Sirolimus (Rapamune, Rapamycin)

I have previously posted on the topic of sirolimus (aka rapamune, rapamycin), as it has been used effectively with some other autoimmune diseases.
Of special interest was this link: www.bloodjournal.org/content/127/1/17

Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial

The following is a fascinating article in the New York Times regarding a doctor who used himself as a guinea pig to treat a rare disease called Castleman's disease. The drug he used was sirolimus .
www.nytimes.com/2017/02/04/business/his-doctors-were-stumped-then-he-took-over.html?smid=fb-share&_r=0

Sirolimus and its rhyming cousins such as everolimus are immunosuppressants that inhibit antigen-driven T-cell proliferation.
I think we should keep our eyes open for any new information related to sirolimus and ITP.

"I think we should keep our eyes open for any new information related to sirolimus and ITP"
Quite agree Rob. A vey interesting read in "Blood"

Some more information on sirolimus:

The nomenclature is confusing. Sirolimus is in a class of immunosuppressants separate from others we are familiar with. Sirolimus belongs to a class of drugs called mammalian (or mechanistic) target of rapamycin (mTOR) inhibitors. This class includes temsirolimus (Torisel) (CCI-779), everolimus (Afinitor, Zortress) (RAD001), and ridaforolimus (deforolimus) (AP-23573). Not all drugs ending in -imus are in this category. The -imus suffix stands for immunosuppressive; for example, tacrolimus is not an mTOR inhibitor.

According to Wikipedia, "mTOR inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2.
[Sirolimus]" inhibits T-cell proliferation and proliferative responses induced by several cytokines, including interleukin 1 (IL-1), IL-2, IL-3, IL-4, IL-6, IGF, PDGF, and colony-stimulating factors (CSFs)."
The most established mTOR inhibitors are so-called rapalogs (rapamycin [sirolimus] and its analogs), which have shown tumor responses in clinical trials against various tumor types."...

Sirolimus is also in a class called proliferation signal inhibitors (PSIs). I believe that mTOR inhibitors and PSIs may be different names for the same thing.

Interesting story.

Looks like Sirolimus is most effective in those that respond strongly to steroids. If I read correctly, Dr. Fajgenbaum first remission was with steroids. I wonder if the mTOR pathway is the same pathway as steroids.

In the Blood Journal article, all the ITP only patients had a 'no response' to nearly all prior treatments - including steroids. Not surprising they had a no response to Sirolimus as well.

It would be interesting to see a study of Sirolimus with ITP patients with a strong, but not durable, steroid response. Probably volunteers for that study could be found right here.

Hal,

I completely overlooked the fact that the four ITP subjects had previously shown no response to all previous treatments, including corticosteroids, IVIG and Rituxan, as shown in Table 2. Nice catch, Hal! Yes, this could easily explain the poor responses to sirolimus. I fully agree that this result implies the need to study the effectiveness of sirolimus for ITP patients who ARE responsive to prednisone.

This article is based on an ongoing study, "Sirolimus for Autoimmune Disease of Blood Cells," at Children's Hospital of Philadelphia, of the use of sirolimus for a wide variety of autoimmune disorders, including ITP. The study is expected to be concluded this month, but I cannot find any more recent information on the study results. Sandi posted the clinical trial two years ago:
pdsa.org/discussion-group/13-general-discussion-for-parents/28646-sirolimus-or-cellcept.html#47837

I have gone back through old posts (searching on rapamycin, Rapamune, and Sirolimus) and found this:

Mark wrote: Over the years I had tried every possible medical strategy to get off of prednisone, with the exception of Nplate or romiplostim. The day before my numbers dropped I started taking the drug rapamycin as part of an experimental trial. Rapamycin is used to prevent transplant rejection. However, no one else in the trial (as far as I know) had seen their ITP get quickly worst like I did.
pdsa.org/discussion-group/7-treatment-general/28711-long-time-no-post-remission-after-splenectomy.html#48753

Mark previously had had a weak response to prednisone (20-30k)

Also, Mel1395 (Melissa) was going to try Sirolimus. However, she was on 80 mg prednisone and her counts never got above 15.
Melissa --- are you out there? If so, please check in!

Rob. That previous study about all ITP falling into either anti-platelet antibodies (two types) or TPO antibodies or TPO Receptor antibodies continues to haunt me. Perhaps taking the questions the study raises one at time will help in understanding it. For simplicity, let me call this study the 'four antibody groups' study. Perhaps the nomenclature GPA / GPB / TPO / TPOR antibody groups are suitably descriptive?

What do you think on this question. For those ITP'ers that have a strong response to steroids, which of the four groups do you suppose those folks fall into ?

I think the size of this population is about 20%. Based on population size alone, could that suggest the TPO group?

As I have theorized on a different thread, IVIG works for GPA, GPB, and TPO groups because TPO Receptors never goes to/through the spleen - which seems to be where IVIG acts. The population size of those three groups is about the same size as IVIG effectiveness - or 75%.

Disproof/Inconsistencies to earlier hypothesis: strong steroid responders are associated with TPO antibody mediated ITP. LOL, just wanted to clear this up.

After giving this idea additional thought, a different but more consistent explanation is possible.
(note: GPIIb/IIIa and GPIb/IX <-> GPA and GPB)

First of all, the argument that the population size is roughly 20% is NOT relevant. It isn't relevant because the GPIIb/IIIa population size, the GPIb/IX population size, and the TPO population size are all roughly the same size - 20 to 25%. So any of these three groups, or even TPO Receptor population, is possible when just population size is considered.

Second, the response time (the 'time constant') of strong steroid responders is NOT consistent with the response time one would expect with a TPO and TPO antibody (feedback) interaction. Strong steroid responders have fluctuating counts that can take several weeks to change when an allergen is inserted or removed from one's environment. On the other hand, TPO and TPO antibodies are freely circulating in the blood stream. They could cross paths / interact in a few hours or days.

Third, but it is consistent for the strong steroid responders to be represented by either GPIIb/IIIa antibodies or GPIb/IX antibodies. These antibodies come from mature B cells - which can take weeks to progress from the immature (affected by environment allergens) phase to the mature phases (producing antibodies).

When the above factors are considered, it is more likely that strong steroid responders are associated with either GPIIb/IIIa or GPIb/IX antibody mediated ITP. One of the two. It can't be both because the population size is just ~20%.

Another positive Sirolimus study:
journals.lww.com/jpho-online/Abstract/publishahead/Sirolimus_as_an_Effective_Agent_in_the_Treatment.98250.aspx
Sirolimus as an Effective Agent in the Treatment of Immune Thrombocytopenia (ITP) and Evans Syndrome (ES): A Single Institution's Experience.
Jasinski, Sylwia MD; Weinblatt, Mark E. MD; Glasser, Chana L. MD
Journal of Pediatric Hematology/Oncology: Post Author Corrections: March 6, 2017
Abstract
Background: Autoimmune cytopenias are characterized by immune-mediated destruction of hematopoietic cell lines with immune thrombocytopenia (ITP) affecting platelets and Evans syndrome (ES) affecting platelets and red blood cells. For patients with persistent disease, limited options for effective and well-tolerated therapies exist.

Objectives: Our aim is to describe our institution's experience with sirolimus as therapy for pediatric patients with persistent ITP and ES.

Design/Method: A retrospective analysis was performed in patients with persistent ITP and ES treated with sirolimus. Responses were categorized as complete response (CR), partial response, modest response, or no response.

Results: Of the 17 patients treated, 12 had ITP and 5 had ES. Seventy-three percent of ITP patients achieved a CR, 78% of them by 3 months. Only 2 patients did not achieve a durable response. Eighty percent of ES patients had a response, with 50% of them achieving CR and the other 50% an asymptomatic partial response. One patient with ES achieved modest response, but discontinued therapy due to an adverse effect. Of the patients that achieved CR, 90% remain off all therapy for a median of 2 years.

Conclusions: Our data suggest that sirolimus is a safe and effective steroid-sparing agent in the treatment of persistent ITP and ES.

And another one.
When I used 'rapamycin' instead of 'sirolimus' as a search term I found this study. In this study they directly compare Rapamycin with Cyclosporine A in ITP patient response. They also combine these drugs with low dose steroids. Apparently the compared drugs both act as immuno suppressants .

downloads.hindawi.com/journals/cdi/2013/548085.pdf
"Effects of Rapamycin Combined with Low Dose Prednisone in Patients with Chronic Immune Thrombocytopenia"

Spoiler. The authors suggest that Rapamycin should provide a more durable response because of the better Treg cell response it provides.