Cheryl-Anne has sent her update from ASCO.. see below.
Sandy
:: ASCO - Novartis Satellite Symposium Report
:: Posted by Cherylanne
:: In Forum: 'Conferences'
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Hello Everyone,
I arrived at the airport in plenty of time to enter my confirmation code in the automated ticket services to get the pleasant surprise of being offered a “random” upgrade for an incredibly small fee – It was a “no brainer”. The small fee gave me access to the maple leaf lounge – wifi, all the magazines I could manage to read and a very yummy hot meal on the plane to Chicago. What a civil way to travel.
The hotel, is another thing, but that is partly my fault for waiting so late to book this trip – but when one is dealing with zero profits and scrounging around for the money, we have to take what we can get. Even though the hotel is meeting bare minimum standards it is still very expensive, I found out this morning that hot water is apparently extra! Brrrrrr...
Last night was the satellite symposium hosted by Novartis Oncology It was titled” The Opportunity for cure in CML – A global perspective on biology, prognostic factors, and response criteria for improved patient outcomes. We started off with a case study and four or five different opportunities to vote. The case was a 35 year old female, dxed with CML, other than some hypertension rather healthy. She has a perfectly matched brother sibling. So what would you do? 1.) allogenetic transplant (2) 400 mg Imatinib (3) higher dose Imatinib (4) second generation TKI’s (Dasatinib or Nilotinib) (5) combination TKI and IFN – hold that thought we’ll come back to it later.
Dr. Cortes chaired the session. Dr. M. Deininger presented Biologic insights to lead us forward in CML: an Animated look at key pathophysiologic events. - pretty cool graphics showing for example the mechanism of ABL activation in BCR ABL, proliferation, apoptosis, genetic instability, BCR ABL mutations. This last one shows precisely why when the dreaded T315I is on the scene NO TKI is going to work. But the later presentations spoke about things such as the Ariad drug and Omacetaxine and others, so there are, as we know things in the works for this very difficult situation.
Next up was Dr. J. Radich – He lead off with the famous slide that you will all see soon as part of Dr. Shah’s presentation to us – 553 patients started in the Imatinib arm of the IRIS trial only 332 remain – roughly 40% went off study and this represents a population for whom there are unmet needs. So, for all my fellow turtle friends – take heart, your minority is not as small as you would have thought. But happily 60% of the patient population are having their needs met. By the way, these are not my words entirely, they are what Dr. Radich said himself. He also went on to show “real life” as in population based versus IRIS – Some key highlights: (1) CCR at 12 months – 69% for the IRIS trial however only 41% in real life (2) CCR at 18 months - ` 75% for the IRIS participants vs. 49% for the “real life” population (3) MMR at 18 months – N/A in the IRIS trial but 26% for the real life population (4) CCR at 2 years = 80% for the IRIS participants, yet only 51% for the real life population.
All of this is leading us to having to rethink the strategy – could it be that second generation TKI’s might be able to improve the response rates in the “real life” - of course the answer will inevitably turn out to be yes, and indeed the case is being made to use these agents front line. I am all for deeper responses quicker...Dr. Radich presented sokal risk and outcomes and noted that you can find somewhere on line to put in your own sokal information and get your sokal risk score – I shall google it and try to find it. If anyone finds it first , please post it here on Jerry’s site. He went on to talk about achievement of certain milestones and how it would indicate the chances for achieving MMR or resistance. This would be correlated with your 3 months BCR ABL PCR/FISH scores. Overall early response to Imatinib leads to response stability. Response to second TKI’s within 12 months predicts survival. So, this makes the case for tightening the response times and making the move to 2nd generation TKI’s much sooner in order to get to deeper responses quicker. He did a quick review of some of the mutations that would interfere with drug response: Those that would be less sensitive to Nilotinib are Y253H, E225K/V and F 359 C/V. Those that would be less sensitive to Dasatinib are : Q252H, V299L and F317L. He talked about intracellular drug transport OCT – 1 and its ability to bring Imatinib into the cell. So in cases where OCT 1 is over expressed Dasatinib or Nilotinib will help you. In the cases where ABCB1 (drug efflux pump) all TKI’s will work but they are concentration dependent in the case of ABCG2, this one as well affects drug concentration but kinase inhibition is only affected with Dasatinib. The problem with OCT 1 testing is that it is hard to do and not relevant at all for 2nd generation drugs.
Dr. Saglio presented “Updates on improvement of response monitoring to CML therapy. Optimal responses are CHR within 3 months, Partial CR at 6 months CCR at 12 months and MMR 1t 18 months. The key message here is that – note the quotation marks, these are not my words “CMR – prodromic to possible discontinuation without recurrence of the disease (cure), is gradually becoming the new therapeutic goal in CML. A fast achievement of MMR is prognostic for achievement of CMR” By the way I had to look up Prodromic my self: pro·drome (prdrm)n. pl. pro·dromes or pro·dro·ma·ta (-drm-t)An early symptom indicating the onset of an attack or a disease. [French, from Latin prodromus, precursor, from Greek prodromos, precursor : pro-, forward; see pro-2 + dromos, running.]
pro·dromal (-drml), pro·dromic (-drmk) adj. DEFINITION OF CMR: Undetectable BCR ABL mRNA transcripts by real time quantitative and/or nested PCR in two consecutive blood samples of adequate quality (sensitivity 10 to the 4th) - as per the ELN recommendations.
What is ultimate Optimal response? (1) 4 log reduction? - less technically challenging, standardization is feasible (2) 4.5 log reduction – technically demanding, standardization achievable? (3) Undetectable BCR ABL – PROBLEM: very hard to standardize for multicentre clinical trials and for eventual practice recommendation AND changes with technology. (4) 5 log reduction? - not routinely achievable today but sensitivity improving.
He showed a standardization map of Europe – Most of Europe has been validated.....
Next up was Dr. J. Cortes - “Chronic phase CML: Clinical trial update in the frontline: He gave a quick review of the 8 year IRIS update. Again he eloquently showed that according to the 8 year IRIS update 37% have unacceptable outcomes – his words used on the slide – not mine.
So, the question is “what needs improvement in frontline therapy of CML?” The key areas are: CCR, MMR, CML, early response and toxicity – all of these show there is room for improvement. Some options to improve these:(1) Standard dose IM (2) high dose IM (3) IM based combinations (4) second generation TKI’s – Dasatinib, Nilotinib and Bosutinib. He made a point about reducing dose interruptions as this is more predictable of achieving a better overall response rate. He talked about the combination trials with IFN and it is clear that the IM and Peg IFN patients had a higher rate of CMR 22% versus Imatinib alone (10%) or higher dose IM or IM with Ara –c (11%). He talked about the front line information as it was reported at ASH. I am going to skip this, we all already know this, besides Monday will have some interesting information for all of us – so stay tuned! He finished off his presentation with the following slide: HOW WOULD YOU TREAT? (1) if it was your family member – answer – second generation TKI (2) If it was somebody else? - Answer – I would treat any patient as if she/he was a family member (3) Imatinib 400 mg is still the standard therapy today – but stay tuned!
Dr. R. Hehlmann form Germany was next up “Current best practices for management of accelerated/ blast phase CML. The overall message from his presentation – stay on top of the case – do not let the patient progress! Here is a scary thing though, there are some cases of sudden onset blast crisis. In 541 cases 23 patients developed blast crisis (4%) of these 4 patients (17%) presented in sudden onset and lymphoid BC is 3 X’s more common than Myeloid BC. The key issue is that (direct quote from his slide) ” BCR ABL drives progression to BC, so prevention of BC is best achieved by elimination of BCR ABL”
Dr J. Goldman was next on the scene “What’s looming on the horizon? Putting new agents in their proper context” The situations where we need new drugs for CML are when there is kinase domain mutations, even if there are no kinase domain mutations and elimination of the quiescent leukemia stem cells in patients in major or complete molecular response. He talked about resistance and offered up a slide covering (1) Pharmacological resistance – poor intestinal absorption, drug interactions, binding with plasma components (2) Leukemia cell related, heterogeneity of leukemia cells , amplification/incresed expression of BCR ABL, reduced levels of transcriptor e.g. OCT 1, increased levels of exporter eg MDR1, acquisition of ABL kinase domain mutations (3) patient related poor tolerance.
He covered BCR ABL kinase domain mutations – great graphic showing how T315I totally blocks the pocket where the TKI’s access to stop the disease. New drugs? Dasatinib, Nilotinib, Bosutinib. For T315I, Omacetaxine, Ariad, Danuserib, aura kinase inhibitors. There will be more on Monday on this, so I am skipping.
The main point I want to say about Dr. Goldman’s presentation were his final words. He essentially said, yes we have seen a major improvement with Imatinib for the treatment of CML – but we are not out of the woods – the disease is still not cured, there are still many challenges and we all must remain vigilant that is patients and physicians alike!
Stay tuned – more from ASCO coming!
Cheers
Cheryl-Anne
