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Nilotinib plus Peginterferon Alfa 2a and use of Milk Thistle and Globe Artichoke

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Hi Sandy and Members of CML Support Group,

I recently read a thread by Sandy commenting on the use of milk thistle supplements whilst taking TKIs saying that she believed there weren't any contraindications. And other threads by various members who've also used milk thistle and peginterferon. They were positive with milk thistle but negative with peginterferon.

I was wondering if Sandy and any other members in the know, can assist with some advice here? My mother, 82 yrs old, was prescribed peginterferon alfa 2a - trade name, Pegasys in March 2021 to assist with getting her bcr-abl down. From March to November her bcr-abl went down from 6.70% to 0.084% - achieving MMR for the first time since diagnosis in late 2018. But the side effects have been pretty tough - increased liver enzymes - ALP, GGT and Billirubin; heptasplenamegaly worsened with now the presence of ascites in her belly, feeling weak in the lower limbs affecting her mobility; loss of appetite, fluid/edema worsened where she's had a cellulitis and/or pleural effusion & hypertension/shortness of breath every month since March (except July), with about 3-4 hospitalisations, insomnia, itchiness - in the back requiring constant scratching and general feeling of being unwell.

I now know that Peginterferon Alfa 2a was once used to treat CML but was ceased due to the toxic affect it had. But since then, recent trials have been done with Peginterferon Alfa 2b - not sure if same side effects?

Following the last blood test done in Nov. 2021 and my mother suffering yet again another cellulitis episode plus persistent cough and coughing up phlegm, we've decided not to continue with pegasys due to the side effects. We'll continue with Nilotinib but I now want to ensure her liver is supported given what it's been through and have had discussions with a naturopath about milk thistle 550mg and Globe Artichoke 250mg (promotes bile flow from liver) as a liver tonic. I know that simply removing the pegasys, her liver should somewhat recover, but given that one of the side effects of Nilotinib is also heptasplenamegaly, I'm wanting a supplement that will afford some protection from side effects moving forward.

In my research I've read that both supplements use the enzyme cyp3A4 and deemed inhibitors of CYP3A4. Nilotinib uses this enzyme for its metabolism. The naturopath said that because the dose is not major and if I get my mum to take it say 2.00pm - 5 hours after her morning Nilotinib dose and 7 hours before her night Nilotinib dose, she should be ok. I've read various article re. interactions between milk thistle and Nilotinib - some say it does but other say it doesn't. One article published by a reputable American organisation - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901834/ - tilted "Herbal Interaction with Chemotherapeutic Drugs - A Focus on Clinically Significant Findings" says that a daily dose of 600mg milk thistle didn't show any interference when used with TKIs - meaning it could be as a result of a relatively low dose.

My question to Sandy and anyone else with any experience or knowledge in this area, is should I go ahead and use the supplements which as stated won't be taken with Nilotinib but several hours apart and monitor the liver enzymes given the positive effects they're suppose to have on the liver? I've asked my mother's GP but she's asked me to ask the hematologist who to date hasn't responded to my e-mail. I know for a fact, that supplements have assisted my mother especially VD3 + K2 and Magnesium with her bone pain.

Would greatly appreciate your feed  back.

Regards,

Maria

 

 

 

 

 

 

 

 

 

 

Hi Maria,

It sounds like you have done some good research. PegIFN does have similar side effects to IFN and that drug on its own failed to control CML for the majority of patients, the side effects were pretty intolerable too. So when TKIs came along the long term prognosis for the majority changed dramatically.

So - even with PegIFN I have heard that there are still significant side effects. You are probably correct to suggest that your mother stops this drug. Is there a reasons she has been prescribed nilotinib in particular? Have you/her haematologist considered another TKi with a different side effect profile?

Nevertheless, your naturopath is probably right to advise here taking milk-thistle etc away from nilotinib- and given your research results on drug interactions, you are probably safe to include the herbals to support her liver. It sounds like she's having a miserable time.

Of course it is her decision, but it sounds to me that you have a pretty sound take on the situation.

Hope all turns out well for her and the side effects diminish quickly. 

Best wishes, Sandy

Hi Sandy,

Thanks for our response and valuable feed back.

Long story.....She initially started on Imatinib - max dose and it drastically depleted her platelets and white blood cells causing her breathlessness, fluid retention etc... and going back to hospital 2-3 times. The dose was constantly being adjusted which probably didn't help things. I was so concerned I saw a naturopath "oncologist" but whilst her supplements improved her blood count, the bcr-abl increased.   In hind sight, I think the practitioner didn't get the dose right from the beginning and things just got worse. Some hematologists get ready (or inpatient) and just insist on the max dose. I believe that a slow and steady approach is best i.e. starting with the lowest dose and only increasing if absolutely necessary. But we were constantly told to increase the dose for fear of drug failure or mutations.

Eventually we were told to change TKIs and went with Dasatinib. Once again, I specifically said to start on the lowest dose but she gave my mum the max dose - 100mg which caused her drug induced pulmonary arterial hypertension (well documented side effect of Dasatinib)  - which cleared once off Dasatinib. I then requested to re-commence Dasatinib on the lowest dose of either 50 or 70mg - whichever was available in Australia as it was very good at rapidly decreasing her bcr-abl. But the hematologist refused and put her on Nilotinib and again on the max dose which caused her an inflamed gall bladder which had to be removed (, cardiac problems and pulmonary arterial hypertension, bone pain etc.. etc..  (all well documented side effects of Nilotinib). We were told to constantly increase the dose to max 4 x 200mg notwithstanding she made very good progress on 2x 200mg daily. We've now changed hematologist and she suggested peginf with Nilotinib, but we've had to manage the side effects with use of diurectics to keep the fluid at bay and I give her supplements to support her immune i.e. vd3+k2, magnesium, potassium & iron and I monitor their levels via regular blood tests.

I'm in consult with the hematologist at present as I would like her to change TKIs as I can't understand why my mum's liver and spleen has increased in size + ascites - most likely due to peginf yet the bcr-abl is now MMR? Hopefully all will resolve now we're off peginf and on liver tonic and may change TKIs - I was thinking going back to Dasatinib but on say 50mg or lower if available here or back onto Imatinib now that she's MMR. I just want her to keep on CCR or MMR as not fussed about reaching a Deep MMR if it means her not having a functioning liver. If you have any thoughts on this, would like your feed back Sandy.

My mum's amazing to have put up with all of this since late 2018 and still alive! She wants to live and I think that mentality helps getting through each day - but it's been a very hard slog.

Maria

 

 

 

 

 

 

Hi Sandy,

Forgot to tell you that when my mum was initially started on Imatinib, she had previously been prescribed hydrea (chemo drug) 1 x 500 mg in 2018 whilst the hematologist ran other tests, as she wasn't sure what disease she had. But this only made her condition worse and her wbc more than doubled and made her feel worse. She was later hospitalised due to side effects of hydrea and was told to increase the dose to 4 x 500mg (as they said the dose wasn't high enough causing the side effects) and when CML was confirmed, she started Imatinib, but we suspected that the hydrea wasn't cleared out of her body at the time of starting Imatinib and may have contributed to the side effects mum was experiencing - predominantly thrombocytopenia causing breathlessness & edema. At one stage her platelets went down to 17.

Anyway, for your information I've received information from the a senior pharmacist who works with our hematologist to confirm that milk thistle (and globe artichoke - same family) doesn't appear to overly inhibit (or induce) the metabolism of Nilotinib but to be on the safe side, I will still separate when each are taken. He did mention that for diabetes people, to be aware that the supplements can cause hypoglycemia. But, Nilotinib actually increases blood sugar so this really shouldn't be a problem if taking Nilotinib (in fact, it's a positive from where I stand) but should still be monitored.

Anyway, if you have any thoughts on what TKIs would be better with less side effect i.e. cardiac and/or pulmonary, that would be good.

Maria

 

 

 

Hi Maria,

All TKIs have side effects (grades 1 - 4) and it seems that it depends on the individual whether they are manageable or not. Some fortunate people do not have significant side effects at all. 

I would say you need to talk to your mum's clinician in order to assess which TKI may be more tolerable for her. All a bit hit and miss/try it and see unfortunately.

I hope your mother's quality of life improves - maybe a smaller dose of nilotinib rather than a change to another TKI would help? If her molecular response is good, as well as stable - this may be one answer. I am sure she will improve anyway since you have elected to stop the PegIFN.

Sandy

Thanks Sandy,

Have suggested a dose interruption until her fluid is under control and then dose reduction now that she's MMR, which has been oked by the hematologist. So will wait and see.

Maria