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Running out of options

Hello. My wife was dx with CML in 2012@ age 36. started on 100mg sprycel. Had great success was @mmr within 10 mos. for a couple of years pcr was steady between .08 and .02. 2014ish. she had plural effusion and pericardicial effusion at the same time ..stoped treatment and drained fluids after about 30-45 days started gleevac. pcr remained below .06 thru this period. she was only able to tolerate gleevac (400) with the help of nausia meds. after about  one year switched to bosulif due to continued gastro issues. pcr  stayed steady between .1 and .025 thru gleevac phase. on bosulif (300) pcr range was .01 and .005 however her liver #’s were elevated. so we had to stop and restart at lower dose (200) remained between .01 and .006. now at 41 she was hospitalized for severe PAH so bosulif has been withdrawn. We dont know what to do anymore. the other tki’s remaining have known cardio issues or are know to cause pah  since shes been consistently below .01 and .005 should we consider letting her body take a tki break for a while ? other than tki events shes been healthy. i feel the tki’s will take her out before the CML. 

thank you CML community. 

Based on previous discussions on here I wonder if lower dose sprycel might be the answer. Scuba is the expert on this (I've done well on imatinib, so haven't much experience on sprycel). I believe Scuba is maintaining MMR on 20mg. Have a look at some of his earlier posts on this and see if that helps  - or I am sure he will respond before too long. 

Hi, I'm sorry your wife is having problems... especially with the diagnosis of PAH https://www.nhlbi.nih.gov/health-topics/pulmonary-hypertension.

As this can be a rare condition that can pre-exist or can be caused by certain TKIs like dasatinib. As she still has a low molecular level of BCR-ABL  - 0.1% to 0.005% - she obviously responds well to bosutinib (bosulif) I think she is safe to stop TKi therapy for a while, as long as she is adequately monitored by PCR. This issue with PAH is potentially very serious. I believe there are different classifications of PAH so you need to ask her cardiologist.

Regarding dasatinib, nilotinib ... both carry risks for cardiovascular damage. As bosutinib does not target the C-KIT or PDGFR pathways it is probably the safest of the TKIs re CV effects. I would caution you about the other TKIs given she now has PAH. Talk to your cardiologist about her options.

Sandy

Start 20 mg Sprycel, increase dosage if required.  

I am currently in CMR (not MMR) - or "undetected" while taking 20 mg Sprycel.

She could consider low dose Sprycel (20 mg) given her current PCR levels to test that she maintains response and reduces (or eliminates) side effects she can feel. I have no side effects I can feel - but do experience continued minor blood suppression which I can not feel.

thank you all for the response.  Her PAH is “severe” according to the cardiologist.  

Scuba  when she was on sprycel (100) mg she had a very mild pah and the effuions.  The onc and cardiologist and my wife was reluctant even talking sprycel esp due to the Pah.   

is there any data that shows bosulif causes pah or oast useage of sprycel can cause reoccurring issues even after cessation. 

 

To be clear - precisely because she had effusions - Spyrcel may be work better than other TKI's against CML.

See this article:

https://www.spandidos-publications.com/10.3892/or.2016.5110

from the article,

"Second, the occurrence of PE was related to the treatment response, especially the early molecular response. In patients with PE, the cumulative MMR rate was significantly higher in the PE-positive group than the PE-negative group ..."

Because Sprycel may actually be a better drug for PE indicated patients, management of PE while taking Sprycel is a relatively new protocol:

https://www.sciencedirect.com/science/article/pii/S2152265016305687

Pleural Effusion in Dasatinib-Treated Patients With Chronic Myeloid Leukemia in Chronic Phase: Identification and Management

 

The key idea is that your wife may actually be able to achieve a dramatically high response while taking a very low dose of Sprycel and avoid side effects including P.E. Incidence of PE on low dose Sprycel is very low and likely not to be a problem for most patients who had PE; while incidence of P.E. on normal dose Sprycel (i.e. 100mg) is much higher (30% or more).

I can't write this enough - 100 mg Sprycel should never be prescribed initially. In addition - drug stopping followed by low dose re-start should be considered for patients with P.E.

Show these articles to your wife's doctor. It would be a shame to give up on a drug which may actually work terrifically if dose is managed. P.E. and PAH can be managed.

Switching to another drug is certainly a consideration.

Scuba

Thank you for the article. it’s certainly encouraging. I will mention this after the dust settles. Though the article focuses strictly on effusion.  her latest incident is severe PAH. That will be the the concern more so than the pe.

 

This is a tough nut to crack.  I know there are people on the old LLS (US) forum who struggled with PAH - I'm hoping they come forward to help.  I seem to remember some case studies and the takeaway was that the PAH was improveable if not curable off the offending TKI.  But as to your question of what to do next, I don't think I've come across anything to say which TKI to choose post-PAH.  Therefore, my advice would be to contact one of the CML specialists and see them, if you can where you are.  I have successfully emailed Dr. Cortes and Dr. Drucker - they were terrific and got right back to me.

What about Gleevec at a very low dose, say 200?  I agree that if one has to take anti-nausea and anti-diarrhea meds just to make it through life, it's definitely not the drug to choose.  But a lot of people have seen great improvement in Gleevec SE's on a much lower dose and with closer attention to eating just the right amount at the right time.  And maybe a daily dose of Benefiber, which is not onerous.  It seems your wife did well on Gleevec, PCR-wise.  Maybe she could sneak back on it at 200 or even 100 mg, when the PAH is under control.

I, too, would like to know a LOT more about Bosulif.  It's like the mystery TKI.  There are wildly different patient reports of satisfaction/dissatisfaction.  I manage a very small chronic PE on Sprycel 20 mg and a PCR of 0.005% IS.  My onc wants me to switch to Bosulif to get rid of the PE, but I can't find any data to say the whole fluid retention/immune response thing would change.  The same would be true for PAH - there seems to be no data with Bosulif.  (And pericardial effusion, also.)  So, I would try and get to one of the biggies - the researchers - and ask.  Good luck and keep us posted.

Hi, I can find little information on bosutinib and PAH as a common adverse event.

The Medscape page on bosutinib cites the risk of PAH in CP CML as 1%.  Also this: https://www.ncbi.nlm.nih.gov/pubmed/28639957

* "Dasatinib-induced PAH usually seems to be reversible with the cessation of the drug, and sometimes with PAH-specific treatment strategies. Transthoracic echocardiography can be recommended as a routine screening prior to dasatinib initiation, and this non-invasive procedure can be utilized in patients having signs and symptoms attributable to PAH during dasatinib treatment."  

*https://www.ncbi.nlm.nih.gov/pubmed/29334406

** "Patients with prior dasatinib-intolerance related to cardiovascular events, gastrointestinal events, musculoskeletal or skin events did not experience these toxicities in a more severe form while on bosutinib therapy."

** https://www.pbm.va.gov/PBM/clinicalguidance/drugmonographs/Bosutinib_Monograph.pdf

--------------

ELNet Recommendations for TKI management in CML

See full publication here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991363/

Snippet from above publicaton:

ABSRACT

 

Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available.

For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. 

  • First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective.
  • Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means.
  • Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible.
  • Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment.
  • Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life.

Pulmonary arterial hypertension- PAH
Incidence and severity: Pulmonary arterial hypertension (PAH) has been reported with the use of dasatinib 94, 95, 96, 97 at an estimated incidence of 0.45% and a median delay between drug initiation and PAH diagnosis of 34 months (range 8–48 months).

At PAH diagnosis, most patients had severe clinical, functional and haemodynamic signs of failure, some of them requiring vasoactive drugs and management in the intensive care unit.... 97

Clinical and functional improvements were usually observed after discontinuing dasatinib; however, the majority of patients failed to demonstrate complete haemodynamic recovery .... 97

Prevention and management: The presence of dyspnoea and syncope not explained by pleural effusion should prompt the suspicion of PAH. Although rare........ prompt withdrawal of dasatinib may totally or partially reverse PAH, but pharmacologic treatment may be needed, 94, 95 and referral to a suitable specialist is mandatory.

 

Thanks, Sandy, that was really informative.  Now I've got one fact, that there is a 4% incidence of pleural effusion emerging in 2 years of bosutinib as a 2nd line therapy.  This was in 2011; I wonder about a clinical update now that there are more people on bosutinib.  I also saw confirmed that the Src kinases are implicated in PAH as well as PE.  I just really wonder what people are going to do, going forward, who have PAH or PE on all the TKI's?

Hi Kat

Thats precisely my fear with my wife.  

The PE ‘s can me managed but not sure od PAH can be managed the same way

Any updates?  How is the PAH?  What TKI is she going to try now?

Hi Kat

She has been home from the hospital for a few days now. She has been put on Remodulin thru a pic line to treat the PAH. Its been now 3 weeks off the bosulif. We are awaiting pcr results (last .014). we will be following up with Dr’s in a couple of weeks to discuss next course of action. 

Thanks for the update.  Sounds like you're hanging in there.  Let us know what they decide to do - more and more of us are turning up with this nasty surprise of PAH.

UPDATE.....

The pcr after being off bosulif for about 3 weeks came in at .0039. Onc floated the idea of trying the gleevac again due to the fact its known to help PAH. unfortunately my wife is hesitant as she already had intolerance in the past. She wants to advocate staying off tki for a bit to let her body recoupe. We will be actually meeting with onc in a couple of weeks   so we shall see.  

Sounds like a reasonable plan... it's a very good sign that her PCR is continuing to show a deep molecular response. If imatinib helps alleviate PAH then I would go with that - but it's totally understandable that she would want to stay off therapy for a while.

Sandy

Deven,

what was your wife’s liver numbers at their highest while on Bosulif?

Stephanie

Deven,

i replied to Sandy by accident.  I am curious as to where your wife’s liver number were at their highest while on Bosulif.  I recently went to 200 from 100 and my liver numbers increased as well.  Thank you

stephanie

hello

he liver #’s went to 250 before she went off. once they went back down she went on a lower dose. of course now she’s off permanently as it has caused a severe event. 

 

Hi Scuba

may be you have explained this elsewhere but can you elaborate on why 100mg should not be used initially  ? I understand the probability of PE been the main issue but could there be other reason like infection risk as in this 140mg study (scary stuff..)

https://www.ncbi.nlm.nih.gov/pubmed/19744184

and also T315i risk? In the DASISION trials, 17 people developed mutations, 11 of them are T315i. Sokal score did not seem to have a influence on this probability.  Gleevec had 18 and only one developed T315i. In the ENEST trial for nilotinib , only 1% of low Sokal patients developed mutations. I know it is a different cohort but I think it have been acknowledge in the past (by Dr Tim Hughes)  that Sprycel is associated with  higher T315i and I think are some paper suggesting Nilotinib is a better performer. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559757/

https://www.ncbi.nlm.nih.gov/pubmed/21524239

Could dosage be the problem here ?

I really wanted to move back to Gleevec and better, Nilotinib after researching the matter but Sprycel have put me into MMR after 4 month with minimal side effects so there is no reason to change and I am already thinking of reducing dose. 

I am new here but understand that you are the resident TKI expert , Would Love to get your opinion on the matter which been on my mind for awhile. I have no problem with Sprycel per se but just want to get to the bottom of this. 

Thanks

Vince 

 

 

 

Hi Vince,

Welcome to CML Support.

There was a study titled: "Early Results of Lower Dose Dasatinib (50 mg Daily) as Frontline Therapy for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia"  that was published earlier this year.  The preliminary findings are that dasatinib at 50 mg per day achieves MMR at a faster rate than 100 mg per day did in previous studies.

https://www.cmlsupport.org.uk/article/early-results-lower-dose-dasatinib...

For example: at 50 mg dose for 9 months, MMR was achieved by 82% of the patients. At 100 mg dose for 9 months, MMR was achieved by 39% of the patients. Hopefully these results will be replicated with a larger cohort of 50 mg dosing.

It seems with Sprycel, less is better until it's not enough to be effective.  The question is, where is the sweet spot with Sprycel. Is it 50?  Maybe 40 might be even a little better.  We've known for quite a while that 140 is too much for most. And now this study seems to be showing that 100 is not as good as 50 in the early stages of treatment.

Regards,

Kirk

PS - I have the full article in PDF.  If you would like a copy, let me know and we'll figure out how to get it forwarded to you.

 

 

Hi Kirk

Thanks. I have actually come across this paper and showed it to my doc (who was not aware of it..), it is just counterintuitive that a lower dose would lead to better response. I do have to say that we have a completely different cohort from the 100mg trials and we can't do a direct comparison since Sokal scores, age and other factor come into play here.

In any case, it is very encouraging results and I hope to go down to 50mg soon.

Vincent

 

If you put the DOI (digital object identifier) into http://www.sci-hub.tw you can usually get the full paper. 

For example, the DOI for the latest DESTINY data is 10.1016/S2352-3026(17)30066-2

http://sci-hub.tw/10.1016/S2352-3026(17)30066-2

David. 

Is it really counterintuitive that a lower dose leads to a better response? 

We are basically interested in a sort of homeostasis. If we have a bacterial infection, we take antibiotics. We could take loads and loads, and kill it with "fire", but we don't ... we take the right amount to kill what needs to be killed, and leave what needs to be left and our body to recover the rest. 

Nobody really knows all the "side jobs" that TKIs do, so we need to take the smallest amount possible that do the job we want, but not the jobs we don't want.

For me, less is more. 

David.

Thanks David,

I put "Early Results of Lower Dose Dasatinib (50 mg Daily) as Frontline Therapy for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia" and it returned the original article perfectly.