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
BRUIN Study: phase 1/2 study of Pirtobrutinib (formerly Loxo 305) in relapsed or refractory B-cell malignancies 
