Faslodex + Pablociclib(Ibrance) treatment combination -
Comments
-
It was rhetorical :-) I can look it up.
I'm just feeling sorry for myself. People do seem to get more upper respiratory tract infections with Ibrance.
In the normal scheme of things I'd say to myself "cold, will feel better in three days, take benadryl and suck it up". Not possible when on one of the immunosuppressive drugs.
0 -
Hi pajim - hang in there. Ladies on the Ibrance board have taken mucinex otc with good results. So true about our suppressed immune systems, but you are our research writer and so savvy! Please don't let this set you back. I also gargled with salt water which helped. Feel better soon.
0 -
Thanks! The cancer center had me come in for a blood draw and to listen to my lungs. I gather that if my neutrophil count had been really low they'd have provided antibiotics.
In any case no issues, it's only a cold, take benadryl, suck it up :-) (they didn't say that, they said to feel better soon)
Good to hear my white count is OK. Took the last pill of cycle 1 tonight; it's all uphill from here.
0 -
Officially now on a two to three week break from Ibrance as my ANC and WBC are lower than they've ever been. My onc was kind of freaking out and worried I might end up with cellulitis again. I started inspecting my lymphedema arm and said no wounds or burns so I should be okay. She asked if I had a cut or burn the last time and when I said yes, I cut my finger, she visibly breathed a sigh of relief. She thought my cellulitis appeared spontaneously. So, good news I guess.
Received Faslodex shots in the upper hip today instead of my bum. The nurse did a fine job as I basically felt no pain - only the stick but that was pretty much it.
Have a great weekend all.
Amy
0 -
Hi goils!
pajim, that happened to me too! I had to do 7 days of Levaquin just be safe. I think your correct in the neutrophil and lymphcyte question however, i think that theory applies to people with normal immune systems. Honestly ladies, our immune systems (and by extension our bodies) are beaten up with all of our pills, chemo, pain, lack of sleep, energy etc.
I'v been taken off my second cycle on day 18 (yesterday) as cell counts were again really low (ANC .7, platelets 100 and WBC 1.0). So I got a Neupogen shot to help bump before I start XRT next week. MO says we'll lower to 100mgs dose next cycle starting April 4th. I'm starting my second XRT spot next week. I also get those dreaded shots with my Zometa infusion this coming Thursday. We're gonna try back/side of thigh this time as there is "more meat". lol
I really don't get a treatment break for 2 months. I'm tired. Having a low cell count also doesn't help. MO gave me an RX for magic mouthwash and toothpaste for mouthsores but all in all second Ibrance cycle hasn't been that bad.
Discussed next PET/CT and while it's time, I have only been on Ibrance for 2 cycles. My MO and I like to wait 90 days between scans. He did say we may switch to a nuclear bone scan and CT vs. PET/CT. Reason is the spots that have irradiated will light up very bright and will be hard to determine if any healing or shrinkage has happened in those areas. I didn't know that but did express my concern about nuclear bone scans not picking up my osteolytic leasion. That has happened before and I'm not a fan of those. Either way, we're gonna wait until end of April.
Sounds like we're hangin' in there! one foot in front of the right?
xo- shelby
0 -
Hang in there Shelby! My cold is proving difficult to shake, and the fever is back but at least I know there's no cause for alarm. One of the docs in my office said if I got pneumonia I'd know it. I'd be sick as a dawg.
0 -
my blood platletts went from 64 to 20 on Ibrance. Anyone else having issues?
0 -
Health News Review grades news releases on 10 criteria - satisfactory or not?
Here's what they say about recent release on fulvestrant/Faslodex and palbociclib/Ibrance. I excerpted the not satisfactory criteria to keep it simple. Click on article title to read the whole thing.
Release omits key safety findings of breast cancer drug combo study
Does the news release adequately discuss the costs of the intervention?
Not Satisfactory
The news release does not mention cost. The wholesale cost for fulvestrant 500 MG is $1,845/month and palbociclib is approximately $9,850. A 2015 report on palbociclib's cost by a pharmacy benefits manager stated it could potentially be one of the top 10 most costly cancer drugs.
Does the news release adequately explain/quantify the harms of the intervention?
Not Satisfactory
The news release downplays a number of side effects named in the journal article. According to the news release, the drug combination apparently has few severe side effects. The news release identifies a drop in white blood cell count as a common, but non-severe, side effect. But when we looked at the study's table of side effects we found a considerable number of grade 3 or 4 (more serious) adverse events. Some of this is confusing to interpret. For example, the study says that grade 3 or 4 adverse events
occurred in 251 (73%) of 345 patients in the fulvestrant plus palbociclib group and 38 (22%) of 172 patients in the fulvestrant plus placebo group. The most common grade 3 or 4 adverse events were neutropenia [low white blood cell count] (223 [65%] in the fulvestrant plus palbociclib group and one [1%] in the fulvestrant plus placebo group), anaemia (ten [3%] and three [2%]), and leucopenia (95 [28%] and two [1%]).
The study later says,
"Serious adverse events (all causalities) occurred in 44 patients (13%) of 345 in the fulvestrant plus palbociclib group and 30 (17%) of 172 patients in the fulvestrant plus placebo group."
The study may be drawing a distinction between "serious" and "severe" events and including or not including grade 3 events in these different tallies. Regardless, the release misleads by omission when it calls severe side effects "rare" while not mentioning these relatively common less-severe effects. And that's leaving aside the issue of grade 1 and 2 side effects that appeared to be quite common and more frequent in the experimental treatment group. The study notes, for example, that "Infections, fatigue, nausea, anaemia, thrombocytopenia, alopecia, rash, and stomatitis, among others, were also more common in the palbociclib group."
Does the news release seem to grasp the quality of the evidence?
Not Satisfactory
The news release provides a nice summary of the parameters of the randomized controlled trial. However, there are a few important caveats to the research. Notably, the news release fails to note the difference between surrogate outcomes — which this study focused on — and overall survival. There's ongoing discussion among oncology experts that stalling progression is one goal, but it's not the most important goal for patients, which is survival. Some question whether delaying progression in metastatic disease for short periods is truly an advance for patients, especially with drugs that carry numerous risk for side effects and huge price tags. In a Milwaukee Journal Sentinel "Side Effects" column, investigative health journalists John Fauber and Elbert Chu describe the trend of drug companies introducing therapies that may increase "progression-free survival" for a few months but don't extend life. In many cases, writes Fauber, "The FDA does not routinely push companies to do studies that prove a drug can extend or improve life as a condition of approval. When the agency does, drug companies sometimes ignore it."
0 -
Thanks for the Health News Review assessment, LTS. I think we all realize that glowingly positive new releases produced by drug companies tend to minimize the negatives surrounding their newest research and offerings The line that jumps out at me, and I'm sure it will others, here is...
"Some question whether delaying progression in metastatic disease for short periods is truly an advance for patients, especially with drugs that carry numerous risk for side effects and huge price tags."
While we all hope and pray long term survival is the goal of research, with so many "loose ends" in even understanding what causes bc and how and why mbc develops, I doubt very much if any of us would turn down a drug that has the potential to double the progression-free time of existing drugs to give us more milestones, more months with our families, and more time in which to hope that more advancements will continue to come along to prolong our lives. The "some" referred to -- and we all know who they are -- surely are not living with metastatic cancer.
0 -
Woke up with raw bleeding gums and runny eyes. After much un-sticking of eyes, I read Stephanie's Health review article. Still hoping for good results on Ibrance/fas cocktail, but sobering stats re: "serious adverse events" = all casualties (44) taking this combo. Yikes.
0 -
That caught my attention, too, lalady. But how many women were in the study? What percent of the total is that? Where were their mets and what other pre-existing conditions might they have had?
Maybe Stephanie can clarify... Were the 44 all attributed solely to the med combo(s), or to other concurrent events? Clearly, we are on a couple of very powerful drugs, and the combo is new. But I don't want that "44" figure to worry us more than it should.
0 -
Hi DLB,
I think I straddle more than several worlds:
While I totally believe in a patient's right to choose whatever approach is best for them, including integrative, complementary and alternative treatments, I also believe in informed consent.
And, yes, I do spend a lot of time reading both source medical journal articles and news releases like this one.
What information we get, how and from whom influence our treatment approaches, so it's important to understand the gulf between the research in medical journals and the drug company news release.
Unfortunately, most people only hear the glowing reports about progression-free survival and miss the more nuanced details like those adverse events, overall survival (OS) and costs of treatments. As a patient with decent insurance coverage, cost of treatment doesn't mean much to me...while harms of treatment and OS mean a lot.
DLB, I've requested the article from the UCSF medical library and hope to read it soon...but I see from the summary that it's based on the big phase III PALOMA-3 study and should carry a lot of weight.
Will let you know more if and when I get the article.
Healing hugs and regards for all, Stephanie
1: Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Mar 2. pii: S1470-2045(15)00613-0. doi: 10.1016/S1470-2045(15)00613-0. [Epub ahead of print] PubMed PMID: 26947331.
0 -
Oh, here's the abstract with its dense medico-speak...the article itself will be more dense:
Lancet Oncol. 2016 Mar 2. pii: S1470-2045(15)00613-0. doi:
10.1016/S1470-2045(15)00613-0. [Epub ahead of print]
Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.
Cristofanilli M(1), Turner NC(2), Bondarenko I(3), Ro J(4), Im SA(5), Masuda N(6), Colleoni M(7), DeMichele A(8), Loi S(9), Verma S(10), Iwata H(11), Harbeck N(12), Zhang K(13), Theall KP(14), Jiang Y(13), Bartlett CH(15), Koehler M(16), Slamon D(17).
Author information:
(1)Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, IL, USA. Electronic address: massimo.cristofanilli@nm.org. (2)Institute of Cancer Research and Royal Marsden Hospital, London, UK. (3)Dnipropetrovsk Medical Academy, City Multiple-Discipline Clinical Hospital #4, Dnipropetrovsk, Ukraine. (4)National Cancer Center, Goyang-si, South Korea. (5)Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. (6)NHO Osaka National Hospital, Osaka, Japan. (7)Istituto Europeo di Oncologia, Milan, Italy. (8)Center for Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA. (9)Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. (10)Sunnybrook Odette Cancer Centre, Toronto, ON, Canada; Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada. (11)Aichi Cancer Center Hospital, Nagoya, Japan. (12)Brustzentrum der Universität München (LMU), Munich, Germany. (13)Pfizer, San Diego, CA, USA. (14)Pfizer, Cambridge, MA, USA. (15)Pfizer, Collegeville, PA, USA. (16)Pfizer, New York, NY, USA. (17)University of California, Los Angeles, Los Angeles, CA, USA.
BACKGROUND: In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses.
METHODS: In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients-ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0-1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy-were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant.
The primary endpoint was investigator-assessed progression-free survival.
Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135.
FINDINGS: Between Oct 7, 2013, and Aug 26, 2014, 521 patients were randomly assigned, 347 to fulvestrant plus palbociclib and 174 to fulvestrant plus placebo. Study enrolment is closed and overall survival follow-up is in progress.
By March 16, 2015, 259 progression-free-survival events had occurred (145 in the fulvestrant plus palbociclib group and 114 in the fulvestrant plus placebo group); median follow-up was 89 months (IQR 87-92). Median progression-free survival was 95 months (95% CI 92-110) in the fulvestrant plus palbociclib group and 46 months (35-56) in the fulvestrant plus placebo group (hazard ratio 046, 95% CI 036-059, p<00001).
Grade 3 or 4 adverse events occurred in 251 (73%) of 345 patients in the fulvestrant plus palbociclib group and 38 (22%) of 172 patients in the fulvestrant plus placebo group. The most common grade 3 or 4 adverse events were neutropenia (223 [65%] in the fulvestrant plus palbociclib group and one [1%] in the fulvestrant plus placebo group), anaemia (ten [3%] and three [2%]), and leucopenia (95 [28%] and two [1%]). Serious adverse events (all causalities) occurred in 44 patients (13%) of 345 in the fulvestrant plus palbociclib group and 30 (17%) of 172 patients in the fulvestrant plus placebo group. PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients for whom these data were available. Neither PIK3CA status nor hormone-receptor expression level significantly affected treatment response.
INTERPRETATION: Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy.
FUNDING: Pfizer.
Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID: 26947331 [PubMed - as supplied by publisher]
0 -
As a numbers gal - I read 345 ladies in the Ibrance+Fas study and 172 ladies in fas+ placebo (sugar pill) = 517 ladies in this study. Of those, 44 casualties in first group, 30 in second. No info on how far along mets are/were in either group. What is clear is that 65% of first group (Ibrance + fas) had neutropenia, and 48% of those had Grade 3. Furthermore, in Study 1 (below) which my UCLA onc oversaw; 75% has neutropenia, 41% had fatigue, 35% had anemia, and 22% had hair loss like me and Kaption, etc. These metrics are important for all of us to understand and recognize the seriousness of possible SE's. For me, fatigue, bleeding gums, requiring my first blood transfusion ever after round 1 and needing a hair halo are enough to put this combo up there with IV chemo (which I had 6 rounds of and did not lose my hair thanks to cold caps). It's rough for some of us, and SE free for others. Thanks again Stephanie for alerting us.
Table 4: Adverse Reactions* ( ≥ 10%) in Study 1
http://www.rxlist.com/ibrance-side-effects-drug-center.htm
0 -
Ooo baby, the article is both dense and sprawling and while I sorta grok it, it's a tough read and would be impossible for me to translate into a little bco message box.
If anyone wants a copy for personal use, please PM me with your email address and I'll send it as an attachment. May take me a few days to get to this, so thanks in advance for your patience.
Sorry, I can't do better than this.
warmly, Stephanie
0 -
Steph - you are our grok star. What a fun read that book was, sorry so many find ourselves "Stranger in a Strange Land" of cancer. Pam are you feeling better after your cold? I hope you are back on track. Shelby when do you start XRT? Sending good thoughts your way...
0 -
I can get the full article (for free) for anyone who would like to receive it -- just PM me. The abstract Stephanie provided is missing a few decimal points. It's not 95 versus 46 months but 9.5 versus 4.6 months until progression.
FYI to everyone, usually if a research article (one published in a decent journal) is more than six months old it should already be free. The inital palbo/Fas paper published in the NEJM is already free.
http://www.nejm.org/doi/full/10.1056/NEJMoa1505270
0 -
lalady - I start XRT for second spot next Monday. It's a higher dose 5 day treatment to coincide with the low cell counts. I have 2 weeks off chemo as cell count just isn't high enough for chemo but high enough for radiation. I get my Faslodex/Zoladex shots this Thursday. I'm so confused sometimes!
0 -
shelbymarie - rooting for you - hope you do well. I get round 4 fas shots + xgeva next week, and a lung drain this Thursday. Pam can you explain why my Ibrance box literature states 20 mos to progression yet this study says 9.5 mos?
0 -
Yes, actually. There have been two major studies of Ibrance reported (a third is on-going).
The first one was Paloma1. They randomized a smallish number of newly diagnosed women to Ibrance plus letrozole or letrozole alone. The initial PFS (progression-free survival) was 20 months versus 10 months. See
http://www.thelancet.com/journals/lanonc/article/P...(14)71159-3/abstract (its free)
They then enrolled for Paloma2. It's a much bigger study of the same question. Women just diagnosed who were on their first treatment. Pfizer finished enrolling for that at least a year ago and it's on-going. I find it interesting they haven't reported any data yet. Probably means not many patients have progressed.
Meantime Pfizer was looking for some fast[er] answers. So they started Paloma3. They enrolled women for whom letrozole had failed. They were randomized to Faslodex plus or minus Ibrance. We only have PFS data. That's the New England Journal of Medicine paper I referenced above.
So far as I know we are waiting for overall survival data for all these studies. The reason we don't have it is that women are living much longer with this disease. Don't get me started on the two schools of thought about whether this drug will or should show a difference in survival. :-)
0 -
Hi Pajim,
Not to get you started, but it took many years and many failed studies to convince me that PFS (progression free survival) doesn't always correspond to OS (overall survival), especially when significant adverse events are involved.
I had such high hopes for palbociclib/Ibrance, but I know of very few who can tolerate the 125 mg dosage at the usual schedule without stopping or scaling back due to unwanted adverse events. Have no idea what grade their adverse effects were, just the disappointment among my friends, which is more feeling than fact, but still instructive.
I'm uncertain which school I'm in...probably "better safe than sorry".
best, Stephanie
0 -
Pam. I for one would love to get you started! My brain still can't seem to wrap itself around the idea that these drugs can increase PFS without somehow increasing OS. Thanks for the info on research articles.
Stephanie, I am one of the lucky ones, still at 125mg and never had to take extra time off for low counts. I wish more of us fell into this category. I do wonder if maybe 125mg is just too high a dose for most.
0 -
Stephanie, so far I am also one of the lucky ones... still @ 125mg... about to start my 8th cycle, albeit w/some unpleasant but tolerable SEs. One thing I've observed since its approval is that many oncs did not have an initial comfort level w/this drug and in some cases were pulling patients off it after just a cycle or two, and not necessarily based on Pfizer's guIdelines.
Jobur, hopefully with Ibrance and future targeted therapies and immunology vs. harsher chemotherapies, we will start to see longer PFS times translating to longer OS.
0 -
OK, but remember you asked. This is about evaluating treatments.
One school of thought believes that when you are testing an "early" treatment, you can't (shouldn't? don't need to?) show an improvement in overall survival. Their reasoning is that there are so many confounding issues with how women are treated later on; that everything is so muddy there's no way to show anything. In other words, there are so many more lines of therapy that it all comes out in the wash. This goes with the [known] fact that each woman responds to different drugs. Your magic bullet is not my magic bullet.
The second school of thought is that if you are truly bending the disease curve with your drug, in other words, if you're extending progression by a year (in this case), you should be able to bend the survival curve. Otherwise all you are doing is extending one progression but must be hastening the next progression or death. To put it a different way, if you didn't give your drug, women survive 48 months (say). But if you gave the drug, even though PFS was extended 10 months women are still going to live only 48 months? Then what good is the drug?
Now the numbers I'm throwing out are usually medians (when published). 50% of the women die or progress before that, 50% after. There is no mention of responders versus no, or stuff like that. Any individual is not on the median.
I have heard well-reasoned, well-respected oncologists espouse both points of view. I was brought up on the second school of thought, but the first school has valid reasoning and excellent points. Near as I can tell, the [US] FDA used to be much closer to the OS concept but is moving towards PFS is "good enough".
FYI there were two major trials of Faslodex as first line therapy (plus or minus anastrozole). The first showed a PFS advantage and an OS advantage. So it is possible to extend survival. The second study showed neither. The differences are thought to be due to differences in the patient population (one US, one Europe) but no one knows for sure.
0 -
Now for the personal. I'm slowly getting over this cold. The low neutrophils didn't help, I'm sure. Still not quite there. I'm supposed to restart on Thursday (blood draw tonight).
I'm pretty sure the blood work will be fine.
Do I ask for a postponement? Or soldier on? Is it best to feel "tip top" before starting the next cycle? Or does it not matter?
0 -
pajim, if I test at the end of my normal cycle, I typically have to wait a few extra days for my granulocytes to go from 800 to 1100, which is my normal pattern. The one time I'd gotten really sick since being on this combo, I waited a total of 16 days (usual 7 plus 9 more) before restarting Ibrance. I still wasn't feeling 100%, but was shocked to find out that my granulocytes had rebounded to 3100. It's so hard to tell b'cuz we're all so different, but I don't think it hurts to wait a few extra days, rather than layer Ibrance SEs on top of already feeling bad. My onc had also advised me to wait that time until I was feeling better, and to get my labs redone before restarting.
And thanks for your thoughts and explanation on the two schools of thought re. PFS & OS. It's such a fascinating topic. As a patient or patient's family, it's very difficult not to hope that the next tx will be the magic bullet, and that added PFS time can keep us here until the next big breakthrough.
0 -
There is an interesting discussion on the following thread:
Better PFS but not better OS?
0 -
Pam - thanks for the explanation. My next PET in April should let us know if PFS is happening or not. I for one would love to toss the Ibrance in favor of fas + xgeva. The SE's for me are rough, thus pondering if say I only have "48 mos" then why be "poisoned" for the duration for the same outcome? If there was a product that made me feel better and/or didn't make me feel worse (again with same duration) - where is that? ps. I'm not referring to pain meds as I am not taking any, nor do I want to. Shetland thanks for that thread.
Stephanie you have me thinking. Jobur happy to hear you are SE free. But lots of questions to ask my onc next week for round 4. FYI I've had 6 rounds of IV chemo, 28 rounds of rads and soldiered on as I believed there was a good ending ahead. Now on Ibrance #125 I question whether 12 or 20 mos of this toxicity will be a good ending or not. Just venting...0 -
Thanks Pam and Jobur, I got so startled by these stats and trials I had to retract my post, lest anyone think I'm getting morbid. But if mortality/casualty is not forestalled, how is the quality of life measured merely because a patient is PFS; which does not mean pain-free or SE free? Shetland Pony and Stephanie's comments had me gorging on Ibrance stats. Jury is definitely out on what it will or will not do long term, other than SE's for more patients than not, and some very serious. Hoping my PET in April shows PFS, but if not I may rethink this "treatment" and ask about other magic bullets to add to my fas + xgeva + arimidex.
Pam - I would try to soldier on unless blood count is off. But please feel better, we need you!
0 -
I think my onc balances quality with quantity better than I do. I didn't want to go down to 75mg Ibrance, but wow I feel like I am living again. I'm glad I can feel she is looking out for me in that way. I told her I'm ready to do more chemo if my recent scan, symptoms and TMs mean progression, but she wants it to be faslodex. I looked up faslodex and it does seem that it can work even after an aromatase inhibitor failure.
0
