Jan Geissler's Summary of the ASH meeting, Sanfranscisco, 2008.

Dear friends,

There were so many interesting things at ASH 2008, so it's difficult to tell what I found most interesting. In general, I found it quite exciting because around 23.000 haematologists from around the world met in one single place to share knowledge and research results on all blood cancers. I was able to see many of the top CML doctors we always read about: Goldman, Hochhaus, Kantarjian, Cortez, Mahon, Apperley, Rosti, Shah, Hughes, Guilhot, O'Brien, Baccarani, Nicolini were all there.

More specifically, there's been a lot of good progress in CML. This is basically good news because CML is such a rare disease, and companies struggled to invest in treatments on rare cancers before Glivec came up. Even Novartis had to be convinced by doctors like Brian Druker to bring this drug to the market, as they did not expect it to be commercially viable...

Just ten years ago, the majority of CML patients were dying just within three to four years, because all available treatment options were either pretty dangerous (transplant) or ineffective (first line interferon). Today, nine out of ten CML patients treated with Imatinib first-line are alive after seven years of treatment. Four out of five achieve a complete cytogenetic remission. Of those that achieve such a remission and remain stable for one or two years, only a very small number (3%) suffered from progressive disease later on. No new long-term side effects have been observed in the 7 year IRIS data - only what has been already reported in the first three years. So in summary, those who tolerate imatinib well and achieve a stable complete cytogenetic remission for more than two years have almost no risk of progression or death!

For those that cannot tolerate the treatment or do not respond adequately, there are more options available now. This year's ASH has shown two years of experience in Tasigna/nilotinib and Sprycel/dasatinib. Both have shown a quicker and deeper response than Glivec/imatinib. However it still needs to be seen whether the speed of response really translates into some long-term benefit. Even if tolerated well in general, side effects of both dasatinib and nilotinib are considerably stronger and more frequent than imatinib. More than than half of all dasatinib first-line patients had to interrupt their treatment at least once because of side effects, and about one third interrupted more than once. Additionally, the long term effect of dasatinib's SRC inhibition on the body still needs to be observed. From an economical perspective, both dasatinib and nilotinib are about twice the cost of standard dose imatinib (400mg) therapy. So clinically it is great news that there are potent drugs available for those that fail imatinib or cannot tolerate it, but I didn't see any strong evidence at ASH 2008 that would really justify first-line administration or early switchover to the newer agents.

One of my surprises at ASH2008 was the data on bosutinib/SKI606. It seems to have a similar potency against resistant cells as imatinib, but with a better side effect profile than dasatinib or nilotinib because it is much more selective against BCR-ABL than the other two.

Most resistant mutations, except T315I and F317L, can be treated with the drugs mentioned above. However, there are still a number of patients that fail on all three TKI's - imatinib/dasatinib/nilotinib- because they carry an extremely resistant mutation. I was quite happy to see there's a lot of drugs in the pipeline and in clinical studies today to face that problem. This includes HHT/Homoharringtonin/Omacetaxine, PHA-, MK-0457, AP24534, AT-9283, SGX393, XL228, DCC-2036 and others. Someone from the MD Anderson was giving a very comprehensive presentation on early data of these drugs against T315I.

Additionally, the data presented on transplants was quite encouraging as well, especially for elderly patients. One presentation on the acute leukemia (AML) area from MD Anderson had shown that the maximum age of 65 for transplant is about to disappear. Dose reduced conditioning, methodological improvements and different chemotherapies, as well as TKI-Transplant-combinations in the CML space, have achieved a better tolerability of conditioning, as well as improved management of graft versus host disease. Hence, the difference of transplant related mortality between the age groups seems to disappear. Still, stage of the disease, compatibility of the donor, general condition of the patient remain as the main risk factors. Patients are dying through transplant and are suffering transplant-related morbidity, so it is no longer a first-line choice for CML, but a very valid option in case of multi-drug resistance.

I quite liked the CML presentations on Interferon as well. First of all, the French SPRIIT study compared imatinib monotherapy with imatinib-PegInterferon combination therapy. They observed that more patients receiving the combination achieved more cytogenetic and deeper molecular responses. On request, Prof. Guilhot mentioned that the dose selected in the study (90µg of Pegasys/week) was probably too high, and 45µg/week would rather be what he would suggest today. He also said that Interferon might be an "effective protective shield against progression and resistance in complete remission". Unfortunately the German CML-IV study was still presented with blinded arms, because they are still recruiting and don't want to provide bias by publishing preliminary data to the recruiting doctors.

Furthermore, two studies on stopping imatinib therapy were presented at ASH 2008. Prof. Mahon from France presented the Stop Imatinib (STIM) study where a significant proportion of patients relapsed after stopping Glivec. However, those that had received Interferon prior to or during imatinib therapy were much less likely to relapse when stopping all CML therapy. In contrast, the relapse rate was higher in those that only received imatinib before stopping therapy. So another indicative information for the "protective shield" of Interferon.

There were some interesting presentations on research about sleeping stem cells (quiescent cells) and the mechanisms of targeting those with new therapies. Some researchers are working on this to take the "last bastion" of a cure for CML. Additionally, the community is working on predictive methods, bio-markers and gene profiles, to predict response -- in order to avoid wasting time with a therapy where genes would have told early that therapy most likely will not work.

The European LeukemiaNet's Recommendations for the treatment and management of CML, published in 2006, still remains valid. This includes the criteria and timelines on suboptimal responses or treatment failure, as well as the requirements for regular molecular and cytogenetic monitoring. The group is currently working on an update of the recommendations, which is expected to be published some time in 2009. However I heard there will be no revolutionary changes.

My general impression of ASH 2008 was, that it was exciting and relaxed at the same time. CML experts are actively researching in all different fields. Some researchers are assessing new ways in maintenance therapy or attacking sleeping stem cells, and cracking also the troublesome T315I resistance. Long-term data on imatinib is good, as is the early data from the second generation drugs. More than a dozen drugs against the most resistant clones are in clinical trials, which is good.

So I went home with a very positive attitude.

Please note that this summary reflects my personal observations and layman's interpretation of ASH 2008

Jan Geissler, January 2009.
CML Advocates Network and Leukamie-Online Germany
www.cmladvocates.net
www.Leukämie-Online.de