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Should I try TFR??

I was diagnosed 3 years ago in Sep 2016 and started on Tasigna 600 mg/day.  I reached MMR in 82 days and have been at <.003% (>MR 4.5) or undetected since April of 2017.  My last PCR was undetected on June 24th of this year.  I experienced multiple side effects early in treatment and worked with my onc to reduce my dose to 450 mg/day on 3/10/17, then to 300 mg/day on 6/15/17 and finally to 150 mg/day on 9/18/17.  Virtually all side effects are gone now except for heart arrhythmia. I have had extensive cardio workup including echo and nuclear stress test.  Bottom line: I have benign PAC's and PVC's and my cardiovascular system is excellent with no structural problems or blockage of any kind.  My cardiologist even said I don't need a cardiologist.  I workout 5 -6 days a week, weigh 170 pounds (5' 11") and scored the highest on the stress test that my cardiologist has ever seen for my age group (I am 66).

Nevertheless, I suffer from the arrhythmia on a daily basis - it is uncomfortable and disconcerting even though I know it is benign.  I have also read that although uncommon, this could develop into a fib. I have tried beta blockers, calcium channel blockers and am being evaluated next week for sleep disorders that could potentially cause the arrhythmia which I suspect will be negative. There is no way to prove that Tasigna is causing the arrhythmia other than stopping or switching TKI's.

I met with my onc yesterday for a thorough discussion of this issue and I have 4 options:

1. Go off the TKI for a month or so and see if the arrhythmia goes away - if it does, I can switch TKI's, but my onc would require me to start any new TKI at full dose (100 mg Sprycell, 400 mg Bosulif), which I am not willing to do (I know Scuba will say that I should switch oncs, but I am also not willing to do that at this time).

2.  Switch TKI's now and see if the arrhythmia goes away, but again I would have to start at full dose which I am not willing to do.

3.  Try TFR - I qualify (3 years treatment and 2+ years of sustained DMR) but just barely. The EUROSKI and DESTINY studies showed that TFR success increases between 2 and 8% per year with each year of treatment and each year of sustained DMR, so based on this, my chances at success are meaningfully less than if I waited another 2 - 3 years.  My onc said that since my response was deeper and faster than most, my success chances could be higher than someone on treatment longer that took longer to reach DMR. I am not sure this is supported by the data, but that's what he said.

4.  Do nothing - stay on 150 mg per day of Tasigna and hope the arrhythmia gets better - it went away one time before for about 4 - 5 months, but has been back consistently on a daily basis since March of this year.

So, I am torn between options 3 and 4 since at least for now 1 and 2 are non-starters for me. I would love to hear what option others on this forum would choose.  Thanks.

Hi Jax,

I copied this from the LLS CML forum (credit to AdamJ):

NCCI has the following guidelines:
Criteria for TKI Discontinuation (Outside of a clinical trial, TKI discontinuation should be considered only if ALL of the criteria included in the
list below are met)
• Age ≥18 years.
• Chronic phase CML. No prior history of accelerated or blast phase CML.
• On approved TKI therapy for at least 3 years.1,2
• Prior evidence of quantifiable BCR-ABL1 transcript.
• Stable molecular response (MR4; BCR-ABL1 ≤0.01% IS) for ≥2 years, as documented on at least 4 tests, performed at least 3 months apart.
• Access to a reliable qPCR test with a sensitivity of detection of at least MR4.5 (BCR-ABL1 ≤0.0032% IS) and that provides results within 2 weeks.
• Monthly molecular monitoring for one year, then every 6 weeks for the second year, and every 12 weeks thereafter (indefinitely) is recommended for patients who remain in MMR (MR3; BCR-ABL1 ≤0.1% IS) after discontinuation of TKI therapy.
• Prompt resumption of TKI within 4 weeks of a loss of MMR with molecular monitoring every 4 weeks until MMR is re-established, then every 12 weeks thereafter is recommended indefinitely for patients who have reinitiated TKI therapy after a loss of MMR. For those who fail to achieve MMR after 3 months of TKI resumption, BCR-ABL1 kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for another 6 months.
• Consultation with a CML Specialty Center to review the appropriateness for TKI discontinuation and potential risks and benefits of
treatment discontinuation, including TKI withdrawal syndrome.
• Reporting of the following to an NCCN CML Panel Member is strongly encouraged:
Any significant adverse event believed to be related to treatment discontinuation.
Progression to accelerated or blast phase CML at any time.
Failure to regain MMR after 3 months following treatment reinitiation.

 

I think option 3 would be worth a try.  But, if you look at the NCCN guidelines for TFR above, it mentions consulting with a CML specialist.  Since your current onc doesn't seem to be a CML specialist, would you be willing to consult with one before a TFR attempt?

How does your current onc explain their intransigent position on using a lower dose if you were to change to a different TKI?

Kirk

Thanks Kirk.  My onc is at Mayo Clinic in Jacksonville FL.  He began his career as a CML specialist but focuses more on multiple myeloma now.  He still has 7 or 8 CML patients.  I would be willing to consult with another specialist primarily on the issue of whether or not I could switch to another TKI at low dose. My onc will not permit this because he says all the TKI's are different and starting at a low dose could lead to resistance to the new medicine.  I thought the whole resistance theory has been pretty much discounted now but I find it difficult/uncomfortable to directly challenge my onc on this.I need recommendations on where to find other CML specialists.  I went to one here in Jacksonville at Baptist Medical Center when I was looking to reduce Tasigna dose in early 2017, but did not care for him at all. Perhaps Moffitt in Tampa would be my best next option - do you have any suggestions?

 

Option 1 and 3 could be tried together. I think that it is a good start to figure out if Tasigna is the culprit by stopping for a month (or more if your pcr stays the same?) with pcr every month. What if stopping does not stop your arrhythmia? No need then to go through anxiety with a new TKI.

Option 2. You could try Sprycel half dose (50mg). You can show your onc papers on newly diagnosed patient on 50mg (Dr Cortez) and it seems to work as well (and maybe better) as 100mg with less side effect.

Option 3. Don’t forget the Destiny trial that shows that if you take half dose for a year your chance at TFR is greater (70%). The rationale is that your immune system recovers at lower dose and helps to keep CML low.

Hope this helps....

 

Saw your post on LLS site and Trey's response with which I agree.

You should definitely be taking a magnesium supplement at 400 mg per day (all of us should be). If you are experiencing an unknown mineral deficiency (blood tests do not necessarily reveal mineral deficiencies), supplementing with magnesium could immediately end your arrythymia. If you eat lots of fruit, potassium won't be an issue, but if not - add potassium too.  I have found when I added a 1/4 teaspoon of sea salt (himalayan variety), my heart "palpitation like feeling" went away. Salt - has been given a bad name in the medical press. We need salt - every day - sodium being the most important. Because I do not salt my food, I drink a glass of water with 1/4 teaspoon of salt added. With a bit of lemon it's great tasting.

Your PCR level is excellent. You can easily stop treatment and test if that is the cause of your arrhythmia. You may actually find out your PCR doesn't change - AND if that is the case - go another month without your TKI. And another and another - you may find yourself in a treatment free remission. You can always re-start if your PCR climbs and regain your response.

If you do switch drugs - you should consider a very low dose Sprycel (20 mg) to start. Your doctor is wrong about "resistance". Cancer doesn't work like bacteria. He should know that. Low dose sprycel has been very effective for patients in your situation - it will either work or it won't. Finding out is a prudent course.

(p.s. I was prescribed low dose sprycel (20 mg) and achieved PCRU while taking it. Just another data point that low dose does not equal resistance)

The National CML Society has a couple of CML specialists listed in Tampa, so that would probably be your best bet.  Dr. Cortes is in Augusta now, so that wouldn't be too far.  I don't know if he's accepting new patients since his recent move from Texas.

We've got room for you to crash at our place for a few nights if you could get an appointment with Dr. Drucker here in the beautiful Pacific Northwest. smiley  It's about a half hour drive from our house to Oregon Health & Science University.  I've never met him, but I hear he knows a thing or two about TKIs. wink

https://www.ohsu.edu/providers/brian-j-druker/1CB5EB18F9E644669D009F8F5C...

Javier Panilla-Ibarz, MD, PhD
H. Lee Moffitt Cancer & Research Center
Tampa, Florida

Kendra Sweet, MD - Moffitt Cancer Center - Tampa, FL

 

 

Regarding Dr. Cortes:

https://www.augusta.edu/cancer/about/faculty.php

Looks like he has moved into attending 'rubber chicken' dinners and fund raising. That is what "directors" are hired to do!

He will be good at it. Hopefully he will find time to do some research. Augusta University has acquired the best of the best.

Thanks Karinne - I have actually thought about 1 and 3 together.  And by the way, I have already reduced my dose to 1/4 of starting dose and have been at that dose for 2 years now. 

If I try 1 and 3 together and the arrhythmia improves or goes away and I don't stay in DMR, I will share the 50 mg data with my onc.

So appreciate your help :)

Thanks so very much Kirk.  I am now also considering another option.  Since Tasigna now comes in 50 mg capsules, I could further reduce dose to 100 mg/day, then 50 mg/day and see if the arrhythmia improves.  Would mean more frequent testing, but worth it if it works.

Thanks Scuba - I now you are chomping at the bit about the whole resistant argument as the reason my onc won't approve a switch to low dose Sprycell or Bosulif. I am too, but trying to work with my once since he's local and with mayo.  Plus, he worked with me on my Tasigna dose reductions at a time when it wasn't as accepted as it is now.

Scuba:

Do you think Dr. Cortes would respond to me if I snet him an email about this?

Thanks Scuba - all good points.  I started on magnesium taurate supplement  nearly 2 years ago taking 600 mg per day. When the latest bout of arrhythmia started 6 months ago, I increased the dose to 1200 per day and it had no noticeable effect, so about 4 weeks ago, I stopped taking this altogether, again with no noticeable effect.  

My diet is already rich in potassium, so do not feel the need to supplement that.  If I was to try supplement, what daily dose would you take?

My preference would be to either stop or reduce dose further to see if that improves the arrhythmia.  If it does, but my PCR starts to rise, I do NOT want to start on full dose of any other TKI.  Unfortunately, my onc will not approve anything other than full dose of a different TKI (e.g. 100 mg Sprycell).  Given my side effect history at full dose Tasigna and my history of pneumonia, I'm afraid I'd be staring at a pleural effusion within no time.

Ideally, I'd like to find an onc that would permit me to lower Tasigna dose now or switch to low dose Sprycell (20 mg) or Bosulif (100 mg) if that becomes necessary.  Until I can do this, I am hesitant to start TFR.  

Do you think Dr. Cortes would respond to me if I email him? Do you know any other oncs who would be supportive of this?

Also, I've been using himalayan sea salt for at least 2 years now.  Have it on eggs in AM and dinner. 

Tough decision.  My husband's CML specialist took him off Tasigna 400 mg daily (or maybe he was down to 300?  Can't recall) because of concerns about vascular issues.  That was his first TFR attempt after 4 years MMR.  It only lasted 3 months but was a nice break.  

Started on 70 mg Sprycel and went immediately back to MMR.  Due to severe shortness of breath (SOB) cut dose to 50 mg (and in retrospect probably should have cut to 20 mg) and remained in MMR.  SOB continued even though PE and PAH all ruled out. After 2 years took a drug holiday that turned into 18 month TFR attempt.  As I posted elsewhere on this forum, he is now going on Bosulif after PCR of .32.  Returning to a low(ish) dose Sprycel was another option but he HATED the SOB so much that he didn't want to consider it.  He's avoiding Gleevec due to a previous eye bleed.

My husband's journey is similar to yours.  He's 75, in excellent condition, on the eliptical, stairmaster and bike almost daily.  He's also a fast and deep responder (both times - after initial dx and after TFR-1) so we are hopeful.

My advice is to see one of the top CML specialists who really has experience with medication/dose changes, TFR, etc.  I know from the LLS and FB forums that many drive long distances or fly for consultations with specialists like Dr. Druker (Oregon), Dr. Mauro (NYC), Dr. Talpaz (Ann Arbor), Dr. Cortes (just left Houston) or many others at MD Andersen in Houston. There are many others across the country -- these just came to mind. This is assuming you are in the US -- I have no idea where you are located.

That's what I would do in your situation.  These specialists (and others) are used to consulting with patients from afar and seeing them only occasionally while the community oncologist handles day-to-day care.  You could post in LLS or FB forums your location and easily track down the closest top specialist.  If you are out of the US I'm sure people in other countries can make similar recommendations.

Good luck on this journey.

Dr. Cortes has taken a new position as Director Georgia Cancer Center in Augusta. I do not have his new email address (yet), but I suspect he will still be involved in some limited research and perhaps even clinic hours seeing a few patients.

As Director, however, he is likely to be very busy administratively herding cats and attending all kinds of fund raising dinners.

So I asked my onc if he would approve lowering dose to 100 mg and then to 50 mg if warranted - here's his response:

I would think that since lower doses have not necessarily shown proven benefit, continuing on further lower doses would not necessarily be supported by any clinical data from any of the trials. The dose that you are on was typically the lowest dose that was used in most of the clinical trials previously. So it will be hard to say that lower dose actually has any benefit. At the moment you are on 25% of the prescribed dose. Below this in my opinion would not be of any proven benefit so I am not necessarily in favor of that.

I have challenged this and asked him why cessation, which he has approved, is less risky than lowering dose from 150 to 100 mg per day and am awaiting an answer.  Needless to say, I am frustrated with his logic, which does not make sense to me.

He's a doctor. Logic is not what they study in medical school.

Further - he's a practicing physician, not a M.D. / Ph.D. researcher who makes the discoveries and are at the forefront.

By definition, practicing physicians will always be behind the curve. Somebody else will have to lead. It won't be him. Too risky.

You could try and convince your doctor to try low dose sprycel (20 mg) and test via PCR once a month for six months to verify efficacy. This is done all of the time by the bigger leukemia centers. I am a current patient in that protocol although I only test once every six months because I have been undetected for so long. Progression (i.e. loss of response) has not been seen in patients who do this. And if 20 mg sprycel works for you - you will be in a much better place (heart wise).

Show your doctor this paper:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901015/

Dasatinib dose management for the treatment of chronic myeloid leukemia

Perhaps he can be educated. If not - yep - get a new doctor.

 

 

Hi,

can I ask who your consultant is and where you are seen? 

I would question the advice you have on options 1 and 2. If a low dose of Tasigna keeps you in MMR a low dose of another drug would do too probably. For instance, I just switched from imatinib due to fatigue issues and my doctor (Jane Apperley, Hammersmith) told me to go for 50mg Dasatinib at first which is what I am doing. People who switch due to side-effects not lack of response don’t necessarily need the full dose, at least to start. 

Try to get in touch with Hammersmith and maybe even go to the next patient meeting to discuss with them. They are the leaders in CML in Britain and could give you the green light. I can help you get in touch if you need. 

Best, Tom 

Hi Tom,

CmlJax is located in or near Jacksonville, Florida so I think they are looking a little closer to home for a second opinion.  Does Dr. Apperley make house calls?  cheeky  If so, I'm sure CmlJax would like a consult with her!

Kirk

Hi Tom - Kirk is correct - I live in Jacksonville FL. Do you think Dr. Apperley would respond to an email from me? If so, could you perhaps share her contact info with me?  Thanks 

I forget that in this day and age doctors can do virtual house calls! blush  I've heard that Dr. Druker responds to emails.  Have you tried reaching out to him yet?

Now that I see where you live in JAX (should have guessed from your screen name) I give another vote for seeing the specialist in Tampa after you look up his research.  Or trying to get appt with Dr Cortes in Augusta if he is taking new patients.  Or seeing if a specialist at Emory?  Or in Birmingham? The person who offered you a spare room near Portland was awfully nice!   Dr Druker is a great option but there may be others within driving distance.  I also suggest trying to see one of these specialists in person. Once you establish a relationship and they have your medical records you can do more by email. 

P.S. just saw how close you are to Augusta. I totally suggest seeing if you can get in to see Dr Cortes. Good luck!

Let me contact someone in her team. My email is tomnash321@hotmail.com if you need it. 

Thanks so much for your help

I spoke to someone at Hammersmith today and they suggested talking to MD Anderson. I actually have Dr Cortes' email as he gave it out at a talk I went to in Buenos Aires last year. I would suggest that first, and if it goes nowhere let me know and we can try one of the doctors in UK. His email is Jcortes@mdanderson.org.  Tom

Thanks Tom.  I have actually already sent an email to Dr. Cortes this morning.  He recently moved from MD Anderson to Georgia Cancer Center in Augusta, Georgia.  His new email (make a note of this Scuba) is jorge.cortes@augusta.edu.

You have gone above and beyond for me.  Hope i can return the favor at some point down the road.

So when I pushed my onc for his rationale for why he wouldn't approve me to switch to low dose Sprycell  or low dose Bosulif, here's his reply:

Because below a certain dose level, we are not able to differentiate a therapeutic benefit vs. Placebo effect. 150 mg daily is the lowest sustained dose of nilotinib reported and that too as in case reports, not in any large number of patients. That's why I am hesitant in doing this. As you know that for antibiotics we do not take half doses due to a concern of giving rise to resistance, the same rationale applies to TKIs in cancer.

I thought the whole resistance theory has been pretty much disproven.  Am I correct, and if so, is there specific data or research that I can show him?

I can understand why he will not go lower on Nilotinib but that resistance theory is new to me. 

Let me know if Dr Cortes helps, if not I can give you other contacts. It just frustrates me to see someone in a tough situation getting bad advice. 

I’ll note down that new email! 

Thanks