Tuesday, 15 December 2009
ASH 2009"Actually, why do I always spend St Nicholas in the US, instead of with my family", I asked myself when I boarded the plane to the USA on 4 Dec, in anticipation of a boring 16 hour trip to New Orleans, arriving jet-lagged, hiding for days in the dungeons of a large convention center, lacking any sense of the city I am in. Year by year, more than 20.000 hematologists and healthcare people attend the annual meeting of the American Society of Hematology, lovingly called 'the ASH' by repatriates. Its publications are all available on the Internet. "Is it really worth the effort being there again, instead of just using my browser?", I thought. It is. Definitely.
If there is a place to see latest research and treatments for blood disorders, it is 'the ASH' -- the place where just about every expert is that has a say in leukemia research. All top experts from the CML space are presenting their research here. I can't withstand the impression that the whole hematology community keeps quiet about a year of research results – just to be able compete for the hottest piece of news from trials at ASH. Some unnamed hematologist, when I asked, has admitted that they need to pick straws who has to stay at home to keep the clinic's services up and running
during their absence. It became already apparent on my flight from Munich to the USA: I had the impression I was almost the only one not knowing everyone else in the plane. A plane full of hematologists. So I went there again this year. It's all been a little compressed because I didn't want to spend too many days out of office and away from my family. Hence I missed the satellite symposia on Thursday as well as the last sessions on CML on Tuesday. But the days I've been there have been "full speed download" to my brain. Being back in Europe now, I am now trying to grasp the most important things I learned. I will share the most interesting abstracts in a separate document, so this is mainly to summarize what I found most impressive in the CML sessions.
Brian Druker On the first day, I attended the Education Sessions. It is thought to give hematologists an overview on the current status quo of managing CML. Dr Druker, Talpaz, Goldman and Hughes spoke. In the room I felt like a single BCR-ABL gene in a good molecular response – the biggest meeting room in the convention center can probably hold 10.000 people at a time -- a couple of hundred participants almost got lost in there. It was impressive because Dr Druker held a keynote, honouring the 10th anniversary of Imatinib given to CML patients. A chart what the CML survival was in the pre-Imatinib era again struck me. Before bone marrow transplants were introduced in the 1980s, the only way to treat CML was palliative, meaning, reduction of symptoms until the unavoidable death within months. Today the key challenges in CML are managing resistances and relapses in those patients that to not achieve good remission, or to investigate whether stopping or less aggressively maintaining therapy in good remission is feasible. Overall survival rates in early diagnosed CML are pretty close to the general (healthy) population. We've come quite far, fortunately. But not far enough. People still become resistant or cannot tolerate the drugs, and need to cope with a life-long therapy. Dr Talpaz and Dr Goldman summarized quite well where we stand in CML therapy today:
* What we have: effective first line and second line treatment;
* What could be improved: managing toxicity, improving response rate and duration, avoiding development of resistance, when to change drugs, coverage of "Archilles heel" mutations;
* What is missing: T315I inhibition, elimination of the leukemic stem cells, and treatment discontinuation.
First line CML therapy
In terms of first line therapy after diagnosis, it's been quite simple for newly diagnosed, chronic phase CML patients over the last four, five years: Imatinib was the the gold standard, the only first treatment of choice. Clear treatment guidelines were provided, based on the "ELN recommendations" which were updated just last summer. At this year's ASH, all experts seemed to refer to these criteria and recommendations on managing standard treatment, suboptimal response, treatment failure and monitoring. Now, with the new "second generation" drugs striving for "first line" treatment, we can see a number of new options (and questions) coming up. At ASH 2009, the first line data of comparing Nilotinib and Imatinib in newly diagnosed patients was presented. In the past I have always been a little
suspicious about the enthusiasm for Nilotinib and Dasatinib becoming first-line: for Novartis to be ready with something equally expensive when the Glivec-patent ends in 2016, or for BMS to get a larger piece of the tasty (and huge) Glivec cake. Now there is first evidence that a more powerful treatment at the start might actually make sense.
Along these lines I found interesting that Imatinib-800mg frontline therapy in chronic phase has come a little out of focus. Last year at ASH, some experts were still enthusiastic about "more-is-better" and proposed 800mg/day as first-line, given it had shown quicker responses than Imatinib-400mg. The latest results from the the TOPS and GIMEMA studies have now marginalized that after 18 months: There seems to be no advantage in outcome of Imatinib-800mg in comparison to 400mg. In addition, other comparisons presented by Dr Cortes have shown that response rates of both
Nilotinib and Dasatinib are higher than Imatinib-800mg, with less side effects. So high dose imatinib as initial therapy in chronic phase seems to be no longer regarded (in chronic phase – in advanced phases of course this
seems to be a different story). Other approaches that were discussed by Prof Goldman as initial therapy were combining Imatinib with familiar agents (Cytarabine, Interferon/IFN, Omacetaxine, Arsenicals), or the three TKIs in varying sequence.The French SPIRIT study, as presented by Dr Guilhot, has demonstrated a significant higher rate of optimal molecular responses in the Imatinib-IFN combination (BCR-ABL/ABL below 0.1% at 18 months: 36% on Imatinib400+IFN vs. 19% in Imatinib400 alone). Similar findings were presented on a poster by Dr. Simonsson from Sweden (major molecular responses after 12 months: 86% of those on Imatinib400+IFN, 54% on Imatinib400 alone). More about that below.
Much has been published in recent months about managing resistance to Imatinib. While only a small proportion (15%) of patients treated in chronic phase develop a resistance or show suboptimal response, choosing the most
promising follow-up treatment has been a key topic of interest. More than 100 different mutations are known today. Only a very small number, mainly the fearsome T315I mutation which makes up around 15% of all mutations, is resistant to all of Dasatinib, Nilotinib and Bosutinib. Most mutations can be overcome by dose increase or one of the three drugs – but which one to pick in which case is still a key question. To have a tool for decision making, researchers compiled a table of sensitivities of mutations based on "IC50 values", which measure the level of inhibition of cells in vitro. However, first question marks came up, when Dr Laneuville observed discrepancies between IC50-insensitivities in the lab, and observed response in real patients. He said that obviously some mutations respond differently in the body than in-vitro data would predict. More data on real-life results would need to be collected and documented.
In terms of T315I, Dr Cortes reported about Omacetaxine (Homoharringtonine) which is an intravenous chemotherapy with specificity against CML cells in general, but also frequent side effects. About 27% of patients achieved a major cytogenetic response, even though it was not very durable (median 5 months). More than half of chronic phase patients with T315I have seen a reduction of T315I clone, but only 9% a complete reduction. More pulsating, there are two new promising targeted therapies to BCR-ABL, using a different mechanism than Dasatinib, Nilotinib and Bosutinib. They seem to be effective on the T315I mutation with good tolerability: Deciphera's DCC-2036 and Ariad's AP24534. Dr Talpaz presented first facts on oral DCC-2036, even though he mentioned first trial data won't be available before ASH next year. Dr Cortes presented a phase I study with oral AP24534 where 43% of patients with T315I achieved a major cytogenetic response – quite encouraging. Furthermore, there were reports of MK0457 and XL228, both aurora kinase inhibitors which block an important signaling pathway in leukemogenesis independent of T315I/BCR-ABL. However these are both given intravenous.
However, experience with these drugs are still very early, and trials are rare – so as Dr Nicolini presented, bone marrow transplant currently remains the treatment of choice in case of T315I, if a donor is available.
Dr Hughes presented the Australian "Imatinib cessation" study. In that study, 32 patients were included that had shown complete molecular remission for at least 2 years prior to the study. 17 of them were previously treated
with IFN and then Imatinib, 15 had Imatinib as initial therapy. About half of them relapsed within 18 months, most of them within 6 months after cessation of Imatinib, independent of IFN pre-treatment. Dr. Mahon presented the "STIM" (Stop Imatinib) study. In the pilot study, patients needed to be in complete molecular response (PCR negative) for at
least 2 years before entering the study. 69 patients were included, 34 with previous IFN treatment and 35 only with Imatinib. Of these 69 patients, 41 patients relapsed within the first 7 months. There was no difference between the groups that were pre-treated with IFN, or those that did not have IFN before. He concluded that it is possible to stop treatment in patients with sustained complete molecular response, but recommends discontinuing only in a clinical trial with strict molecular monitoring. During the discussion of STIM, Dr. Talpaz raised the question about the
anxiety of patients stopping therapy. Dr. Mahon answered that patients seemed to be happy because Imatinib side effects disappeared with cessation of the therapy. However this was debated because by experience, side effects
would have been minor in most patients after the 2nd year of Imatinib already.
Dr. Guilhot presented the French SPIRIT Trial on 12 month follow-up with 695 newly diagnosed patients. Treatment arms were Imatinib-400mg, Imatinib-600, Imatinib-400+AraC, and Imatinib+PegIFN. 636 patients were now analyzed. Now at 24 months, there was a clear advantage of the Imatinib+IFN group, with 46% of patients in optimal molecular response (PCR smaller 0.1%), while only 26% of the Imatinib-400mg patients achieved the same response. 22% of Imatinib-PegIFN-patients became PCR-negative, compared to 10% on Imatinib only. Overall, 5-10% of patients discontinued Imatinib during the first year, and 45% of patients discontinued PegIFN. Average doses of Peg-IFN were
54µg/week. He concluded that the superiority of Imatinib+PegIFN combination in term of molecular responses was confirmed at 24 months. Weekly dose of PegIFN has now been decreased to 45µg for the first 3 months of treatment.
There is a relationship between duration of PegIFN exposure and the depth of molecular reponses (which seemed to say, my personal interpretation: better a constant low dose, rather than a high dose of IFN with the risk of
interruptions). In a Nordic CML Study Group (Denmark, Finland, Norway and Sweden) and Israel multicenter study a total of 130 newly diagnosed patients were randomized. CML patients had to be in complete hematological remission following 3 months of Imatinib-400mg induction therapy. The study arms were Imatinib-400mg, and the combination of Imatinib-400mg and Peg-IFNa2b (PegIntron, Schering-Plough). Imatinib dose was fixed at 400mg. Peg-IFN was
started at 30 µg/week but could be escalated to 50 µg/week or reduced down to 15 µg/week depending on tolerability. Major molecaluar response rate at 52 weeks was significantly higher in the Imatinib+PegIFN arm (82%) compared
to the Imatinib-only arm (54%). No unpredictable complications or adverse events were reported.
Interestingly, the presented observation in the German CML-IV Study (comparing Imatinib-400, Imatinib-400+AraC, Imatinib-400+IFN, Imatinib-800, and Imatinib-after-IFN-failure) did not come to the same conclusions. In the trial, so far 954 patients were evaluated. In this study, incidence of major molecular response was higher in Imatinib-800 (61%) as compared to 42% (Imatinib-400) and 45% (Imatinib-400+IFN). Overall survival by therapy did not show any significant difference between the arms. When I asked off the record, some were assuming that the difference might be due to "normal" Interferon being used in the CML-IV study, while the above studies used pegylated Interferon, leading to better tolerability and hence better exposure of the CML cells to Peg-IFN.
Lastly, the Italian GIMEMA trial comparing Imatinib-400mg with Imatinib-400+IFN: While there had been initial advantages of the combination arm, at 24 months these differences were lost. No surprise: the proportion of patients in this trial continuing IFN dropped from 41% at 12 months to 18% at 18 months, 13% at 24 months, 3% at 36 months, and by the end of the fourth year, all patients were off IFN. No information about IFN dosage was given (but some might suspect dosage was the problem).
Dr Burchert (Marburg) presented an update to the German Peg-IFN maintenance study. He reported that while Imatinib has shown high efficacy, it fails to eradicate leukemic stem cells and suppresses leukemia-specific immue responses. At the same time, Interferon stimulates T-lymphocytes against CML cells. In the study, 20 patients were treated with Imatinib+IFN. 19 were in complete cytogenetic response, 15 in major molecular response, and 2 were PCR negative. Patients stopped Imatinib and continued with Interferon only. After 2.8 years, 4 had further improved their response, 9 remained stable, and 5 had a gradual relapse. As a conclusion,Dr Burchert said that achieving PCR negativity would not be a prerequisite for successful Imatinib termination and IFN maintenance therapy.
CML in Children
One of the unforeseen surprises was the presentation of data on Imatinib treatment of children with CML. Childhood CML is extremely rare, with only 2% of all childhood leukemia cases, so data is very limited. Prof Suttorp from Dresden presented the results of the PAED-II study. 51 patients were recruited. Median age was 11 years (1-20), 48 in chronic phase, 1 in accelerated phase, and, 3 in blast crisis. 6 of 42 patients stopped Imatinib because of insufficient response. 4 received 2nd generation TKIs, 2 opted for stem cell transplant. 49 of 51 patients are alive today. The researchers observed an impact on bone metabolism: the effect is that Imatinib decreases osteoblast development and activity, decreasing bone growth. As a conclusion, Suttorp said Imatinib treatment results in high response rates, while side effects are tolerable. Therefore, stem cell transplant has been shifted to a 2nd line strategy also in pediatrics. Changes in bone marrow metabolism and growth impairment are of special concern in not yet outgrown pediatric patients.
The issue of adherence, or compliance to therapy, remains to be a challenge with TKIs. Dr Goldman presented data collected at the Hammersmith hospital. In a trial, they had provided patients with a medication bottle whose cap had some electronics built in. The bottle automatically recorded each time the bottle was opened. That way they observed that more than every fourth CML patient did take less than 90% of the prescribed dose, and every seventh less than 80%. They found a strong association of response to therapy with adherence rate: the 6-year probability of achieving major molecular response was 28% with those patients taking less than 90% of prescribed doses, and 95% for those that were adherent. The same applied for complete molecular response (0% vs 44%). Interestingly, when comparing the electronic measurement against what patients said to their doctor, patients claimed to be much more compliant than they actually were. This shows the lack of adherence remains largely underestimated (Abstract 3290).
It was again a great time at ASH, not only from the perspective to meet friends and top doctors, but also from coming home with the confidence that even though CML therapy has already radically improved over the last years, there is exciting progress and a lot of enthusiasm to close the existing gaps. There is still a lot of room for improvement – about every seventh CML patient does not respond to Imatinib up front, and a number of patients can't tolerate it. However, the second line data of (lower dose) Nilotinib, Dasatinib and Bosutinib presented this year seems to be a great step forward, and for the "last bastion", the T315I, there are a number of new drugs in trials which seem to be targeted, promising and tolerable. This is great news to me, in comparison to ASH 2008.
In terms of finding a cure, there could still be more progress. However, I could see progress in research targeting residual stem cells, understanding mechanisms behind suboptimal response, avoiding early progression with improved first-line treatment, and considering new (and/or more affordable and/or more tolerable) long-term maintenance therapies. In contrast, the results of the "STOP" trials from France and Australia have not convinced me – if the relapse risk is fifty-fifty, I would be hesitant trying it if I can tolerate treatment well, even if re-starters seem to respond again to
Recent reports about low-dose Interferon as maintenance therapy in minimal residual disease – in combination with Imatinib or not – are promising, as shown in Germany and Sweden. Maybe further research will show who has an immune response to Interferon, and those might have a minimal relapse even after stopping all therapies. However, it seems low dose Interferon requires adaptive dosing: In the Italian GIMEMA trial all patients stopped Interferon treatment within 3 years because of side effects, while the Swedish and the two German trials had shown long-term benefits with good tolerability. But one of the best ASH messages for me was from Childhood CML: In CML kids, whose decisions should be based on the expectation that they should expect another 80 years of life, transplantation has now become second line after Imatinib. I think – and hope – this is a message for all CML patients: that experts are expecting current therapies to keep us alive in the long term. Chances seem to be good that we have the chance to grow very old, as long as we adhere to therapy – until someone has found the bullet to kill also the
small gang of stubborn CML stem cells off.
All this is encouraging. And this is why I spend St. Nicholas in the US.
Jan Geissler, 13 Dec 2009