ASH 2009 Recollection: a patient perspective

"Actually, why do I always spend the St Nicholas holiday in the US, instead of with my family", I asked myself when I boarded the plane to the USA on 4 Dec 2009, in anticipation of a long 16 hour trip to the USA, hiding for days in the dungeons of a large convention center. However, from a patient perspective, it was again worth it. Year by year, more than 20.000 hematologists and healthcare people attend the annual meeting of the American Society of Hematology. All top experts from the CML space are presenting their research here, competing for the hottest piece of news from clinical trials.

Education Sessions

On the first day, I attended the Education Sessions, providing an overview on the current status quo of managing CML. Brian Druker, Moshe Talpaz, John Goldman and Tim Hughes presented. 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 interested in CML almost got lost. Dr Brian Druker held a keynote, honoring the 10th anniversary of imatinib given to CML patients. A chart showing the CML survival 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. Today the key challenges in CML are managing resistances and relapses in those patients that do not achieve good remission, or to investigate whether stopping or less aggressively maintaining therapy in remission is feasible. Overall survival rates in early diagnosed CML are pretty close to the general population. We’ve come quite far, fortunately. But we are not yet there. Some patients still become resistant or cannot tolerate the treatments, and all need to cope with a life-long CML 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 I was glad to see how active the CML research community is to close these gaps.

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 to five years: imatinib was the Gold Standard, with clear treatment recommendations which were recently updated. 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 new questions) coming up. In the past I have always been a little suspicious about a purely commercially-driven enthusiasm for nilotinib and dasatinib becoming first-line: due to the end of the imatinib patent, or to get a larger piece of an existing huge cake. Now there seems to be first evidence at least that due to the lower progression rates in the first year of nilotinib first-line, a more powerful treatment for induction might actually make sense. Some more years are required to get more clarity. The challenge of adherence to nilotinib due to a twice daily schedule, as well as the requirement not to eat before and after taking the drug, will remain a challenge though. First-line data on dasatinib is expected to be published at EHA2010. Along these lines I found interesting that High-Dose-imatinib in frontline even chronic phase has come off focus. The latest results from the TOPS and GIMEMA studies after 18 months seemed to have marginalized the “more-is-better” approach. Prof Goldman also addressed initial therapies combining imatinib with familiar agents (Cytarabine, IFN, Omacetaxine, Arsenicals), or administering three TKIs in varying sequence.

Managing Resistance

Much has been published in recent months about managing resistance to imatinib. While only a relatively 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 making up around 15% of all mutations, are resistant to dasatinib, nilotinib and bosutinib. Most other mutations can be overcome by imatinib dose increase or one of the three second line drugs – but which one to pick in which case remains a key question.

A table of sensitivities of mutations based on “IC50” has since been used, which measure the level of inhibition of cells in vitro. However, first question marks came up when people e.g. Dr Laneuville observed discrepancies between IC50-insensitivities in the lab and observed response in real patients. More data on real-life results would need to be collected and documented.

In terms of T315I, Dr Cortes reported about omacetaxine (Homoharringtonine). 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. There are two new promising targeted therapies to BCR-ABL with T315I, using different mechanisms: Deciphera’s DCC-2036 and Ariad’s AP24534. Dr Talpaz presented first facts on oral DCC-2036. Dr Cortes presented a phase I study with oral AP24534 where 43% of patients with T315I achieved a major cytogenetic response – encouraging. Furthermore, there were reports of MK0457 and XL228, both aurora kinase inhibitors which block an important signaling pathway in leukemogenesis independent of T315I/BCRABL. However these are both given intravenously. Experience with these drugs is 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.

Stopping treatment

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 interferon (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. 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.

Imatinib-Interferon combination

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. At 24 months, there was a clear advantage of the imatinib+IFN group, with 46% of patients in optimal molecular response, while only 26% of the imatinib-400mg patients achieved the same. 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 PegIFN were 54µg/week. He concluded that the superiority of imatinib+PegIFN combination in term of molecular responses was confirmed at 24 months. There was an observed relationship between duration of PegIFN exposure and the depth of molecular reponses (which seemed to say: 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, presented by Dr. Simonsson, a total of 130 newly diagnosed patients were randomized. CML patients had to be in complete hematological remission following 3 months of imatinib induction therapy. The study arms were imatinib- 400mg, and the combination of imatinib-400mg and PegIntron. Major molecular 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, imatinib-IFN combination and high dose imatinib did not come to the same conclusions. Overall survival 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 PegIFN, leading to better tolerability and hence better exposure of the CML cells to PegIFN.

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 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 suspected dosage was the problem).

Interferon maintenance

Dr Burchert (Marburg) presented an update to the German PegIFN maintenance study. He reported that while imatinib has shown high efficacy, it fails to eradicate leukemic stem cells and suppresses leukemia-specific immune responses. At the same time, interferon stimulates T-lymphocytes against CML cells. In the study, 20 patients were treated with imatinib+PegIFN. 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 with 51 patients. The researchers observed an impact on bone metabolism, 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 grown pediatric patients. Adherence 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 took 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.

Summary

It was again a great time at ASH, coming home with the confidence that even though CML therapy has already radically improved over the last years, there is still exciting progress and a lot of enthusiasm to close the existing gaps. For the “last bastion”, the T315I, there are a number of new drugs in trials which seem to be targeted, promising and tolerable. In terms of finding a cure, there could of course still be much more progress. The results of the “STOP” trials have not yet been convincing – 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 imatinib.

Recent reports from Germany and Sweden about low-dose/PegIFN as maintenance therapy in minimal residual disease – in combination with imatinib or not – are promising. Maybe further research will show who has an immune response to IFN, and those might have a minimal relapse even after stopping all therapies. However, the difference between the trials shows that IFN requires adaptive dosing to be tolerable and effective as a maintenance therapy. But one of the best ASH messages for me was from childhood CML: For 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. Chances seem to be good that we CML patients - as long as we adhere to therapy (until someone finds the bullet to kill also the small residual gang of CML stem cells) have the chance to grow very old.

All this is encouraging. And this is why I spend St. Nicholas in the US.

Jan Geissler (CML Patient since 2001), 13 Dec 2009
Full text article: http://www.cmladvocates.net
Contact: jan@cmladvocates.net
Jan is also the iCMLf Communications Coordinator