ASH 2008: Impressions from a CML patient advocate

welcome_to_ash2.jpgEvery year, around the day of St Nicholas in December, hematologists from around the world meet at the annual congress of the American Society of Hematology (ASH). It has become the most important event for this profession. This year, around 23.000 experts from more than 100 countries met in December 2008 at San Francisco for the 50th "ASH Annual Conference" to share knowledge about the latest results in research on leukemias. We've also had the chance to join this year, and we'd like to share our subjective impression on progress in CML therapy. An impression from a layman perspective.

shah_talpaz_mauro.jpgThere were so many interesting things at ASH 2008. In general, we found it quite exciting because around 23.000 hematologists 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: The doctors Goldman, Hochhaus, Kantarjian, Cortez, Mahon, Apperley, Rosti, Shah, Hughes, Guilhot, O'Brien, Baccarani, Nicolini and many more all were 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 into treatments on rare cancers before Glivec became successful. Even Novartis had to be convinced heavily by top doctors to bring this drug to the market, as at early times, there were some doubts about its commercial viability.

Just ten years ago, a majority of CML patients were dying just within three to four years, because all available treatment options were either pretty dangerous (transplant) or ineffective on first line (interferon). Today, long-term follow-up data from the IRIS trial shows 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 seven year IRIS data - only what has been already reported in the first three years. So in summary, those who do tolerate Imatinib well and achieve a stable complete cytogenetic remission for more than two years have almost no risk of progression or death.Cortez

For those that cannot tolerate the treatment or do not respond adequately, there are more options available now. At this year's ASH conference, two years of experience in Tasigna/Nilotinib and Sprycel/Dasatinib were presented. Both have shown a quicker and deeper response than 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 on 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 kinase" inhibition on the body still needs to be closely observed. From an economical perspective, both Dasatinib and Nilotinib are about twice the cost of Imatinib 400mg therapy. So clinically it's great news that there are potent drugs available for those that fail Imatinib or cannot tolerate it, but many experts think there's still no supporting evidence that would justify first-line administration or early switchover to the newer agents.

One of the 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/Nilotinib because it is much more selective against BCR-ABL than the other two.

Most resistancies except T315I and F317L can be treated with the drugs mentioned above. However, there's still a number of patients that fail on all of Imatinib/Dasatinib/Nilotinib because they carry a difficult resistance. We were quite happy to see a lot of drugs in the pipeline and in clinical studies today to face that problem. This includes HHT/Homoharringtonin/Omacetaxine, PHA-739358, 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 from MD Anderson in the acute leukemia (AML) sessions had shown that the maximum age of 65 for transplant is getting less important. 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 led to 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 to be the main risk factors. Patients are dying through transplant and are suffering transplant-related morbidity, so it's no longer a first-line choice, but a very valid option in case of multi-drug resistance.

hochhaus_giora_jan.jpgWe quite liked the CML presentations on Interferon as well. First of all, the French SPRIT study compared Imatinib monotherapy with Imatinib-PegInterferon combination therapy. They observed that patients receiving the combination achieved better cytogenetic responses and deeper molecular responses. On request, MD 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 create recruitment bias by publishing preliminary data to the recruiting doctors.

Furthermore, two studies on stopping Imatinib therapy were presented at ASH 2008. MD Mahon from France presented the "Stop Imatinib" (STIM) study where quite a considerable proportion of patients relapsed within 6 months after stopping Glivec. However, those that had received Interferon prior or during Imatinib therapy were much less likely to relapse when stopping all CML therapy. In contrast, relapse rate was higher with those that only received Imatinib before stopping. This seemed to be another indicative information for the "protective shield".

There were some interesting presentations on research about sleeping stem cells and the mechanisms of targeting those with new therapies. Some researchers are working to take the "last bastion" of a cure for CML. Additionally, the community is working on predictive methods, biomarkers 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 (ELN) Recommendations for the treatment and management of CML, published in 2006, still remain to be valid. This includes the criteria and timelines on suboptimal response or treatment failure, as well as the requirement for regular molecular and cytogenetic monitoring. The group is currently working on an update of the recommendations, which are expected to be published some time in 2009. However when speaking to someone involved, we heard there will be no revolutionary changes to the recommendations.

Our 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 remains to be good, as is the early data from the competing second line drugs. More than a dozen drugs against the most resistant clones are in clinical trials.

And probably the best part was to have the opportunity to spend the time with other advocates. Giora, Zavie, Jan, Erin, Pat, Mei Ching, Anna, Cheryl-Anne and Anita have been there this year - and probably more we unfortunately haven't met!

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We went home from San Francisco with a very positive attitude and hope for all our future.

Please note also this reflects our personal observations and layman interpretation of ASH 2008 - not an official summary or even a doctor's review.

Zavie, Giora & Jan

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