Grade II Astrocytoma (IDH1 Mutant) treatment plan

Hi Stephen and all,

Thank you for allowing me to create this thread. I am a 31 years old male from Australia.

I recently got diagnosed with a Grade II Astrocytoma with histopathology report as follow;

Clinical Notes: Incidentally found left Insular region glioma

Mitoses: 0/HPF

Immunohistochemical Stains: Block 1

Ki67: 1%

How estimated: Visually and IDH1, Ki67 dual stain

IDH1 R132H: Positive

ATRX:  Lost

P53:  10%(moderate/strong staining)

EGFR:  Negative

Other Positive:  GFAP, PHH3 highlights 2 mitotic figures, however, it remains possible that these cells are not tumor cells hence it shouldn't be used in grading

MGMT promoter Methylation: If clinically indicated. Block 1 Tumor 60%. Patient Agreement required.

I had Gross Total Resection and according to my neurosurgeon, there is no residual tumor left. Size upon diagnosis was around (14mm x 13mm x 10mm).

I had a few questions regarding Histopathology, wondering if you all can help, please?

1) Should I push for a more thorough genetic study on this tumor? Is it worth it at this point in time to get PTEN, MGMT (as it looks like they haven't performed this test) & Ip/19q codeletions? I know it is unlikely for it to be 1p/19q codeleted since it has p53 staining & ATRX loss.

  

2) Why does it mention mitotic figure: 0/10HPF, then goes on to mention PHH3 highlights 2 mitotic figures but 'possibly' nontumor cells? How do they know that they were nontumor cells?

3) Does Ki67 index & P53 values mean much?

My neurosurgeon has advised holding off any chemo/radiation for the time being and adopt a 'watch and wait' approach. I am happy to hold off chemo/radiation too but I do want to start taking supplements and other medication to possibly delay the recurrence. I plan on taking the following supplements and medication (Please tell if I am mental for doing it).

Supplements:

Curcumin (Longvida)

Vit D (4000IU)

Fish Oil

Vit C (4g)

Magnesium

Resveratrol

Green Tea Extract

Selenium

Milk Thistle

Sulforaphane (From broccoli sprouts)

ZINC: Should I add this? I read on this forum somewhere that it is not really beneficial for people who have enough Zinc levels in their blood. 

Medication:

Aspirin daily 100mg daily (COX 2 Inhibitor) or should I consider Celebrex?

Melatonin (10g - 15g daily)

Metformin 1000mg daily (Keeping the blood sugar level down)

I am thinking of using;

Metformin 1000mg daily (Keeping the blood sugar level down)

Betablocker (Propanolol)

Low dose Mebendazole (Cycle off every after a month use)

Angiogenesis Receptor blocker

DCA

Clomipramine

Thank you for pointing out Isosidenib and Vorasidenib Steph!

- I am really worried about my glioma acquiring hypermutation, is it possible that Agios inhibitors can turn IDH1 into Wildtype by how they operate? 

- I know no one knows for sure, but is it normal to adopt watch and wait approach for Grade II astrocytoma? 

- Are there any clinical trials I should consider? I can't seem to find any trials on LGGs at the moment.

Thank you so much for taking out the time to read this.

Regards

Ruki

Results of Ivosidenib (inhibitor of mutant IDH1) for nonenhancing IDH1 mutant gliomas

Just published in the Journal of Clinical Oncology

Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma
https://sci-hub.tw/10.1200/JCO.19.03327

• out of 35 patients with nonenhancing glioma, objective response rate was 2.9% with one partial response
• of these same patients, 30/35 (85.7%) had stabilization of their disease.
• for these same 35 patients, median progression-free survival was 13.6 months.
• the drug was well-tolerated with no dose-limiting toxicities reported.

As seen here, many of the patients with non-enhancing glioma have had disease stabilization for three years or more.  Not bad for a drug that is so well tolerated and with no dose-limited toxicities.

Oligo Treatment

Hello everyone,

In a couple weeks I'll be beginning proton radiation therapy. I have a basic cocktail and diet strategy for the 6 week treatment and I wanted to run it by this blog community while also asking a few questions.

My story so far:

Focal seizure in Oct 2018.

4.5cm mass, frontal/parietal, no contrast enhancement, everything else typical for an oligo.

Surgery late Dec. GTR, no visible tumor remains.

Pathology: Grade III oligo, with 10/10 HPF mitosis, dense cellularity, moderate atypia, no vascular proliferation, no necro.

TMB 6.8
IDH1 mut
TERT mut
CIC mut
1p19q codel
P53 retained
ATRX retained
MGMT methylated

Current plan is proton+TMZ then up to 12 cycles of TMZ.

Did 1 cycle of TMZ in between surgery and radiation start.

Cocktail

Keppra, 1g x 2
Longvida, 1.6g x 2
GTE 1g (450mg egcg) x 2
PSK 1.5g x 2
Maitake, 50mg x 2
CBD  (don't have it yet, still considering dosage)
Omega-3 3g (total EPA+DHA)
Pterstilbene 150mg x2
Resveratrol 250mg x2
D3 5000 IU x2
Berberine, 600mg x3
Silymarin, 450mg x3
Probiotics via yogurt or pills (occasional, can reduce gut diversity?)
Selenium 200mcg
Melatonin, 10-20mg
Magnesium, ~200-300mg

Still trying to get
Celebrex
Chloroquine

Ketogenic diet rough plan
72h fast 3 days prior
Protein under 65g, carbs under 20g and GKI as close to 1 as possible.
1000cal per day, possible 20:4 intermittent fasts 3 days per week, alternating

Lots of walking and probably very light but consistent exercise throughout.

Questions

1) Will any of these supplements (antioxidants specifically) potentially interfere with oxidative stress on the tumor cells?

2)The majority of this cocktail and diet plan is ripped from GBM research and GBM/AA3 posts on here. Are there IDHmt/oligo specific supplements/drugs etc that I may be missing?

3) I've heard GTE can be toxic. I have Nusapure GTE and Swanson's Teavigo caps as well. What are people on here buying for EGCG?

4) Is chloroquine as promising to an oligo as it is to a GBM?

5) Is cal restriction necessary if I were regularly fasting, and vice versa? This is a bit of a grey area that I don't quite have figured out yet.

Also, as of now, I intend to save PC chemo for future recurrences. TMZ is a much less damaging chemo. My main concern with TMZ, however, is hypermutation. I'm not sure how to possibly mitigate that.

Thanks in advance.

Need advice....IDH1+, (maybe) unmethylated GBM..MANY conflicting opinions

I have been reading this message board for years and been impressed with the knowledge of many of the participants.  I was hoping I would never need to post...

As posted by Stephen previously,  my now 25 y/o son was diagnosed in 2011 with OA Grade 2 (now felt to be AA3) and treated with surgery and then surgery to get "leftover" in 2012.  He was found to be IDH1+. Because of the infiltrative nature of tumor on path, he then entered into a clinical trial on the cognitive effects of proton therapy, which he completed 11/12.  No chemo was given.  (No apparent cognitive effects in his case either...did very well in college and is/was in med. school.)  On routine MRI 12/17, he was found to have a 6-7 mm area of enhancement in the middle of his resection cavity (tumor never enhanced before).  Advice was to watch for 2-3 months, but we moved up the surgery.  Note that his tumor grew about 1 mm in each dimension in 6 weeks.  He had a very generous GTR 2/15 and has had a pretty easy recovery--no apparent deficits.
Unfortunately, the path showed GBM IDH1+ unmethylated.  They also looked at his tumor from 2012 and it was also unmethylated.    Foundation One is not back yet.  We have been looking at different options and consulted physicians from several different areas.  Many have been very generous with their time and there is no consensus.  Opinions below...

(he didn't qualify for TOCA due to small tumor size and no prev. treatment)
--Local neuro-onc:  olaparib + Temodar + more proton.  Wasn't really certain of dosing.  (PARADIGM2 could provide that)
--Tumor board at Mass. General....some said NO treatment, some said Temodar.  Told to wait on radiation as scans might be too difficult to interpret
--Physician who is expert on IDH1....feels that IDH1+ GBM shouldn't be considered as really a GBM.  Rec. no radiation and PC(noV) since it has been shown to work.
--Physician at another institution who is involved with IDH1 studies...PCV.  He said to delay radiation because of  "better things coming" and it will probably take radiation + chemo to really eradicate tumor
--Second Opinion from well-regarded cancer institute....PCV has not been shown to work.  Use Temodar and radiation, though consider immunotherapy.
--UCLA...IDH1+ more indolent, possibly PARP + Temodar...perhaps immunotherapy depending on mutation burden.  Not good luck with olaparib, though don't know about mutant status of those patients. Told that IDH1+ SHOULD  be methylated and that test not very accurate.

So....he just missed a slot on the BGB-290(pamiparib) + Temodar (but without radiation) trial...expansion cohort likely opening in 4 weeks.   Evidently fairly well tolerated.  He strongly wants to return to school in August, which seems somewhat unrealistic, but not impossible.  Waiting 4 weeks for treatment doesn't seem like a great idea, unless one accepts the idea that this is a more indolent tumor.

Would really appreciate advice in this matter!  Thanks,   Marcia
(And thank you so much, Stephen!)

SNO summary, episode 2: AG-120 phase 1 trial for IDH1-mutant glioma

AG-120, a first-in-class mutant IDH1 inhibitor in patients with recurrent or progressive IDH1 mutant glioma: updated results from the phase 1 non-enhancing glioma population.

Summary by SW who attended the presentation and took photos of the slides.

Ingo Mellinghoff of Memorial Sloan Kettering Cancer Center presented results of a phase 1 trial of AG-120 (ivosidenib), a mutant IDH1 inhibitor, for IDH1-mutant cancers.  The presentation specifically focused on a subset of patients in the phase 1 trial: those with non-enhancing (no contrast enhancement on MRI images) IDH1-mutant gliomas.  This analysis included 11 patients in the dose escalation phase, and an additional 24 patients from the dose expansion phase, a total of 35 patients.  The primary study objective was to evaluate safety and tolerability of AG-120, and determine the maximum-tolerated dose and/or the recommended phase 2 dose.

28 out of 35 patients (80%) of patients in this analysis were treated with 500 mg of AG-120 daily.  The majority (24/35, or 69%) of patients in this non-enhancing glioma cohort were WHO grade 2 gliomas.  An additional 23% were WHO grade 3.  Only one grade IV glioma (3%) was included.

Most patients in this analysis had been previously treated with either radiation (57%) or chemotherapy (69%) and the median number of prior systemic therapies was 2.

AG-120 was well tolerated, and the maximum tolerated dose was not reached. The majority of adverse events were low grade, and only 20% of patients experienced a grade 3 or higher adverse event. 

Pharmacodynamic analysis of tumor tissue in two patients revealed that AG-120 treatment strongly suppressed 2-hydroxyglutarate levels in the tumors.  2-hydroxyglutarate is the oncometabolite produced by the mutant IDH1 enzyme.

By far the most common response to AG-120 treatment in this cohort was stable disease, which was achieved in 83% of patients. Only two patients (5.7%) achieved a minor response, including one grade 2 and one grade 3 glioma. Only four out of the 35 patients (11%) had progressive disease with neither stabilization or response.  

More important is the duration of stable disease without progression.  Median duration of AG-120 treatment for all 35 patients is 16 months. For the grade 2 gliomas, representing nearly 70% of the population of this study, median progression-free survival has not yet been reached, and looks to be at least 19 months at the time of the analysis (data cutoff May 12 2017).

When volumetric growth rates pre- and post AG-120 treatment were calculated by imaging studies for the 24 patients in the dose expansion group, the mean percentage change in tumor volume per six months was found to be 24% prior to treatment, and 11% after AG-120 treatment.  In the 1p/19q intact (that is, the astrocytoma) subgroup of 15 patients, before and after AG-120 growth rates per six months were 38% and 14%.  This confirms that the primary effect of AG-120 in this group of non-enhancing (mostly) lower grade gliomas is to significantly slow tumor progression, which was deemed to be a disease stabilization in the majority of cases.

A different drug by Agios Pharmaceuticals, called AG-881, is a dual inhibitor of mutant IDH1 and IDH2, is more brain penetrant than AG-120, and is also being studied in clinical trials for IDH mutant gliomas.

IDH1-inhibitor drugs?

Hello all,

I've not fully understood how mIDH1-inhibitors work? I know they reduce 2-HG levels but does that lead to tumour regression, or is there some other mechanism simultaneously?

I've been looking into different mIDH1-inhibitor trials, but have doubts if they work as monotherapy?

Br,
Juha