There must be a lot of people who have already dealt with this issue but I didn't see any discussions on it.
I'm 47 years old with a recurrent grade 2 Astrocytoma previously treated with surgeries. Just over 12 years ago it was also treated with radiation, but not with chemotherapy. It's IDH1 mutated, unmethylated and 1p/19q are intact. I'm deciding between radiation followed by PCV or radiation with Temodar and adjuvant Temodar.
The results of RTOG 9802 make PCV appear to be a reasonable option, but RTOG 0424 Temodar results are just as good. My doctor's say Temodar will be as effective as PCV and more tolerable. The advantages of PCV are: the RTOG 9802 survival plot for IDH1 mutations looks good, it's a multi-agent treatment, the methylation status isn't a factor, and there seems to be less risk of hypermutation.
Has anyone with similar tumor characteristics chosen PCV over Temodar, if so what influenced your decision and how did it work out?
Hi,
I'm updating this discussion for anyone in the future who might be interested.
I've had the 3 opinions below.
UCSF:
They didn't give me any new information about hypermutation. Results of trials will be released in 3 or 4 years.
They confirmed my diagnosis and recommended SOC with 6 cycles. They said there was no information more cycles or a different dose schedule provided any benefit. I wasn't eligible for the Everolimus or the other 2 trials for low-grade tumors.
UCLA:
This is where the recurrence was initially diagnosed.
They recommended SOC. With the following expected response rates for patients similar to me
50% without radiation.
75% response rate with radiation.
I didn't get a definition of response, but I think it means either shrinkage or cessation of growth.
Said there's no data to indicate the ketogenic diet helps, but it won't hurt
UCSD:
Confirmed diagnosis.
Said preliminary study results indicate Temodar works about as well as PCV.
10 or 15 % experience hypermutation.
12 cycles recommended.
Most tumors cease growing and about 15% of patients see a reduction in tumor size.
MGMT is less important in low-grade tumors than high-grade tumors.
IDH1 mutated tumors are more chemosensitive.
Treatment: I decided to go with proton radiation + Temodar. I can always change my mind after radiation if new information indicates switching chemo is best. I'm also taking various supplements and started the ketogenic diet.
I had my first proton and Temodar yesterday and woke up surprised by how much it affected me. Symptoms included: fatigue, headache, and I threw up after only 3 sips of coffee. An extra Ondanestron cleared up the nausea after about 1/2 hour.
Hi Larry,
ReplyDeleteThere has been some discussions related to your situation, but I am sure more specific help can be provided.
But a couple quick suggestions:
1) You can both search using google (ie 'btcocktails ccnu hypermutation') and also Stephen has subject links if you either search the page (ctrl F) or even just scroll down and look for things like 'PCV'.
2) Delete and repost your message , WITH a title. Without a title there is no obvious link for people to click on.
3) Add case details -- ie previous surgeries, whether or not you had genetics tested before, whether you have had a recent biopsy and if so what the current report shows, etc.
4) A lot on info here relates to non-prescription items, but also many prescription only things too. It is possible but challenging to 'back door' some drugs, but is far better to get a doc who will prescribe beyond 'standard of care'. Sometimes the neuro-onc's are more rigid than a family doctor.
5) In terms of some specific ideas, you could look into aggressive keto diet during radiation, any ways to improve surgery vs chemo since with G2 unmeth chemo is not as effective, or ways to improve chemo since you are mgmt unmeth-- metronomic dosing of TMZ, PCV instead of TMZ (though most suggest the 'V' doesn't get into the brain so should be dropped), other MGMT related chemo's like 6-TG, and supplements that help with chemo.
bryan
Also take a look at RTOG 9402. Its generally a better study because of more complete genetic analysis used to break out IDH1,MGMT meth and 1p19q status. RTOG 0424 seems a bit weak between it having used comparisons to historical controls, having about 30% non segregated oligo patients(which would mostly be mgmt meth and 1p19q codel and respond better to chemo) and the fact that they only have data shown for about 4 years of follow up.
DeleteA title was added as per Stephen's instructions.
DeleteCase history details:
2005 surgery followed by radiation. Classified as the now non-existent protoplasmic astrocytoma.
2011 gross total resection upon recurrence.
2016 gross total resection upon recurrence.
genetic testing IDH1 mutated
MGMT unmethylated
1p/19q not deleted.
P53 mutated.
2017 Recurrence: the recurrence is in the resection cavity and not easily identifiable. radiology didn't see a recurrence, an FDopa PET scan was negative, but the NO, at UCLA says, changes on the MRI indicate a slow growing recurrence. Surgery isn't possible because the tumor is wrapped around a blood vessel.
BTW, except for Maitake and Coriolus I stopped all supplements in 2016 after reading it IDH1 tumors might have a better prognosis because they're less capable of neutralizing free radicals.
I plan on replying tomorrow Larry.
ReplyDeleteps you can add a title to your post without deleting it, by clicking on "edit post" which is the pencil symbol below the post.
Unfortunately most of the trials that have reported for lower grade gliomas are out of date before the results can even be published, because they were planned and initiated before the importance of IDH1 was known. As Bryan touched on, RTOG 0424 has no information on IDH1 or other molecular markers, so is of little value.
ReplyDeleteRTOG 9802 at least gives results for IDH1 mutant versus non-mutant, but doesn't go deeper into the genetic subdivisions (for example IDH1mut, non-codeleted; IDH1mut, codeleted).
As for your specific question (TMZ versus PCV) the most informative data yet published was based on the NOA-04 study for anaplastic gliomas. I posted on these results here:
http://btcocktails.blogspot.co.uk/2016/10/long-term-analysis-of-noa-04-for.html
As you can see in the graphs, progression-free survival with PCV was superior to TMZ for the molecular oligos (IDH1 mut, 1p/19q codeleted), but this superiority was not seen in the molecular astrocytomas (IDH1 mut, 1p/19q intact). Keep in mind, continued follow up would likely change the shape of the Kaplan-Meier curves at the farthest times points, but the overall finding would likely remain, that TMZ and PCV is roughly equivalent for this molecular subclass.
The RTOG 9802 charts showing outcomes for IDH1 mut versus wild type don't necessasarily apply to you, because the majority of patients in that trial had oligos or oligo components. I don't doubt that PCV has survival benefit in your tumor type, but a direct randomized comparison of PCV and TMZ, stratified by molecular characteristics (IDH1, 1p/19q) has not been done. The best info we have in answering this question the updated analysis of the NOA-04 trial (which was a trial for grade 3 gliomas, not grade 2).
I'm one of those that feel the vincristine component of PCV likely provides little additional benefit but accounts for many of the adverse side-effects of PCV.
MGMT status most likely does affect the outcome of PCV, given that both CCNU and procarbazine are alkylating agents that can alkylate DNA at the O6 position of guanine, lesions that are repaired by the MGMT enzyme.
https://www.ncbi.nlm.nih.gov/pubmed/7519972
You mentioned having had more than one surgery, so the question is when was the last time you had surgery that was tested for MGMT status? Also, MGMT status can be variable within a tumor, and methylated/unmethylated is not a binary 0/1 proposition, but there are degrees of methylation. So your "unmethylated" tumor could simply mean there was a relatively weak amount of MGMT promoter methylation in the part of the tumor they happened to test, and you could still get benefit from the O6 alkyating chemos (TMZ, CCNU, etc).
Hypermutation is certainly a concern. Given the different mechanisms of action of TMZ versus CCNU, it does seem likely hypermutation is more of a problem with TMZ. I think a big factor here is how much residual tumor exists at the time of chemo. Will you be going for another surgery to resect this recurrence? It seems reasonable that applying TMZ when there is a large amount of residual tumor would carry a larger risk for hypermutation than applying it when there is little to no residual tumor visible on MRI (ie. after a complete resection). Since the mismatch repair gene mutations that are typically the cause of hypermutation are random events, it's a matter of statistical probability whether one of the cells would aquire hypermutation status when there are millions or billions of cells in a sizeable recurrent tumor versus only a scattering of cells post-resection.
Of course another major factor is the better tolerability of TMZ. I personally would feel better about extended TMZ cycles if it were following a complete resection (for the reason explained above). With sizeable residual tumor I would lean more towards PC (procarbazine+CCNU) with the possibility of switching to TMZ depending on the tolerabilty of PC.
Thanks for the information. The doctor mentioned I could always switch to TMZ while on the PCV. I think this is this may be the best route. I can't easily measure the size of the recurrence since it lines the resection cavity and in past surgeries my brain expanded to refill the resection cavity. I can only say the radio-oncologist described it as small and was optimistic; thought I've found radiology to generally be more optimistic than NO.
DeleteHi Larry,
ReplyDeleteI have a large grade 2 oligo tumor thats in a spot that is tough to resect, so in my case chemo is playing a major role. Unfortunately even though I have/had good genetic markers (idh1 mut, mgmt meth, 1p19q codel), like many other low grade patients chemo mainly just slows down the tumor and doesn't actually kill that many cells. There are a couple main reasons: With low grade the division rates are relatively low (in the range of weeks), and so the cancer has time to repair the damage from the chemo. So each cycle you only end up killing a small subset of cells. Also the blood brain barrier is mainly intact , there is minimal vascular growth, and drug efflux pumps are fully functional, all of which results in less chemo for less time in the cell.
The result is that for a long time chemo was considered only marginally effective for low grade. With the more recent genetic grading, patient stratification is now showing in some groups that it is quite effective, but for mgmt unmeth it is much less clear how effective it is. As discussed PCV or just PC may have better efficacy than TMZ. Also metronic dosing of TMZ has some studies showing promise where it essentially outruns the production of MGMT.
Treatment sequence may also matter for minimizing hypermutation. Starting at full std dosing of PC or PCV may result in having to switch to TMZ due to blood counts crashing. But then you will be finishing your last rounds with TMZ which is the more mutagenic route. So you could either do a few rounds of TMZ then PC or alternate. A step further would be to look into BBB disruption (sildenafil) or drug efflux pump suppression (verapamil or less effective but safer omeprazole) in order to enhance penetration/residence of chemo.
Overall though alkylating chemo won't be as effective with MGMT unmeth. With 12 yrs since RT, you may be a decent candidate for re-radiating. Plus RT opens the BBB some and so maybe modest RT followed by chemo would do the most.
BUT seems like its not even that clear yet if you have a recurrence, let alone enough of one that it needs aggressive treatment. Have you had a second opinion?
Last thought would be to look into clinical trials. The AG-881 trial seems like it would be worth investigating as well as Everolimus trial. In fact since Everolimus is FDA approved for other indications it is actually possible that your NO could prescribe that off-label.
Bryan
Hi Bryan,
DeleteHave you shared (if not would you mind sharing) your treatment strategy and experience so far? My NO will not really discuss chemo/radiation options with me as of yet. He says I'm getting ahead of myself thinking about those things. The tumor is highly resectable and they expect a gross total resection. So he says it'll be years before (if) I need to think about chemo and by then more treatment options will be available. Of course, not thinking about it yet is much easier said than done.
Maria
Thanks Bryan,
DeleteMy doctor says PET scans can produce false negatives but the MRI evidence is clear. My surgeon also evaluated the my MRI. I have a radiotherapy doctor working on my proton treatment plan right now. Radiation will begin in 3 weeks in the meantime I'm working on getting a second opinion from UCSF.
My doctor said it wouldn't be worth it for me to get into the AG881 trial. I've never seen any published results on Everolimus. Do you have a link to any results?
Thanks,
Larry
Agreed, PET with LGG is pretty lousy at finding tumor regions. My comment on 2nd opinion was because it sounded like your radiologist and NO disagreed.
DeleteRT retreat sounds like a good plan. CT is certainly a tougher decision in LGG cases, especially with MGMT unmeth.
Its worth checking into the AG881 trial, but RT or CT would exclude you. If RT is a maybe then its still worth checking into the trial, or even just getting reviewed in case it continues to progress after this treatment round. But if RT is a solid yes, then it certainly seems like a better option than AG881 trial. One ‘trick’ is that if your insurance doesn’t cover 2nd opinions then you can often get a free, full review done by doing the initial inquiry into entering a clinical trial. Also important to consider is that while the AG120 and AG881 trials are showing some efficacy in reducing tumor metabolism and thus showing MRI improvements it is not necessarily indicating death of cancer cells (2-HG causes reactive gliosis in the nearby non-cancerous cells which is a large part of the MRI response), and it is not yet shown to actually extend survival and the reduced IDH1 ‘mutabolism’ could actually reduce effectiveness of RT or chemo for some period after stopping the drug.
I don't know of published results on the everolimus trials by UCSF but they expanded their trial of it based on positive initial results. Jennifer Clarke is the PI for it, and so if you are already headed towards a second opinion from UCSF then you can hopefully coordinate with her too. Plus am guessing you are going to get a 2nd opinion on surgery from them too since they are basically top of the field. Note there is indications that combining Everolimus and chemo is more effective than either alone. You could though look up trial results on Everolimus for other cancers, including subependymal giant cell astrocytoma, which while it is an astrocytoma, I think it is a pretty different entity than the usual IDH1mut astrocytoma.
Bryan
I have slides of the everolimus trial from at presentation at the SNO 2016 conference. I'll post the slides (or photos I took of the slides) in the Brain Tumor Library soon (tomorrow).
DeleteHi Stephen,
DeleteCan you post the slides, I don't see them in the library?
Thanks,
Larry
Thanks for reminding me. I just uploaded them. They're in the "Conference Abstracts" folder -> 2016 SNO slides subfolder. I'm going to create a doc to add some notes for the slides because some of them are a little blurry.
DeleteI just uploaded all my photos of slides from the SNO 2016 conference to the Brain Tumor Library (Conference Abstracts folder)
DeleteHi Maria,
ReplyDeleteIn your case, you might ask your surgeon about radical (or super) gross total resection, which is a gross total resection plus a margin of seemingly healthy tissue which the tumor may have invaded. My resection was in fact a super gross total resection but it still recurred right away; my doctor thought it would be years before another recurrence at which point better treatment options would be available. Current treatment options are all unsatisfactory. In the 12 years I've had this disease there hasn't been any improvement in the survival of those diagnosed with low grade brain tumors.
You're not getting ahead of yourself by researching treatment options. You don't want to be caught completely off guard if the doctor delivers bad news.
Thank you, Larry. I have asked my two NO's about supratotal resection and they both said it didn't produce worthwhile results. I didn't ask the neurosurgeon but I will next time. I think it is close to my Broca's region so, at least in that direction, they won't be able to go far. I wonder about future resections if I do the supratotal resection, won't there be less area for them to resect then?
DeleteThere is a lack of research on low grade glioma and, therefore, a lack of new treatment options. This seems like a great loss to me as it seems like LGG maybe much easier to cure than HGG. My understanding is that trials for LGG would take way too long and therefore cost way too much to make it really worthwhile to companies. Sucks for us! However, since most LGG are IDH mutated we may benefit from all of the research currently happening around that mutation. This is what my doctors are referring to.
Wishing you luck and moments of peace as you navigate this crazy disease, Larry.
(PS. I just spoke with a third person who has no evidence of disease following intense FECO therapy. Have you considered that? Kelly Hauf will talk to you directly about her experience too.)
PS - why would AG881 be a waste of time?
DeleteMaybe he meant the results so far weren't good.
DeleteI don't think there is much in the way of results yet for AG-881 (too soon), but it is sort of a newer version of AG-120 and is supposed to have better brain penetration (881 also inhibits IDH2, which is useful in a small set of glioma patients). Anyway, AG-120 trials actually looked pretty decent, but not amazing. Agios seems to be more focused on it for blood disorders (mainly AML) which is a much bigger market than LGG, but have seen some results shown for just glioma:
Deletehttp://www.onclive.com/conference-coverage/sno-2016/ag120-shows-early-efficacy-in-idh1mutant-glioma
One of the claimed benefits is that 2-hg reduction reduces further mutation (less methylation), vs chemo which will drive further mutation. So in theory even if its not a cure it is a clean delay in growth, vs chemo which delays/shrinks but generally drives to a higher grade cancer.
Maria from your checking into Kelly Hauf and others related to THC/CBD treatments, did you get any sense of any of it being suspect? I think I remember you had asked her for MRI images and not sure if you got a response. Or if she will disclose who her NO was.
DeleteThere are definitely studies showing potential for THC/CBD, but when I check out Kelly Hauf or a few others I end up seeing connections back to places that sell marijuana products. So the skeptic in me struggles with the stories of cures or complete remission.
But I would definitely like to learn more about it and would consider trying it if I got more comfortable with the veracity of the claims.
Maria
DeleteHere's a link to an article on Supra total resection. It basically says if the tumor is IDH1 mutated resection to the point of some temporary deficits might be worth it.
https://www.sciencedaily.com/releases/2014/02/140203131520
This link doesn't work for me Larry. What's the title of the article?
DeleteI pasted that link from my phone. Looks like it doesn't copy/paste correctly. Here's the correct link.
Deletehttps://www.sciencedaily.com/releases/2014/02/140203131520.htm
From a quick read of the study, unless I am misinterpreting it, it looks like they actually defined GTR as being full removal of -enhancing- tumor and then complete resection as being less than 5cc remaining of non-enhancing tumor regions.
DeleteSo this study is really looking at impacts of removing nearly all MRI visible tumor and not the same as supra total or the more extreme maximal removal of non-eloquent regions.
For frontal lobe LGG it is I think fairly common on smaller tumors to resect beyond T2 MRI boundaries, especially at institutions that do awake surgery and have newer mapping tools like MEG and DTI (and probably also aided with the advent of 5-ALA imaging - though LGG would need surgical microscope 5-ALA imaging which is limited to a few trials).
So I would tentatively say that this study may not be directly applicable to Maria, but other studies have also shown that OS improves significantly once you start approaching GTR and continues to improve with some added surgical margin.
One odd counter to this study is that I am pretty sure I've seen more than one reference indicating that IDHwt is more prone to recurring at sights farther away from the initial resection cavity and that IDHmt typically regrows at the resection wall.
Hi Stephen and others.
ReplyDeleteNext month, my partner is due to go in for her 3rd surgery for a grade 2 Astrocytoma (previous testing 2 years ago showed low mut burden - idh1 mutated, p53 mutated being the only ones).
We are looking at trial options targeting the IDH1 mutation (for which there do not seem to be many) and the AG-881 looks interesting. I was wondering, in your opinions, how AG-811 would compare with the IDH1 pan-inhibitor produced by Bayer (BAY 1436032) and in trial - https://clinicaltrials.gov/ct2/show/NCT02746081 and which one you would go for?
I have not seen any information on this blog about this drug/trial.
Thanks,
Ryan
They are both small molecule inhibitors of mutant IDH1/2. There's not really enough information available to make a comparison. The superiority of one over the other would have much to do with their human pharmacokinetic and pharmacodynamic profiles, which haven't been published.
DeleteThere is one in vitro/in vivo study on the Bayer drug, which gives some preliminary information.
http://link.springer.com.ololo.sci-hub.cc/article/10.1007%2Fs00401-017-1677-y
I had been trying to get linked in with the Agios trial for a few months now and finally got a consult today! I'm technically not currently eligible because I'm not progressing, but was told that in the spring of 2018 Agios is expanding the trial to add tissue studies and will include patients with stable disease. Basically if a biopsy or resection is planned they want to pre-test, treat for a bit, resect and study.
DeleteThe added bonus was that I got some general 'inside info'. Not much on the Bayer drug but turns out Novartis is pulling funding from the IDH305 trials for financial reasons and not because of lack of efficacy (there are 3 trials still listed online that I guess have actually been killed).
On the positive side though it sounds like Ag120 and 881 are showing good prelim results. Some patients that had recurred after SOC and had progressing disease were treated with Ag-120 and it stopped the growth. 2 early patients are now at 3 years with stable disease.
The main caveat was that while the evidence is good that the drug 'works' and blocks IDH1mut, there is not yet solid evidence showing that this changes OS or that it is actually killing any of the cells. Just that it is slowing the cells down.
In terms of Agios vs Bayer, the one major benefit is that Agios has worked with UnivTex SW in particular plus UCSF and a few other universities to help develop MRspectroscopy tests to measure 2-HG and other IDHmut related metabolites. Bayer lists that they will be trying to measure changes in 2-HG in serum and urine. So the Agios trials have the added benefit of being able to directly monitor tumor activity and changes vs simply doing MRI's. UTSw also has separate clinical trials just for the MRspectroscopy studies that would be useful just for tumor monitoring in LGG patients. I'll be getting a scan done there in a few weeks and can hopefully report back some more info!
Thank you Stephen and Bryan for your very helpful replies and apologies for my delayed response.
DeleteStephen, thank you for that article on the Bayer product – it was very informative and explained the mechanisms well – although it was quite heavy reading The results in the article look impressive.
Bryan, that is excellent news regarding your receiving a consultation for the Agios trial! It is really good to know that there are some good early results.. even if it is not actively killing the tumour cells, a stable or drastically slowed down tumour is still fantastic and could put things in a holding pattern until something better comes along. Also, along with the positive early results, the points that you make about Agios having access to MRspectroscopy to measure the 2-HG levels makes me lean more towards that trial.
Regarding applying for trial, do you know if it is possible for people from outside of the US to participate in trials there? We are based in Australia. Also, do you know how long a patient would remain in the trial for? E.g. is it a 1 month course of medication or would a patient need to be there for a lot longer?
Thanks again,
Ryan.
Hi Ryan,
DeleteI think usually it is a combination of the PI that heads the trial and the drug company that decides on entry requirements. I've seen a few trials that list residency requirements but my guess is that may relate to some linkage from a funding source that required that. I also suspect that in general some 'cherry picking' goes on with trials where patients that are of particular interest for one reason or another will get fast tracked into the trial and maybe even have the rules bent a bit. So in general it is worth just asking the lead contact. For AG-881 the contact is listed as agios : 844-633-2332 medinfo@agios.com for trial NCT02481154.
AG-881 is a phase 1, dose escalation study, 6 months long with option to continue on drug. My guess is it requires testing at least every other week and probably a lot more during dose escalation. During continuation it would be likely possible to take the medication at home and test at home with maybe 2 visits a year. But I am really just speculating.
Note that for me I don't actually qualify for the Ag-881 trial, but am consulting with one of the investigators and there is potentially an Ag-120 expansion phase that is planned for next year.
Hi Bryan,
DeleteThanks for shedding further light on the entry requirements and for providing the contact details for Agios. I emailed them yesterday and have heard back - unfortunately they are not currently enrolling further patients, "as we continue to review the dose finding and safety data". They also mention that they currently do not have a compassionate use mechanism, as they are in the very early stages of development.
I have also emailed Bayer to see about getting into that trial, but have yet to hear back. I will chase them up again in a day or so.
Sorry I had misread your previous comments and thought that you had been accepted to the Ag-881 trial. That is still good news that you have your foot in the door for the potential ag-120 expansion. Would you not qualify for the Bayer trial?
Hey Ryan,
DeleteI potentially do qualify for the Bayer trial, but am in their 'other' category because I'm currently stable grade2 oligo and I haven't yet done RT or surgery. So I'm probably not their ideal patient.
So at this point I am more focused on the MRspec scanning studies to look at 2-HG to a)understand my tumor more, b) help decide if a risky surgery is worth it, and c) I then have Agios as my first choice since there is more data there and more info about it being minimally toxic.
I'm still keeping my eye on the Bayer trial, but wasn't yet ready to put much effort into pursuing it or going for a consult. It is Bayer's first IDH1 inhibitor drug, so they are not nearly as far along as Agios. Doesn't mean it is more or less effective, just a much bigger unknown.
Either way I am definitely interested to hear what you find out from Bayer and will probably contact them myself in a month or so to see if I would even be eligible.
Hello guys,
ReplyDeletejust thinking out loud here and nobody mentioned it...how about trials with PARP inhibitors? If I remember correctly it should work on unmethylated tumors also, but shouldn't be used together/after IDH1 inhibitors.
Yes these are two different strategies that probably won't work well together. Inhibiting 2-HG with the mutant IDH inhibitors would likely make the cells less vulnerable to PARP inhibition.
DeleteThere is a new trial of BGB-290 (brain penetrant, PARP-trapping PARP inhibitor), open in the USA, unfortunately not recruiting lower grade gliomas however :(
https://clinicaltrials.gov/ct2/show/NCT03150862
The other trials of this drug are in Australia. There are trials with olaparib for glioma, but this drug isn't optimal for blood-brain barrier penetration.
https://clinicaltrials.gov/ct2/show/NCT01390571
And yes, adding certain PARP inhibitors to TMZ could sensitize tumors to TMZ in a way not dependent on MGMT status, so could be a useful strategy for MGMT unmethylated tumors. Myelosuppressive side-effects of that combination would likely be the limiting factor.
DeleteThen there's this trial, although not yet open:
Deletehttps://clinicaltrials.gov/ct2/show/NCT03212274
"Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations"