ASH Report by Jan Geissler

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ASH 2009 Recollections – and why I went there again…

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Written by Jan Geissler

Tuesday, 15 December 2009

ASH 2009 " Actually, why do I always spend St 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

jetlagged, 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.

Education Session

DrukerOn 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 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

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, 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.

We know from the IRIS trial, whose 8 year data was presented just with a

poster showing that no new surprises came up in long-term follow-up, that

relapses on Imatinib happen mostly in the first years of treatment: about 6%

of all patients relapse in the first three years, then the relapse rate

drops near zero. Now with the ENESTnd trial directly comparing Imatinib

400mg/day with Nilotinib 2x400mg/day and 2x300mg/day, not only quicker

responses were observed on Nilotinib, but also the progression rate in year

1 was significantly lower than on Imatinib. Of 282 patients in on Nilotinib,

only 1 progressed to advanced disease, while of 283 patients on Imatinib, 11

progressed. In addition, the frequency of treatment interruptions due to

side effects was comparable between the options. This was only a 12 months

follow-up, some more years are required to get more clarity – but it is an

interesting perspective. 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.

Off the record, I heard that similar comparative first-line data on

Dasatinib and Imatinib might get ready for publication by EHA in June 2010.

This is where it will get really interesting, as it will allow us to compare

response rates, progression rates, and side effect profiles of all three

drugs in first-line.

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.

Managing Resistance

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.

Stopping treatment

Dr 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.

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. 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).

Interferon maintenance

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.

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 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).

Summary

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

Imatinib.

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. in the US.

Jan Geissler, 13 Dec 2009

More information

Discuss about ASH 2009 and its findings - CML Advocates Network Discussion

Forum

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iew & id=274 & catid=15> (for members only, registration required)

Download file: Best of ASH 2009 CML Abstracts (PDF File)

<http://www.cmladvocates.net/index.php?option=com_remository & Itemid=28 & func=

fileinfo & id=153> - a collection of summarized and simplified ASH Abstracts

which I found most interesting. (For CML Advocates Members only,

registration required)

Last Updated ( Wednesday, 16 December 2009 )

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Zavie (age 71)

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Ottawa, Canada, K2G 3X3

dxd AUG/99

INF OCT/99 to FEB/00, CHF

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Gleevec since MAR/27/01 (400 mg)

CCR SEP/01. #102 in Zero Club

2.8 log reduction Sep/05

3.0 log reduction Jan/06

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3.6 log reduction Sep/08

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4.0 log reduction Dec/09

e-mail: zmiller@...

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