ABT-199 Trial experience in Australia

ABT-199 Trial experience in Australia

Following are my notes on the presentation by Andrew Roberts, to the Australian Leukaemia Foundation August CLL Teleforum, on Australian experiences with the ABT-199 Phase I trial on CLL patients. Andrew is Australia's ABT-199 trial chief clinician and provided an easily understood and very interesting session on what has been discovered to date about the effectivness of ABT-199 on difficult to treat CLL patients. Naturally any errors are my own.

Andrew Roberts is a Melbourne Australia based Clinical Haematologist with more than 10 years research experience and with particular interest in CLL, lymphoma and myeloma.

He explained that the genesis of ABT-199 came from an approximately 20 year long search for a way to turn off the BCL-2 pathway. About 10 years ago it was thought to be impossible to do this, but based on Melbourne, Australia research, Abbott found a way to switch this pathway off, which led to the development of ABT-263 and subsequent US clinical trials. About a third of patients that no longer responded to other treatments responded to ABT-263, which led to the development of the second generation drug ABT-199 with less side effects.

Two phase I trials of ABT-199 are in progress (checking safety and dosage), with phase II and II trials planned. About 80% of patients respond well to ABT-199, which has been proven to reduce lymphocyte levels from high to normal levels and to clear the bone marrow of CLL. Nodes the size of a small football have disappeared. Importantly, ABT-199 works differently than other CLL drugs and is equally effective with del 17p patients and those without this deletion. The Australian contingent (two Melbourne based trial sites of the eight worldwide) comprises about 30 - 50% of the ABT-199 worldwide recruitment. The trial included difficult to treat patients with some in their 80's.

Still unknown is how effective ABT-199 is for what percentage of patients, how long it will keep working or what the side effects are, though it is thought you may need to stay on it long term. The first patient commenced on the drug in June 2011 and the trial is finishing in about 6 months.

Abbie and Genetec will be expanding trial sites in Queensland, Sydney, Melbourne and possibly Adelaide in addition to one that has just opened in Europe, but these will be for 17p del patients only.

Some will be aware of the unfortunate death of two ABT-199 trial patients in the USA due to Tumour Lysis Syndrome (TLS) affecting the heart. Thankfully no deaths occurred elsewhere. These deaths resulted in a halt to the trial until the protocol was improved whereby patients going onto higher doses are monitored in hospital. (Basically TLS is caused by the rapid action of the drug, which on high tumour load patients can overload the body.)

When I asked Andrew whether ABT-199 could help patients with Richter's Transformation, he responded that like Ibrutinib, it wouldn't work as a single therapy and in fact it had mostly stopped working when Richter's developed. He went on to say that it is thought that Richter's pre-exists for months if not years before it becomes apparent and that perhaps if patients were started on ABT-199 early, progression might be avoided.

Refreshingly, Andrew thanked the CLL patients for their involement on the trial, noting that not all benefited.

Neil

14 Replies

oldestnewest
  • I interviewed researcher/clinical John Seymour about this trial and that video will be posted very soon on patientpower.info. Please be sure to be signed up for alerts at patientpower.info/cll so you will know once it's up.

  • And here's the Patient Power interview about ABT-199 which was done at the recent iwCLL meeting in Cologne:

    patientpower.info/video/how...

  • Dr John Seymour in an OncLive video and transcript on the Efficacy of ABT-199 in High Risk CLL (from ASH 2013)

    onclive.com/conference-cove...

    Dr Seymour again on the Tumour Lysis Syndrome Deaths in the ABT-199 Phase I trial (again taken at ASH 2013)

    healthunlocked.com/cllsuppo...

  • I wonder if ibrutinib has been trialled as a first line treatment for those on watch and wait. I do not want to sto functioning altogether before treatment and it seems logical to use it before chemo rather than have to wait til blood levels indicate chemo is the next route. Any help guys.

  • That's a very good question. There has been some thought by at least one CLL expert that perhaps we should move to using newer treatments like ibrutinib for patients on W & W before treatment is needed. However, there are some barriers to be overcome before that becomes a standard approach, namely:

    1) Proof that patients can stay on the new treatments indefinitely. (Ibruntinib and ABT-199 have stopped working on some patients.)

    2) Proof that this provides worthwhile benefits

    3) Cost

    Perhaps there may eventually be trials for particular subsets of the CLL W & W community where genetic markers indicate (a) a higher risk of progression into say Richters or other complications (b) low risk of becoming refractory to the drug (i.e. the drug ceasing to work).

    It doesn't help that generally B-lymphocytes numbers can get to very high levels without causing apparent problems. See my post How high can you go? for more on this.

    healthunlocked.com/cllsuppo...

    I for one would be very interested to see what a difference this approach would make to people's quality and length of life, but I also wouldn't want to start on a promising treatment earlier than absolutely necessary if there was a significant risk that by doing so my life expectancy and quality of life were worse! That said, I'm sure there would be no shortage of volunteers for such a trial - I'd certainly be tempted.

    Neil

  • Another major barrier to early treatment is clonal drift and subclones, changes that occur over time or because of treatment. Further there needs to be testing available clinically for sub clones like BIRC3, SF3B1, NOTCH1, MYC . Tests are in development but are some time off. A recent study has found almost 70% of CLLers have sub clonal mutations. These subclonal populations are still poorly understood, and the target of current research. They may prove to be as or more important than 13q, 11q, T12 and 17p ncbi.nlm.nih.gov/pubmed/240...

  • Hi Chris do you have a few links explaining clonal drift?

    I have also been fascinated by the argument between researchers about clonal evolution whether this is treatment mediated or part of the natural history of CLL. Hard to prove

    Also the role of sub populations in maintaining homeostasis and slowing disease development by occupying much of the space available in proliferation centres.

    This equilibrium may be upset when treatment removes these clonal types allowing harder to treat more progressive clones that may remain after treatment to occupy this proliferation space,. is this also evidenced following treatment with novel pathway inhibitors?

    I still remember my own consultant answering me on this when first diagnosed; "unfortunately at the moment we can't treat as we don't wish to run the risk of waking a sleeping tiger"

    Nick

  • Sorry, I call it clonal drift, others refer to it as clonal evolution... Check the work of Catherine Wu and Anna Schuh...

  • Ibrutinib has been trailed in the U.S. for first line but only for patients over 65 or high risk like 17p deleted. You can find most trials at this link, there may be trials in the UK not listed clinicaltrials.gov/ct2/resu...

  • Am indeed asking if I can go on trial after witnessing first hand a friend who had 6 months chemo and the devastating effects on her. I feel relatively ok at the moment but have no energy and am constantly having to pace myself. Also get night sweats which wake me up. A shorter but fitter life would be brilliant. Did not know ibrutinib had stopped working in some cases. Will have to research that one!

  • I have a prognosis of survival that went from years to months, in the blink of an eye...I'll take every day I can get... as damaged by chemoimmunotherapy as I have been. Yes, fitter would be nice, but you take what you can... ;-)

  • So sad to hear that you too were damaged by chemo and I agree you take what you can. But if I could avoid chemo that would be the icing on the cake so to speak. I have gone from w and w to v rapid doubling so just want the best option- for any of us who have cll. Take care.

  • Hi I think that for those of us who have been through a bad reaction to chemo and had long term health problems as a result of it anything else is promising.

  • Well said . I guess anything that gives hope is worth exploring

You may also like...