14 replies to this topic

[Buzzm1]

ASCO Annual Meeting: Nilotinib induces treatment-free remission in patients with chronic phase CML http://bit.ly/25ILdhq

 

June 4, 2016

CHICAGO — Frontline nilotinib led to treatment-free remission after relatively short exposure in a majority of patients with chronic myeloid leukemia in chronic phase, according to the results of the single-arm phase 2 ENESTfreedom study presented at the ASCO Annual Meeting.

 

"[More than half] of patients remained in tumor-free remission for 48 weeks. ...The remission that was observed is clinically meaningful and should warrant consideration for a response from the FDA," Andreas Hochhaus, MD, interim head of hematology and medical oncology and professor of internal medicine at University Medical Center in Jena, Germany, said during a presentation.

 

Data show 40% to 60% of patients with CML in chronic phase (CML-CP) who achieve sustained deep molecular response after long-term treatment with imatinib (median duration, 5-7 years) maintain treatment-free remission after treatment stopped.

 

Hochhaus and colleagues conducted the ENESTfreedom study to examine the occurrence of treatment-free remission following frontline nilotinib (Tasigna, Novartis) for patients with CML-CP.

 

The analysis included 215 patients who had received at least 2 years of frontline imatinib and had achieved a molecular response 4.5 (BCR-ABL1IS 0.0032%). Patients continued nilotinib for 1 year and underwent examination using real-time quantitative-polymerase chain reaction assessments at 12-week intervals.

 

Patients entered the treatment-free remission phase if assessments showed no worse than molecular response 4 (BCR-ABL1IS 0.01%), two or fewer assessments between molecular response 4 and 4.5, and molecular response 4.5 in the last assessment.

 

One hundred ninety patients (median age, 55 years) met these criteria and discontinued nilotinib. The median time from first molecular response 4.5 to study entry was 18 months, and the median nilotinib duration prior to treatment-free remission was 43 months (range, 33-89).

 

After 48 weeks, 51.6% (95% CI, 44.2-58.9) of patients in the treatment-free remission phase experienced major molecular response and had not re-initiated treatment with nilotinib.

 

Eighty-six patients experienced a loss of major molecular response (BCR-ABL1IS 0.1%), which triggered re-initiation of nilotinib. Of these patients, 85 regained major molecular response after a median of 7.9 weeks, and 76 regained molecular response 4.5 after a median of 13.1 weeks.

 

The other patient discontinued from the study due to their own choice 7.1 weeks after re-initiation, before they had regained major molecular response.

 

During the treatment-free remission phase, 24.7% of patients experienced musculoskeletal pain, 1.1% of which was grade 3 or higher.

 

No new safety signals were observed on treatment.

 

"CML patients who experience deep and sustained molecular response should be eligible for further trials. However, monitoring is critical especially during the first 6 months following the end of treatment," Richard A. Larson, MD, professor of medicine in the department of hematologic malignancies at University of Chicago, said during the discussion portion of the session. "Discontinuing treatment may seem counterproductive to patients who experience good outcomes, but continuing treatment past tumor-free remission can lead to increased adverse events and high long-term costs for patients. Some patients with CML with deep molecular response to TKI can safely stop therapy." - by Nick Andrews

 

Reference:

 

Hochhaus A, et al. Abstract 7001. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

 

Disclosure: Hochhaus reports honoraria, research funding and travel expenses from, as well as consultant/advisory board roles with ARIAD, Bristol-Myers Squibb, Novartis and Pfizer. Please see the abstract for a list of all other researchers' relevant financial disclosures. Larson reports consultant/advisory roles with Amgen, ARIAD, Bristol-Myers Squibb, Celgene, CVS/Caremark and Novartis and research funding paid to his institution from Amgen, Astellas Pharma, Celgene, Daiichi Sankyo and ERYTECH Pharma.

 

PERSPECTIVE

Ehab Atallah

Ehab Atallah

This is the first and the largest study looking at treatment free remission in patients with CML receiving nilotinib (Tasigna, Novartis). It is exciting on one hand that 50% of patients did not need to restart treatment. It is less exciting on the other hand, though, because of 100 patients with chronic myeloid leukemia, only 40 patients would achieve a sustained deep molecular response to be eligible to stop nilotinib. Of those, only 20 would be able to successfully stop TKI therapy. For the 20% of patients who could stop safely, it would be a very big step for them in terms of improved quality of life, the potential for pregnancy if desired and lowered expenses. Cost to patient and society is one of the reasons discontinuing TKIs is desirable. There are approximately 30,000 patients in the United States who take medication for CML, and those drugs on average cost $100,000 per year.

 

One of the stopping TKI trials which is currently enrolling patients in the US is The LAST trial ( Life after stopping tyrosine kinase inhibitors). This study is an NIH funded trial and is open to enrollment at 14 centers across the US. Patients who stop treatment need to be monitored monthly for the first 6 months, then every 2 months for the next 18 months. After that, it is every 3 months for the third year, which is why we believe that it is best to stop treatment in a clinical trial setting. Most recurrence happens in the first 6 months, which is why that period has the most intense monitoring.

 

A total of 100 patients have been accrued on the trial thus far, with a target accrual of 174 patients by the end of the year. We hope that, with this trial, we will be able to better identify which patients will be able to safely stop TKI treatment.

 

Many challenges remain in the therapy of patients with CML. We need to understand which patients can safely stop treatment. For those patients who do not achieve a deep molecular response, adding other therapies that would get them there. Finally, our goal should remain to cure patients with CML i.e. no evidence of CML and off TKI therapy.

 

Ehab Atallah, MD

Medical College of Wisconsin

Disclosures: Atallah reports that he is the principal investigator on the LAST trial.

 

[scuba]

It will be interesting to see how Trey responds to this. We are now getting significant data - through clinic trials that upwards of 50% of patients who achieve deep molecular responses (and that would include Trey) are able to successfully stop taking Nilotinib (and other TKI's also).

 

My question is what is different about these patients than the others who are not able to stop?

 

Also - as I believe CML initiates more or less spontaneously and expands in people whose immune systems can't check it - someone who had CML will probably always have the potential for new disease to occur even if the old CML has been extinguished. PCR testing will be needed for the rest of our lives, even if we're no longer taking the drug. I can think of worse things.

[mikefromillinois]

 

 

My question is what is different about these patients than the others who are not able to stop?

 

 

 

That is one of the questions the researchers are asking.  I've been in the LAST trial for a year now.  Still PCRU.  My oncologist is Dr. Larson who is quoted above.  I think that in time the answer to this question will be found to be related to "cured" patients (treatment free remission forever) primarily coming from the subset of patients who had a fast and deep response to their tki's - the kind of response typically found with "the more potent" tki's (or more potent dosages). 

 

My personal opinion is that knocking the beJesus out of the CML early - before it has a chance to "take hold" or "mutate" - is the best shot at long term treatment free remission.  It might end up that patients and docs will have to choose between taking a "TFR" track or a "minimal side effect" track.  I suppose the good news is we have choices and will probably have a wider range of choices in the future.

 

I think we are seeing a philosophy shift in the way the researchers and experts are looking at CML treatment, switching from 'let's control this disease for life' to 'let's cure this bad boy'.  To me the following are very important takeaways:

 

"Discontinuing treatment may seem counterproductive to patients who experience good outcomes, but continuing treatment past tumor-free remission can lead to increased adverse events and high long-term costs for patients. Some patients with CML with deep molecular response to TKI can safely stop therapy."

 

"Many challenges remain in the therapy of patients with CML. We need to understand which patients can safely stop treatment. For those patients who do not achieve a deep molecular response, adding other therapies that would get them there. Finally, our goal should remain to cure patients with CML i.e. no evidence of CML and off TKI therapy."

[rcase13]

I would not be surprised if insurance companies started mandating patients that are PCRU for two years try stopping treatment to see if they can have TFR.

50% being able to stop a $120000/year pill is a lot of money for the insurance companies.

Sounds crazy but I bet that is where we will be in a few years.

[kat73]

It doesn't seem to me that this latest report says anything essentially different than what we've been seeing: most people don't get to MR 4.5 and if they do, about half can maintain TFR.  We knew this.  Also, the hunch that fast and furious is better is an understandable human reaction, but the data really only suggest that you join the pool of people eligible to try stopping, sooner.  It doesn't mean you are more likely to end up in the half that then go on to TFR of long-standing.  I wish, but it still looks like only about 1 in 5 can hope to be in a TFR for a period of years - I don't think there are figures for anyone past a few years.  So, yes, someone could "get" CML all over again.  I once asked a nurse practitioner this question about 6 years ago - if the message came down from some genetic screw-up to bust up chromosomes 9 and 22, what's to keep that message from continuing to be sent, even if you kill every last leukemic cell in your body?  She said that was a very good question.

[scuba]

Kat73 wrote, "I once asked a nurse practitioner this question about 6 years ago - if the message came down from some genetic screw-up to bust up chromosomes 9 and 22, what's to keep that message from continuing to be sent, even if you kill every last leukemic cell in your body?  She said that was a very good question."

 

Actually - chromosome 9 and 22 are tightly bound in the nucleus prior to mitosis - and they are tightly bound right where the translocation that creates the bcr-abl oncogene is located. When the chromosomes unwind to prepare for cell division (and DNA replication) translocation errors can (and often do) occur. Cells that have these errors are normally benign and die off (apoptosis), some cells like bcr-abl are more stable and will reproduce with the new gene intact. In sufficient numbers they trigger a T-cell response which attacks them and destroys them (immune response). The immune response doesn't have to be complete (i.e. some bcr-abl or other aberrant cells) - just sufficient to keep the numbers low (i.e. below detection). The bad cells either die out or go quiescent.

 

CML and related diseases (transcription errors) result from a failure of the immune system. There may be a genetic reason for immune weakness which enables CML to start and grow. But I have become convinced that 9;22 translocation errors are common in the population and we - who get CML disease - have an immune failure, not the fact the cells were created in the first place.

[CMLParent]

But I have become convinced that 9;22 translocation errors are common in the population and we - who get CML disease - have an immune failure, not the fact the cells were created in the first place.[/font][/color][/quote]

Scuba great point. The BCR ABL signal does seem to be common in the general population http://www.ncbi.nlm....pubmed/24535287

The immune system as the point of failure is especially pronounced in the pediatric population. The defective immune system is made worse by the fact it is not fully developed. This would explain the extremely short chronic phase and the fairly common presentation in blast crisis particularly in the toddler category. In the immune system is the problem and ultimately there is where we will find the solution.

[scuba]

If you think about what happens during the cell cycle (http://www.cellsaliv...ll_cycle_js.htm) in which we start as one cell and divide, differentiate into trillions of cells all the while increasing in size, complexity and function it is any wonder that we evolved at all. Of course - it did take 4.5 billion years to get the processes set up to "fix" mistakes and keep us humming.

 

Translocations in all kinds of our cells are COMMON - including bcr-abl. What makes it cancer is that nothing occurs to stop rapidly dividing cells from rapidly dividing or differentiating into a final state. 

 

A true cancer cure lies in immunotherapy - either induced or acquired. TKI drugs work to control the cancer - but are not a cure. Those patients who manage to achieve treatment free remission are likely to have re-developed an immunity against the residual defective cells. 

 

In terms of children - I would bet that most children who proceed quickly from chronic phase to blast crisis are lacking in sufficient vitamin D. I have no reference to cite on this - but based on my collective reading, vitamin D drives blast cells (normal as well as leukemic) to differentiate. In children this need is high. It is a shame that more parents are not aware of the importance of vitamin D to their childrens health (http://www.webmd.com...-more-vitamin-d). And it's vital for adults as well. I keep my vitamin D above 50ng/ml and less than 100ng/ml. 

[Buzzm1]

IMO, one of the most important stat facts coming out of the trials, is that the great majority of patients who lose MMR (0.1) during a trial, regain MMR and PCRU/CMR relatively quickly after restarting their TKI.

 

"Eighty-six patients experienced a loss of major molecular response (BCR-ABL1IS 0.1%), which triggered re-initiation of nilotinib. Of these patients, 85 regained major molecular response after a median of 7.9 weeks, and 76 regained molecular response 4.5 after a median of 13.1 weeks. The other patient discontinued from the study due to their own choice 7.1 weeks after re-initiation, before they had regained major molecular response."

 

This hopefully will help to dispel some of the fear associated with stopping, or reducing, TKI treatment.

[scuba]

IMO, one of the most important stat facts coming out of the trials, is that the great majority of patients who lose MMR (0.1) during a trial, regain MMR and PCRU/CMR relatively quickly after restarting their TKI.

 

"Eighty-six patients experienced a loss of major molecular response (BCR-ABL1IS 0.1%), which triggered re-initiation of nilotinib. Of these patients, 85 regained major molecular response after a median of 7.9 weeks, and 76 regained molecular response 4.5 after a median of 13.1 weeks. The other patient discontinued from the study due to their own choice 7.1 weeks after re-initiation, before they had regained major molecular response."

 

This hopefully will help to dispel some of the fear associated with stopping, or reducing, TKI treatment.

 

"Great majority" ... I think there is only one case of a patient progressing to advanced disease after having stopped therapy and re-start - and that case was not CML progression but a new disease associated with many comorbidities. The reality is that all patients who are otherwise healthy and have achieved PCRU were able to regain their status after re-starting their TKI. And they regained it quickly. Those are very good odds.

 

Anyone who has been PCRU for more than two years should strongly consider stopping their therapy with monthly PCR supervision to see if they are one of the lucky ones. The risk is so low that it would be a shame not to try.

[cleocans]

UC Health where I go does the cessation trials.  I have one year left of PCRU and I will be stopping Sprycel.  If I'm not one of the lucky ones I'm hoping to go on reduced dose at least!  For my doc you have to be undetected for all 3 of the PCR tests they do.  My first test with my new doc here I had 2 undetected and one was very low but still detected.  The last 2, I go every 6 months, were all undetected.

[Buzzm1]

IMO, one of the most important stat facts coming out of the trials, is that the great majority of patients who lose MMR (0.1) during a trial, regain MMR and PCRU/CMR relatively quickly after restarting their TKI.

 

"Eighty-six patients experienced a loss of major molecular response (BCR-ABL1IS 0.1%), which triggered re-initiation of nilotinib. Of these patients, 85 regained major molecular response after a median of 7.9 weeks, and 76 regained molecular response 4.5 after a median of 13.1 weeks. The other patient discontinued from the study due to their own choice 7.1 weeks after re-initiation, before they had regained major molecular response."

 

This hopefully will help to dispel some of the fear associated with stopping, or reducing, TKI treatment.

85 regained major molecular response after a median of 7.9 weeks, and 76 regained molecular response 4.5 

 

"Great majority" ... I think there is only one case of a patient progressing to advanced disease after having stopped therapy and re-start - and that case was not CML progression but a new disease associated with many comorbidities. The reality is that all patients who are otherwise healthy and have achieved PCRU were able to regain their status after re-starting their TKI. And they regained it quickly. Those are very good odds.

quickly is the operative word ... if you note above, not all regained PCRU/CMR "quickly."  As much as not all of us initially reached PCRU quickly, some take longer to regain PCRU/CMR, as some did initially.   

[Gail's]

Buzz, I think 13 weeks is "quickly" especially for us turtles.

[Buzzm1]

Buzz, I think 13 weeks is "quickly" especially for us turtles.

Gail, please reread the comment; not all regained PCRU/CMR in 13 weeks; that's the point; some will take longer. 

[Trey]

Tasigna does not seem to have any significant advantage over Gleevec or Sprycel for cessation success.  All results are about the same.  Of those who are well qualified for cessation trials using any drug, maybe 40 - 50% succeed, but total success rate for all patients is still about 20%.  Also, when success includes loss of PCRU that is not a good metric for succeeding in my opinion.  So even the 50% is skewed.