomal abnormalities are fairly common in CLL and predict both time to first treatment and overall survival i.e. how long someone will live. Sadly, those with a 17p deletion have the worst outcome and a poor prognosis.
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