At the 54th annual conference of the American Society for Hematology (ASH 2012), 159 results from clinical studies on CML were presented: 36 were presented orally, and 123 were featured on posters. We have personally chosen a selection of these in order to summarize the most important news e.g. updated data and new drugs in CML therapy, a new milestone to achieve <10% BCR-ABL at 3 months, "deep molecular remission" as a pre-requisite for a possible cessation of therapy, and Interferon combination studies.
(English, German and Hebrew versions by Giora & Jan, Russian translation by Sodeystvie, Chinese translation by Shanghai Roots & Shoots, Serbian translation by CML Serbia, Arabic translation donated by Nicola Srouji - thank you!)
1 Established and new CML therapies
2 The decisive first three months in firstline treatment: the 10% PCR milestone
3 The race towards "Deep Molecular Remission"
4 To STOP or not to STOP?
5 Interferon - outdated or the icing on the cake?
6 New avenues - and other interesting observations
7 Why this probably wasn't our last ASH visit
Just a few years ago, choice of therapy for CML in the chronic phase was relatively clear: Imatinib was approved for treating CML in 2001/2002, if a transplant was not indicated. In 2006, Dasatinib was approved for use for those who failed Imatinib, in 2007 Nilotinib followed. In 2010 both medicines were also approved for first-line therapy. After having been in use for 7 to 8 years, all three became "established" and known therapies. Ponatinib and Bosutinib have just been approved in the USA for second- or third-line therapy. An ASH presentation surprised the audience with the heretofore unknown Radotinib (IY5511), another tyrosine kinase inhibitor for CML from Il-Yang Pharma in Korea. In the year 2016, the compound patent for Imatinib will expire in Western Europe and other regions, and generic manufacturers are already on their marks. Many studies are currently underway or being prepared, for example on improving suboptimal response, on the prediction of therapeutic success, on ending therapy in good remission, and on better understanding how to tackle residual CML stem cells. It seems that only a CML expert (or those being treated by one) could evaluate the relevant options. Many of these experts were at the ASH Conference to present new results and publicly discuss the options.
At ASH 2012, there were different updates on the drugs Dasatinib (Abstract #1675, DASISION Study), Nilotinib (ENESTnd, Presentation #167, Poster #1676) and Bosutinib (BELA, Presentation #69, Posters #3779, 3785, 2793, 2798), all of which followed the motto "no bad news is good news," showing excellent rates of response and little negative surprises. The second generation of drugs are further developing their advantages over Imatinib: the percentage of patients who reached a response level of MMR (BCR-ABL <0.1%), MR4 (<0.01%) or MR4.5 (<0.0032%) is significantly higher with the newer drugs: for Nilotinib, Professor Andreas Hochhaus presented 4 years' of data from the ENESTnd first-line study at the ASH, in which 846 newly diagnosed CML patients in 35 countries took part. After 4 years, 56% of patients taking 2x300mg of Nilotinib reached MR4, compared to 32% under Imatinib. The advance of the Nilotinib response compared to Imatinib has further increased in year 4 when compared to the year 1 data (from 14% to 24%). In the DASISION Dasatinib study, of which there is only three years' of data to date, 35% of Dasatinib patients and 22% of Imatinib Patients reached MR4.
If we only look at "bare survival," then for all patients who fall below the 10% BCR-ABL mark after 3 months, and then reach a good molecular remission, survival stays close to that of the normal population in the long term - regardless of whether they reached it using Imatinib, Nilotinib, or Dasatinib. In 4 years, only 4 out of 281 CML patients died while under Nilotinib treatment, and 13 out of 283 died while under Imatinib.
Unfortunately, however, there are patients who do not reach this 10% milestone, who develop resistances, or who do not tolerate the drugs well. Even with the strongest drugs like Ponatinib, the blast crisis survival rates are still depressing (ASH Presentation #915). That is why the focus of the experts is on preventing CML from ever having the chance to progress to that level.
The rates of progression under Dasatinib, Nilotinib, and Bosutinib are significantly lower than under Imatinib, with the second-generation drugs "protecting" about 3% of CML patients from disease progression at early stages after diagnosis (as 1.8% of patients on Nilotinib in ENESTnd and 4.2% on Dasatinib in DASISION progressed to accelerated or blast phase). Therefore, experts actually advise the use of second-generation drugs like Nilotinib or Dasatinib as first-line therapy after the diagnosis in almost all cases, as well as switching to them early on in the case of "warning signals," like for example less than optimal response after 3 months. The data presented at the ASH Conference once again showed the importance of targeted treatment at the hands of CML experts, who are familiar with recent research data and know (and can recognize) warning signals and risk factors.
The choice between Nilotinib or Dasatinib (or even Imatinib) as first-line therapy increasingly depends less on the statistical effectiveness of the drug (which is nearly equal for Dasatinib and Nilotinib), but on individual factors present with each patient. David Marin reminded the ASH of the pros and cons of the approved drugs: Imatinib is somewhat cheaper, it has been well known for over 10 years, and has a once-a-day dosage, but patients respond slower to it than to all of its "successors".
Nilotinib is stronger and is described as being tolerated a little better than Imatinib, but it requires special attention when it comes to patients with diabetes (ASH Abstract #3756) or patients with several concurrent cardiovascular risk factors (smoking, high blood pressure, diabetes, obesity, metabolic disorder, ASH Presentation #914). Some patients also have difficulty keeping up with Nilotinib therapy or see some challenges with returning to normal life, because of the twice-daily Nilotinib dosage, combined with 3 hours of fasting each. In contrast, Dasatinib is not influenced by food intake, and, as being potentially the strongest approved drug, it is also the first choice for advanced CML. However, it also leads to increased accumulation of liquids between the lungs and the ribs (pleural effusions, ASH Poster #3770) and possibly also to high blood pressure in the pulmonary arteries.
The drug Bosutinib, which was recently approved in the USA but not yet in Europe, is also highly effective, but it has led to diarrhea in many patients at the onset of treatment (which is however well manageable).
Many patients diagnosed with CML are in an age group that tends to have additional comorbidities. Selecting a treatment needs to reflect the individual situation of the patient - not just the fact that he/she has CML. All of the individual characteristics of each treatment, along with the CML status, secondary diseases, and psychological factors, mean an experienced doctor must consider all different therapy options on a case-by-case basis. There is no "one size fits all" rule.
Furthermore, none of the drugs mentioned above are effective in the presence of the T315I-Mutation. Dr Neil Shah presented at the CML Satellite Sympoisum that about 2% of chronic phase CML patients will develop the T315I mutation under Imatinib treatment, and a much larger share in in advanced CML phases. Ponatinib (previously AP24534), which was approved in the USA on 14 Dec 2012 for use in CML second-line therapy, is the only one to be able to overcome this mutation. The 12 months' results from the PACE study, presented at the ASH, in which 449 patients took part after failed Nilotinib and Dasatinib treatment, provide great hope: although two or three other TKIs had failed in many CML patients, 34% reached a BCR-ABL of under 0.1% (MMR), and 9 out of 10 patients maintained this response in the long term. The overall survival rate after 12 months is an impressive 94%. Of the 64 patents that showed multi-resistant T315I mutations, 70% attained a good response in the bone marrow (good cytogenetic remission). Different ASH presentations and posters described the rates of response and side effects of Ponatinib (ASH Presentations #163 and #915, Poster #3763). The most common side effects of Ponatinib are skin rashes, dry skin, thrombocytopenia, stomach aches, exhaustion, headaches, aching limbs, nausea, and sometimes also high blood pressure and increased liver values. With the approval, the FDA has also mandated a warning on safety concerns on arterial thrombosis (occurring in 11% of patients, mostly with cardiovascular pre-conditions) and liver toxicity (with 41% of patients showing treatment-related lipase elevation).
In cases where Ponatinib is unavailable, Omacetaxine (ASH poster #2787) which was approved in October 2012 by the FDA, might be another option. It is a protein synthesis inhibitor with modest activity and modest response duration in CML patients e.g. with the T315I mutation.
The definition of milestones during cancer therapy is crucial for medical decision-making. Milestone help to decide whether to proceed with the current line of action, or possibly change the direction. Since 2009, the expert recommendations from the European LeukemiaNet (ELN) have defined CML therapy goals in the 3rd, 6th, 12th, and 18th month after the start of therapy.
One year ago, however, on the basis of the CML Study IV, the German CML research group proposed that reaching the 10% BCR-ABL mark according to international standards after the third month could in itself be a decisive prognostic milestone. This emerged to be a dominant topic at this year's ASH congress: half a dozen presentations were dedicated to the different therapies and to different studies on the topic of "early response". In the ENESTnd and DASISION first-line studies, about 9 of every 10 patients achieved the 10% BCR-ABL milestone under Nilotinib and Dasatinib after 3-4 years, but only slightly two thirds of those taking Imatinib (ASH Presentation #167, Poster #1675).
Experts unanimously agreed: missing the 10% mark after three months is linked with a significantly lower probability of reaching a good molecular response, or even PCR negativity, later on. This observation on Imatinib also holds true for Dasatinib (ASH Poster #1675) and Nilotinib (ASH Poster #2797) as a first-line therapy. Furthermore, Dr. Neelakantan also proved that a 6-month milestone of 1% no longer seems to have any informative value - while falling below 10% after month 3 remains the decisive factor.
ENESTnd, the Nilotinib first-line study, clearly indicates that only 1 in every 10 Nilotinib patients, but 1 in every 3 Imatinib patients, misses the 10% mark after three months (ASH Presentation #167, Poster #1676). The DASISION study data for Dasatinib show very similar results (16% under Dasatinib and 36% under Imatinib). So, could changing therapies if the patient misses the 10% mark after three months lead to the desired response? In the context of the Australian TIDEL study, it was shown that even with an early, quick switch from Imatinib to stronger drugs, there was already progression in some patients before the end of month 3. This seems to support starting with second-generation drugs (Nilotinib or Dasatinib) straight after the diagnosis, in order to give CML as little chance as possible to progress right from the beginning, and to reach the "safe haven" of MMR (BCR-ABL <0.1%). Once that is achieved, regardless of which TKI medicine is used, the patient is "practically safe".
It remains unclear, however, whether rapidly switching therapies after failing the 10% mark after month 3 has real advantages. Patients with slow response, regardless of which drug is used, may have a more "therapy-resistant" form of CML, in which case a poor prognosis would not be changed by switching medicines early. This hypothesis, however, is yet to be substantiated.
However, we need to put this into a realistic perspective: "bad prognosis" is quite relative. The 4 year survival rate under Nilotinib, according to the ENESTnd data, is at 97% for patients in the "best responding" (<1%-BCR-ABL after 3 months) group, and at 87% for patients in the >10% BCR-ABL group. We need to remember this is pure statistics and we should be careful in frightening CML patients with the expression "bad prognosis": the chances of growing old are high for all chronic-phase CML patients across risk classes. What is marked as "bad prognosis" in CML today is actually a survival level still unachievable in most other cancers!
Another dominant theme during the conference was "deep molecular remission". Triggered by the intense discussions around the STOP studies, which require a long-term, stable remission of at least MR4 (BCR-ABL <0.01%) or MR4.5 (BCR-ABL <0.0032%) in order to take part, it is of concern how to extend this option to as many patients as possible.
At ASH, Dr. Tim Hughes introduced the two years' results from the ENESTcmr study (ASH Presentation #694). Imatinib patients could participate in the ENESTcmr study if they had reached complete cytogenetic remission after at least 2 years of Imatinib therapy, but had not yet attained MR4.5 (BCR-ABL-ratio <0.0032%). Half of the patients who participated in the study switched to Nilotinib 2x400mg, while the other half carried on with Imatinib. After two years, about twice as many Nilotinib patients as Imatinib patients had reached a deep molecular remission of at least MR4.5 (42.9% vs. 20.8% of the patients). Note: even under Imatinib, one in every five patients also had this kind of positive response. For many of those who switched to Nilotinib, however, the higher probability of reaching MR4 "came with a price" in the first year: 29% of Nilotinib patients reported significant side effects, compared to only 2% of Imatinib patients, since their side effects had already leveled off some years ago. 9% of Nilotinib patients had to end Nilotinib therapy because of the side effects. After 12 months, however, the Nilotinib side effects had also leveled off - in year 2, only 4% of Nilotinib patients still suffered from significant side effects.
This could mean that switching from Imatinib to Nilotinib (or Dasatinib) during a good, but not perfect remission increases the speed and probability of reaching deep molecular remission (MR4.5, BCR-ABL <0.0032%). MR4.5 might be the condition for entering into STOP studies. The likelihood can be increased by switching to a new drug, which often leads to stronger, but temporary side effects, which patients had long ceased experiencing under Imatinib. The switch may mean starting a drug which must be taken twice a day, with about six hours of fasting time in total. The alternative is to carry on with Imatinib and, over time, to hope for deep remission without changing treatment.
During informal conversations, it seemed that CML experts had different views on how to advise patients who are currently on Imatinib: some were of the opinion that "the lower the better". Even if the above hypothesis maintains that patients with stable MMR (BCR-ABL <0.1%) have reached a "safe haven" and that further CML progression is extremely unlikely, they would be "even safer" with an even lower PCR. Other CML experts, however, are critical of this approach and see it as a tactic: switching patients who have responded very well to Imatinib (which will soon be generic) and who are considered to be "safe" to a drug that is stronger, but ultimately more costly in the long run.
In the end, however, it is important for studies like ENESTcmr to be continued, in order to see if the percentage of Imatinib and Nilotinib patients who reach MR4.5 evens out in the long run, or if the switch does give patients any significant advantage in survival. As survival is already excellent on Imatinib, it is difficult to demonstrate survival advantages of the new drugs within just a few years - a longer follow up is necessary. This also depends on the patients' preferences - whether they want to stop treatment as soon as possible, and therefore agree to switch drugs, or whether they would rather carry on with the current, hassle-free drug, even if that probably means taking it for many more years. At this point in our state of knowledge, there is no right or wrong.
When is it safe for CML patients to stop treatment, without putting themselves in danger? This question has preoccupied the CML community since the first data from the French STIM study (STop IMatinib) were introduced about two years ago. In that study, 100 CML patients under Imatinib treatment took part in the study. During six consecutive PCR examinations over a time period of two years, none of them had shown any more signs of BCR-ABL. The Imatinib therapy was then terminated under strict monthly PCR examinations, and started up again if BCR-ABL values started to rise again above a certain level.
After 36 months, 39% of patients maintained complete remission, but 61% had to start therapy up again. Most relapses happened very quickly, in other words, in the first seven months after treatment was ended. However, there were also later relapses, in months 19, 20, and 22. The PCR often rose very quickly in just a few days, so CML was returning with force. The Australian CML8 STOP study, presented at the ASH conference by Dr. Susan Branford, showed similar results. The good news is that all "relapsed" STIM and CML8 patients once again responded to therapy.
However, experts clearly indicated that stopping treatment outside of the context of a study is absolutely not recommended: monthly PCRs, access to the best PCR laboratories, and an immediate reinitiation of therapy should the PCR go up again, may have been the guarantee that the patients did not slide into accelerated CML. The risk factors to determine who can stop treatment "more safely" than others are still unclear - the STIM data show a slight advantage for female patients and patients who already had a BCR-ABL ratio of less than 1% three months after the start of therapy following diagnosis, also known as "fast respondents". (A German study group has recently published a paper in the "Blood" journal suggesting a mathematical model to predict the long-term response and the individual risk of molecular relapse upon treatment cessation, but this has not been presented at this ASH congress.)
After all the hype around stopping therapy, the question remains: how many patients can even hope for MR4.5, followed by successfully stopping therapy without relapse? Until now, the studies done on stopping treatment in France, Japan, Korea, and Australia show relapse rates following the end of treatment between 76% (in Japan, where treatment was started again after a single positive PCR result) and 39% (STIM2, where treatment is started again as soon as MMR is exceeded). In any case, only a fraction of CML patients ever reach a deep molecular remission which would allow for treatment to be stopped. Dr. Susan Branford estimates, based on the data from all the participants in all the clinical studies at her institute, that after 8 years of Imatinib therapy, only about 14% of patients can successfully stop treatment - and therefore the other 86% of patients would not have reached the appropriate stage of deep remission or would have relapsed after cessation.
In the ENESTnd study, after 4 years, 40% of Nilotinib patients reached an MR4.5, as did 35% of patients under 3 years of Dasatinib treatment in the DASISION study. If we assume that this kind of MR4.5 remission should be maintained for at least another 2 years before treatment can be stopped, and speculate that only half of the patients will stay in remission after therapy cessation, then only about 1 in every 5 CML patients under Dasatinib/Nilotinib first-line therapy could successfully stop treatment.
So, is stopping treatment only of interest for a small minority? Since the stronger drugs, Dasatinib and Nilotinib, lead more CML patients to a deep molecular response, the pool of candidates who could stop treatment may actually be larger using these drugs. Dr. Delphine Rea from France presented the results of her second-generation-TKI STOP study at the ASH congress (ASH Presentation #916). To be eligible, patients had to already have undergone at least 3 years of a TKI therapy, most recently under Dasatinib or Nilotinib, and should have been PCR-negative for at least 24 months. 39 patients took part in this small study. During the first year, a very sensitive PCR test was carried out every month, and from the second year, it was carried out every 2-3 months. Unlike the first STIM study, exceeding MMR (0.1% BCR-ABL) was the criteria starting therapy again, and not an PCR increase by one log - in other words, the relapse criteria were less strict. In this study, 16 patients (41%) lost their good molecular response (MMR) and had to start therapy again. The relapses usually happened very quickly (on average within 3 months), however, in one case relapse took place after 25 months. The observation period of this study is rather short (on average 7 months after starting therapy again, for those who relapsed). Therefore nothing conclusive can yet be said about the rate of response to treatment amongst those patients who relapsed, but 11 of the 16 patients reached PCR-negativity again after an average of 4 months, and three of them also reached at least MMR. Having been switched early from Imatinib to a second generation TKI after suboptimal response to Imatinib was identified as a risk factor for relapse after treatment cessation.
What does that mean in practical terms? As of now, stopping treatment is only an option, and might only be successful, for a small percentage of patients. In informal conversations, all the experts we spoke to were unanimously of the opinion that treatment should only be stopped in the context of a study. There is a growing concern that some hematologists support to stop treatment on individual initiative. In a number of countries, STOP studies are available, or will become available, in the next few months for patients under Imatinib, Dasatinib, and Nilotinib. Studies benefit from a strong safety net (monthly PCR checks, the best possible quality of PCR laboratories, confirmation that all reasonable conditions for therapy cessation are fulfilled, an instant return to treatment if necessary - plus structured learning from joint experience in the study). Those who are currently in a deep molecular remission are not missing out on anything until suitable STOP studies are available - on the contrary, the longer patients stayed in deep molecular remission while under therapy, the higher their chances were of maintaining that remission after treatment was stopped. Continuing therapy today might increase probability to safely stop later.
Do CML patients want to stop treatment, and if so, how is the risk perceived? A poster (#4274) presented the results of a survey of 38 Canadian CML patients of different educational levels in the period between June and August 2012. The patients had been under CML therapy for more than 50 months - a little over half were under Imatinib, and the rest under Nilotinib and Dasatinib. It is interesting to see that patients' preferences changed depending on the expected rate of relapse - while most patients were ready to stop treatment at the prospect of a 20% failure rate, the majority preferred to "carry on" with treatment if the relapse rate was 60%.
The French SPIRIT study (ASH Abstract #168), which had already been presented at previous ASH conferences, shows that the combination of Imatinib with Peg-Interferon can trigger a faster and deeper molecular response than an Imatinib monotherapy. In addition, it is has been known for many years that Interferon even in lower doses can trigger an immune response against CML. There is some evidence that after leukemia has been diminished radically to a minimal level, an interferon-stimulated immune system could possibly keep some residual leukemia under control without any further maintenance therapy.
At this year's ASH conference, the MD Anderson Cancer Center presented 30 years' data on their CML patients, who for decades have received Interferon monotherapy as first-line treatment (ASH Presentation #918). Only about 30% of those patients are still alive today, and 80% of surviving patients had to switch to tyrosine kinase inhibitors or stem cell transplants due to a lack of response to Interferon monotherapy. However it is very interesting to look at those that remained in stable on Interferon only. The 30 years' data was conclusive, because it showed that about 6% of patients maintained stable molecular remission without any kind of therapy after stopping Interferon treatment, even though they still had measureable BCR-ABL levels. The authors attribute this to the long-term immunoactive benefits of Interferon against CML.
The French SPIRIT study research group presented early data at the ASH conference from a single-arm study which combines the even more powerful Nilotinib with Peg-Interferon (ASH Presentation #166). The goal of the "NiloPeg Study" is to examine the tolerability and the response to the combination more closely. To this end, newly diagnosed CML patients first received a month's worth of Peg-Interferon alone, and then a half-dose of Interferon combined with 2x300mg of Nilotinib. The study measured side effects and response, as well as quality of life and the doses actually administered. By month 12, 17% of all patients reached at least MR4.5 (BCR-ABL <0.0032%), a further 34% reached at least MR4 (<0.01%) and another 24% reached MMR - meaning that 3 out of every 4 patients were in very good remission after 12 months. Commonly reported side effects included anemia in 5% of patients and thrombo-cytopenia among 41%, but these side effects showed up most often in months 2 and 3 then tapered off. Furthermore, during the first three months there were certain distinctive features in liver metabolism and serum lipid levels, as well as stomach pains and depression. A French phase III study which will compare Nilotinib administered alone with Nilotinib+PegInterferon is currently being prepared. The German TIGER study, which also uses both Nilotinib and a Nilotinib+PegInterferon combination, is already enrolling patients at several German study centers.
Another interesting poster (#1684) from a Japanese CML work group demonstrated that IFN monotherapy may also represent a promising option for maintaining molecular response after Imatinib discontinuation in CML patients in CMR. 12 patients on Imatinib who had been PCR-negative discontinued Imatinib and then received 3 million units of standard Interferon 2-5 times per week. After a median follow-up of 23 months, three patients lost MMR (but regained it after resuming with Imatinib treatment), and nine remained in molecular remission. The study foresees that all patients who maintain MMR by Interferon for 2 years will then stop treatment with Interferon.
At an evening meeting, outside of the official ASH programme, Dr. Stephen O'Brien from the UK presented the CML Working Group UK's planned "SPIRIT 3" study. The study aims to "evaluate the most effective way to use Imatinib, Nilotinib and Ponatinib in newly diagnosed CML". The study randomizes up to 1.000 newly diagnosed CML patients to Imatinib and Nilotinib as first-line treatment. Slow responders failing the 10% BCR-ABL mark at 3 months will be switched to Ponatinib. If patients have achieved MMR (BCR-ABL <0,1%) on any treatment arm for a duration of at least 2 years, they will reduce their dose to 50%. If they still remain in MMR then, they stop all treatment after one additional year. Monitoring will only be done by PCR and no bone marrow will be required during the whole study. Patients will be supported with mobile phone apps and home delivery of medicines. When we were speaking to other experts about the protocol, opinions varied largely from enthusiasm to unrest, featuring strong opinions e.g. against sub-therapeutic dosing, stopping at a relatively moderate response levels (MMR), and using the relatively unknown Ponatinib on "early switching". New avenues with a courageous trial design, or too many variables changed in one go? We are curious to hear news and discussions about this UK-based study in the future.
Using Thalidomide to treat CML patients who are resistant or intolerant to Imatinib in countries where second generation drugs Nilotinib or Dasatinib are not available was presented by a Mexican research group (ASH poster #1689). Even though this has been a study with a small number of patients, some response has been observed alongside with acceptable toxicity. More data needs to be collected, but the use of Thalidomide with Imatinib may represent a future alternative therapeutic option for patients with Imatinib resistance and without access to other treatments.
An Italian research group (ASH abstract #2784) found that CML patients with high body mass index at diagnosis may be subject to delayed or reduced rate of cytogenetic responses and molecular responses. To the contrary, in a small group of patients on Nilotinib, no difference of with normal and high BMI could be observed. The researchers suggest that CML patients on standard-dose Imatinib which are overweight/obese should be monitored more closely and might be switched to stronger second generation drugs early, or may receive these as first line treatments.
As usual, this year's ASH conference was very interesting, especially because of the presentations, but also because of the informal conversations with experts before and after the sessions. Compared to some other forms of leukemia and lymphoma, CML is privileged having a range of highly effective and well-tolerated therapies.
In the long term, there seem to be only a few new concerns about the effectiveness and safety of Imatinib, Dasatinib, and Nilotinib, which are mainly connected to patients with secondary diseases or risk factors.
Patients diagnosed with CML today can have a nearly normal life expectancy, when they are treated by CML experts (although they are once again in danger if their treatment is less than optimal, or if they do not take the medicine as prescribed). Long-term side effects must still be monitored, especially in connection with secondary diseases, and this also requires experienced CML experts. With Nilotinib, a risk of arterial occlusive disease was documented in patients with cardiovascular risk factors such as obesity, smoking, high blood pressure, or diabetes. With Dasatinib, it has long been observed that a small percentage of patients experience uncomfortable accumulation of fluids between the lungs and ribs (pleural effusions), which require treatment, and which can emerge even after years of therapy with otherwise few side effects. Apart from these, there can also be lighter side effects which do not require treatment, but which can become burdensome to daily life after extended periods of time.
For patients who reach deep molecular remission, the STOP studies may be an attractive opportunity to be free of CML therapy along with all its side effects. This possibility will still be out of reach for a large majority of CML patients, however, either because they do not reach a long-term, stable deep molecular remission at all, or because it takes them several years to ever get there.
In 2013, with Ponatinib and Bosutinib, there will probably be more approved medical options, which for example may be important options for T315I mutations or for patients who do not tolerate the currently available therapies. Evidence for the 10% BCR-ABL rule after three months of first-line therapy, gathered in the course of all therapies, and outcome after switching, should also clarify expert recommendations for an "early, preventive switch" of therapies instead of awaiting a better response later on.
Our hopes still rest on the discovery of how to effectively eliminated residual CML stem cells with as few side effects as possible - a subject which is being studied intensely, even though unfortunately very little was to be seen at this year's ASH conference in terms of results.
The progress made in the last decade in treating chronic phase CML has been immense, and improvements on such a high level are important, even if they are often less spectacular. The significance of these improvements can once again be seen in the lack of progress in therapy for CML in blast crisis: the outlook for patients in blast crisis is still dramatically negative. No efforts should be spared in making sure that CML patients are diagnosed early, and then treated optimally, so that they are never in danger of progressing into blast crisis.
And of course, in the long term, "chronification" of cancer with permanent therapy should not be an option, but the goal must be healing all CML patients by eliminating their residual cancer stem cells.
Until this hope becomes reality, we will have to return to the ASH conferences a few more times.
21 Dec 2012
Jan Geissler, Leukämie-Online / CML Advocates Network
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