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Update on therapy discontinuation (STOP) studies


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#1 ChrisC

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Posted 27 December 2013 - 12:08 PM

This link to entire posting. http://www.cmladvoca...de-effects#stop

• Below is the good news being reported in the "stopping TKI" arena:

Update on therapy discontinuation (STOP) studies

Dr Francois Mahon from France presented an update on the STIM1 study. In the study, patients were stopping therapy after sustained PCR negativity on Imatinib treatment for at least 2 years. After the stop, PCR was performed every month in the first year and every 2nd month thereafter, and recurrance was assumed when detectable PCR was following by a one-log increase in two successive assessment, or a los of MMR at any point in time. 100 patients were recruited into this study. 39% of patients maintained PCR negative at 60 months, with most relapses occured in the first 6 months and none after 24 months. Only Sokal risk score (based on age, spleen size, platelets and blasts at time of diagnosis) was predictive for molecular relapse, but not gender, prior interferon therapy, time from diagnosis to PCR negativity, duration of PCR negativity or duration of prior Imatinib therapy. When looking at the Sokal risk score, 47% of patients with low sokal risk score relapsed, while 73% with high Sokal risk score. Economically, the drug cost savings of the participants on trial was around 4.6 million EUR. The researchers again underlined that discontinuation should be proposed only in a clinical trial with strict molecular monitoring and long-term follow-up. (ASH-Abstract #255)

To assess less stringent failure criteria of therapy-free remission, the French group conducted the A-STIM ("According to STop-IMatinib") study. While eligibility criteria were similar to STIM1, loss of MMR (BCR-ABL >0,1%) was the criterion to restart treatment. Of 81 patients that discontinued, 51 (61%) were still in MMR without medication after a median of 31 months. Of these 51 patients, 45% were in sustained BCR-ABL negativity, 24% had occasional BCR-ABL positivity, and 31% had BCR-ABL fluctuations meaning at least 2 consecutive positive PCRs. Of those that relapsed, all patients regained MMR, but one patient experienced progression on Imatinib. In summary, the treatment-free remission rate is at 60% on Imatinib when MMR is the failure criterion, while only 40% on STIM1 study remained in remission. (ASH-Abstract #381)

Similar results like STIM1 were presented by the French group in the STIM2 study. In this study with 127 patients who had been PCR negative for at least 2 years, more than half (75 patients) remained in treatment-free remission. Of the 52 patients who had relapsed, 48 relapses accurred during the first 4 months, and 4 more relapses until month 9. Of the 75 patients that remained treatment-free, 40 patients had detectable PCR above MR4.5 for short periods (= fluctuating PCR results), but did not relapse. The researchers conclude that positive fluctuation of PCR results on very low molecular levels do not lead to CML relapse or progression, therefore complete eradication of residual leukemic stem cells may not be necessary to discontinue Imatinib therapy in deep molecular response of at least 2 years duration. (ASH-Abstract #654)

The Nordic CML study group presented first findings from an immunology substudy of the EURO-SKI trial. Their research suggests that patients who relapse after TKI discontinuation may have a lower proportion of natural killer cells and their functioning at the time of drug discontinuation. While mechanisms need to be further investigated to predict individual relapse after discontinuation, targeting these mechanism might also lead to improved treatment-free rates in the future. (ASH-Abstract #379)


Be alert, but not overly concerned.

 

• Dx Oct. 22, 2008, WBC 459k, in ICU for 2 days + in hospital 1 week

• Leukapheresis for 1 week, to reduce WBC (wasn't given Hydroxyurea)

• Oct. 28, 2008: CML confirmed, start Gleevec 400mg

• Oct. 31, 2008: sent home when WBC reached 121k

• On/off, reduced dose Gleevec for 7 months

• April 2009: Started Sprycel 100mg

• Sept. 2009: PCRU 0.000

• Sept. 2011: after 2 years steady PCRU & taking Sprycel 100mg before bed, quit Sprycel (with permission)

• Currently: still steady PCRU, testing every 6 months 🤗

— Fatigue, hearing loss continue, alas, but I prefer to think it is all getting better!

 

 


#2 valiantchong

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Posted 29 December 2013 - 12:33 PM

Any recent update that this practice is standardized in all hospital in Europe or US ? If the article is so convincing why this stop practice is not put into actual practice rather than trial only ?



#3 ChrisC

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Posted 29 December 2013 - 12:58 PM

Perhaps as there are so very few patients who meet the guidelines used in their studies so far, there is little incentive to make this standard practice.

And perhaps as more trials are conducted with combinations of TKIs, and with positive results to share, things will get in gear :)

Here is more on that subject:

http://www.cmladvoca...sment-of-riches

Alternative Approaches to Eradicating the Malignant Clone: Tyrosine-Kinase Inhibitor Combinations and Beyond (Dr. Richard Van Etten)

Dr. Richard Van Etten from the Tufts Medical Center in Boston presented on alternative approaches to eradicating CML stem cells with a perspective on TKI combinations and beyond.

In his presentation, he outlined that according to the current stop studies, TKI monotherapy is not curative for the majority of CML patients. Therefore the main questions towards a cure in this area are still whether CML stem cells are the cause of relapse, and if so, how they could be targeted, and such a biological finding could be translated into clinical practice in patients.

Dr. Van Etten then explained the critical pathways driving leukemic stem cell survival in CML and discuss the most promising approaches to leukemia eradication. More specifically, he outlined the nine different biological mechanism that are currently under investigation in 26 clinical trials (on clinicaltrials.gov) to eliminate CML stem cells: JAK2 inhibitors (like Ruxolitinib), mTOR inhibitors, COX inhibitors, GSK-3beta inhibitors, MNK inhibitors, Hedgehog pathway / SMO antagonists, 5-LO inhibitors, HSP90 inhibitors, Arsenic targets / PML degradation, Authophagy inhibitors (Chloriquine), Pan-HDAC inhibitors (like LBH589), SIRT1 inhibitors, Pan-BCL2 inhibitors and protein synthesis inhibitors. A number of those are currently in early Phase I/II studies. Furthermore, Interferon alpha (e.g. German TIGER study), four different vaccines (e.g. CML0206), one monoclonal antibody and other cell surface antigens are being investigated. Waking up sleeping stem cells with Imatinib plus G-CSF has also been tested for more than 5 years.

In summary, Dr. Van Etten said that while there are plenty of candidate drugs in hand, it would not be easy to prove the difference - also because large numbers of different cohorts of patients on similar TKIs would be required for quite a long observation time. Recruiting patients into these clinical trials might prove to be difficult, given also the high effectiveness and tolerability of current TKI treatment, so any intervention or combination needed to be safe and equally well tolerated in order to be acceptable by patients.


Be alert, but not overly concerned.

 

• Dx Oct. 22, 2008, WBC 459k, in ICU for 2 days + in hospital 1 week

• Leukapheresis for 1 week, to reduce WBC (wasn't given Hydroxyurea)

• Oct. 28, 2008: CML confirmed, start Gleevec 400mg

• Oct. 31, 2008: sent home when WBC reached 121k

• On/off, reduced dose Gleevec for 7 months

• April 2009: Started Sprycel 100mg

• Sept. 2009: PCRU 0.000

• Sept. 2011: after 2 years steady PCRU & taking Sprycel 100mg before bed, quit Sprycel (with permission)

• Currently: still steady PCRU, testing every 6 months 🤗

— Fatigue, hearing loss continue, alas, but I prefer to think it is all getting better!

 

 


#4 GerryL

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Posted 29 December 2013 - 06:59 PM

They are starting another trial in England - info from http://www.cmlsupport.org.uk/node/8174

DESTINY trial is now OPEN!

At long last, the DESTINY study is now officially open, as of Friday. Liverpool Royal University Hospital (Prof. Richard Clark is the lead investigator of this UK study) seeing their first patients for screening on Monday- i.e today.

The Liverpool Trials Team will now be focussing on getting the other 20 study sites open nationally. This will help open up the sites more quickly but it will ultimately depend on the individual local R & D approval. If you want to enrol in this study and you know your treatment centre is taking part, then you should contact them directly and get your name on the list.

DESTINY: (DeEscalation and Stopping Treatment of Imatinib, Nilotinib or sprYcel in chronic myeloid leukaemia)

The DESTINY trial will evaluate the feasibility of de-escalation and then stopping treatment in chronic myeloid leukaemia patients with excellent responses to prior treatment. DESTINY is conceived as a pilot for including this strategy in the next phase III study for the UK (to be known as SPIRIT3). Patients are eligible if in first chronic phase; have been treated with imatinib, dasatinib or nilotinib for at least 3 years from original diagnosis; and whose BCR-ABL1 levels have been at or below 0.1% on all tests for the past 12 months. Two groups will be studied; those in whom BCR-ABL1 has been undetectable for at least 12 months in at least 3 samples, all of which have at least 104 control transcripts (molecular remission at the 4-log level, abbreviated as the 'MR4' group), and those in whom BCR-ABL1 is detectable on some or all tests in the past 12 months, but always below a level of 0.1% (major molecular response, abbreviated to the 'MMR' group). Both MR4 and MMR groups will be treated identically though analysed separately, by initially de-escalating treatment to 50% of the standard dose for 12 months. If the BCR-ABL1 level remains at or below 0.1%, treatment is then completely stopped, and observation continues for a further 24 months. The objective of DESTINY is to determine the safety and efficacy of initially de-escalating and then stopping TKI treatment, in CML patients with either undetectable disease or with stable MMR. (from UKCRN Portfolio)

http://www.controlle.../ISRCTN74084226



#5 GerryL

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Posted 02 January 2014 - 08:08 PM

Hi,

They are looking to run a survey for how people feel about stopping in a couple of hospitals in Australia.

 

WHAT DO YOU THINK ABOUT STOPPING THERAPY?

 

An Australian survey of patients' thoughts and feelings about stopping tyrosine kinase inhibitor (TKI) treatment, to be conducted in early-2014, will be a world first.

The principal investigator, Dr David Ross, said the study would assess the attitudes of people who had achieved a good response to TKI treatment with drugs like Glivec, Tasigna and Sprycle.

 

"We hope that everyone who is invited to take part in the study will take the time to answer the questions, regardless of whether they are for or against stopping treatment. The greater the

number of people who respond, the more accurate the results will be," said Dr Ross, of Flinders Medical Centre and SA Pathology (Adelaide). "When Glivec was invented I assumed that patients would have to stay on it forever to keep the CML under control. Early experience suggested that if you stopped treatment, the CML would come back," he said. However, two important studies found that around 30-50% of patients (selected for having a complete molecular response to TKI treatment for at least two years) could safely stop their treatment without relapse. The first of those patients in Australia stopped Glivec seven years ago and is still in molecular remission without any treatment. "Nothing bad has happened to those people who went off their TKI in these trials. If the CML came back, they restarted treatment, which brought the disease under control again. Forthem CML is a long-term disease."This is a significant result,"said Dr Ross, commenting on

the Australasian Leukaemia and Lymphoma Group (ALLG) CML8 trial with 40 patients from around Australia. The other study involved 100 patients enrolled in France. "If people can stop treatment, this avoids having to deal with a lot of mild, lingering side-effects, and it means an enormous cost saving for the health system. "At major CML meetings everyone is interested in the possibility

that TKI treatment might be stopped in carefully selected patients. Researchers are now trying to find ways to get more people into molecular remission, so they may have the chance to stop their drug.

"It is currently estimated that around 40-50% of patients will become Q-PCR negative (molecular remission) after many years on imatinib and that 30% of them (i.e. about 10-20% overall) will be able to stop the TKI and achieve a stable treatment-free remission. "This is still a relatively small proportion but if we can push that higher by using newer TKIs or by combining an existing TKI with

an experimental treatment more people could eventually get to a treatment-free remission. "The key piece of information that's missing is what patients think. How many of them want to stop? How many would be prepared to try a new treatment to get that chance?

If you want to read the full article go to http://www.leukaemia...d+leukemia+news

and open

Chronic Myeloid Leukaemia (CML) News - November 2013

Page 3 is the start of the article, plus info on who would be involved if the survey takes place on page 2.






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