Posted by Guest Blogger on November 10, 2010
Jan Geissler, an advocate and CML survivor in Germany, is our Guest Blogger. Jan is co-founder of the CML Advocates Network, as well as the founder of the German patient group Leukämie-Online e.V.
Meeting overview: The first two days of the ESH-iCMLf programme covered stem cell biology, targeting stem cells, mathematical modeling, kinase effects & 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.
Click here for the full programme of the ESH-iCMLf meeting.
Personal account: Not being a doctor or a biologist, but just a well-informed patient, I must admit I really had difficulties to follow the very scientific presentations on biology, genomics, and signaling pathways on the first two days. However I was really impressed about the intensity of research geared to understand 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 stopping therapies could be predicted, what the role of immune response in combating CML is, how transformation of the disease to advanced phases works 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.
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, Ariad, DCC 2036, Danusertib (formerly PHA-739358), XL-228, the new first line therapies, the role (or return) of Interferon, 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 (formerly AP24534, by Ariad), presented by Dr. 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 15% of 15% of all newly diagnosed patients are developing the T315I mutations. 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 become 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. 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 might be even more promising.
First preliminary results of a phase I study with DCC-2036 (Deciphera) were also presented, 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 Dr. 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 already 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.
On a different note, a final highlight was Dr. 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.
In a nutshell, this was what I perceived as key highlights from ESH-iCMLf 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. From my personal perspective, the meeting was 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.