iCMLf-ESH Meeting in Washington DC: a patient's perspective

From 24-26 September 2010, the iCMLf-ESH conference on Chronic Myeloid Leukemia (CML) brought together around 400 CML experts from all across the world in Washington DC. Speakers and audience discussed the biological mechanisms of the disease and its treatment, and also about news from clinical trials with 3rd generation therapies.

I had the pleasure of attending this meeting, in addition to the fact I was there to support the development an educational programme that the International CML Foundation (iCMLf) will launch at the American Society of Hematology meeting in December in order to support CML experts in emerging countries.  

The first two days of the iCMLf-ESH programme covered stem cell biology, targeting stem cells, mathematical modeling, kinase effects and genomic instability, immunologic aspects of CML, resistance including TKI mutations, mechanisms behind progression to advanced phase, Diagnostic tests and prognostic markers. The third day was more focused on the clinical aspects of CML therapy, including new drugs in development and current clinical controversies in CML management.  

The full programme can be found at http://www.esh.org/agenda10/cml/cmlprog.html

Not being a doctor or a biologist, but just a well-informed patient, I must admit I really had difficulties in following some of the very technical presentations on biology, genomics, signalling pathways on the first two days. Even though I would consider myself as an educated advocate who can cope with quite some science, many of the presentations were just all opaque to me (but it was kind of reassuring that I heard from some experts with medical education, that it was a challenge for them too).  

However I was really impressed about the intensity of research geared to understanding how leukemic stem cells survive despite current TKI treatment and which mechanisms could be used to wake up sleeping stem cells and kill residual leukemia, how the risk of relapse in patients who stop therapies could be predicted, what the role of immune response in combating CML is, how transformation of the disease to advanced phases occurs and what different pathways could be used to tackle mutated clones and resistant stem cells. The presentations gave me good hope that, over and above the progress in clinical trials with first, second and third generation TKIs, a lot of very important lab research work is going on. There is hope this will eventually help us get rid of the CML altogether. Given that ASH presentations usually focus more on the (most important) green side of the CML tree (= progress in clinical trials in today's patients), these sessions were all about laying the axe at the roots of the CML. My wishes and hopes are with all these engaged researchers who all work in the labs will also quickly translate into progress at the bedside. We really need a cure for CML, and our health systems too.  

However the third day of the conference was really a highlight for me, focusing on trial results and innovative clinical approaches in managing resistance and residual disease. It covered latest results from the trials with bosutinib (formerly SKI-606), omacetaxine, SMO inhibitors, ponatinib (AP24534), DCC 2036, danusertib (formerly PHA-739358), XL-228, the new first line therapies, the role (or return) of Interferon alpha, and the prognostic importance of CMR.  

Unfortunately I was not quick enough to make proper notes in most of the presentations, but I want to highlight three which I found most astonishing.   First of all, the results of ponatinib (, Ariad), presented by Jorge Cortes: As we know, survival for those patients that develop the T315I mutation today is still pretty poor, as all first and second generation TKIs fail. Luckily only a small proportion of patients, roughly 2% of all newly diagnosed patients (estimated 15% with T315I of the 15% of patients developing resistance)  develop the T315I mutation. However if it happens, there is not much beyond stem cell transplant, if possible at all. Ponatinib as a once-daily oral drug seems to be an exciting candidate. It targets a number of tyrosine kinases – not only BCR-ABL, but also VEGF-, FGF-, and PDGF-receptors, c-KIT and SRC kinase. According to first results of phase I studies presented at the ESH-iCMLf meeting, the drug seems to be well tolerated, with any-grade adverse events being thrombocytopenia, anemia, increased lipase, nausea, rash, arthralgia, fatigue, pancreatitis in less than one fourth of patients. Only 5 out of 57 patients had to reduce the dose due to rash and pancreatic side effects. Most interestingly, of those 9 patients (out of 38) that had the T315I mutation, 6 patients achieved a major cytogenetic response, 5 patients a complete cytogenetic response, and 4 patients even a major molecular response. We also need to remember that the patients participating in this Phase I study were heavily pre-treated so the results in earlier stages of the disease should be even more promising. Phase II studies were initiated in September 2010 in the USA - and European trials were said to enroll soon, too.

First preliminary results of a phase I study with DCC-2036 (by Deciphera) were also presented. This is another oral drug active against T315I which maintains potency also against gatekeeper, P-Loop, and A-Loop mutants, which seems also to be promising in terms of first responses and tolerability.  

Another presentation by Jorge Cortes discussed the issues around the new first line treatments Nilotinib and Dasatinib, raising the questions whether starting with the more expensive second generation drugs can be justified and are really expected to deliver better results, compared to Imatinib followed with Dasatinib/Nilotinib only in case of Imatinib failure. Opinions still seem to vary largely: in comparison to 12 years of Imatinib experience, new surprising long-term side effects of Dasatinib and Nilotinib have not been observed in the 6-7 years of experience since Phase I studies started, supporting that all these drugs might be considered equally safe. However any long-term clinical advantage of "preventing versus treating Imatinib failure" is still unclear. Treatment costs of course are an issue, with both Dasatinib and Nilotinib basically being double price to Imatinib today - and especially when anticipating the end of the Imatinib patent in 2016. By that time, regulators are expected to require clear answers on justifying very expensive first line treatment, as a number of speakers like Steve O'Brien and Charles Schiffer noted.  

Another highlight was Andreas Hochhaus' presentation entitled "Should IFN come back?". He pointed out that a number of studies have demonstrated that Interferon not only activates T-lymphocytes against CML cells, but may also activate dormant CML stem cells making them sensitive to TKI. Chronic stimulation of the stem cells through Interferon could lead to their exhaustion. A smaller German trial with 20 patients has also shown that, other than in the STIM trials, stable remission on Interferon maintenance therapy after Imatinib withdrawal led only to a relapse rate of 25%, with all relapsed patients responding to Imatinib thereafter. Further research, for example the anticipated two-arm German CML-Study V, aims to bring more clarity. It will compare Nilotinib-monotherapy followed by stop of therapy if complete molecular remission is achieved and sustained for at least 12 months, with Nilotinib+Interferon, followed by low dose IFN monotherapy after more than 18 months of major molecular remission, followed by stop of all therapies if minimum 12 months of complete molecular remission are achieved.  

In a nutshell, this was what I perceived as key highlights from iCMLf-ESH 2010 - which is of course a very subjective selection and not at all a fair representation of all the great work presented by all the CML specialists from all across the world. Much more impressive research was presented, on which I just lack notes or memories in my jetlagged mind – or the medical education to understand heavy biology mechanisms.  

From my personal perspective, the meeting has been very valuable to attend, giving hope that there is a lot of momentum on both ends of CML: the basic lab research on the path to cure, and the clinical evaluation of new therapies against multi-resistant disease and minimal residual disease in patients today.  

I am looking forward to the ASH meeting in Orlando in December 2010, seeing more encouraging results from trials from the different research networks. I fear I won't see much more of Orlando than I did of Washington DC: No time left for tourism, given that I really don't want to miss being a witness to the  great research on the path to a cure of CML.

Jan Geissler (CML Patient since 2001), 20 Oct 2010
Full text article: http://www.cmladvocates.net
Contact: jan@cmladvocates.net
Jan is also the iCMLf Communications Manager