PRIMACY OF THE GUT
Ruxolitinib was mentioned at the AGM. This would be a competing product in the 12+ age group; it has less efficacy in GI GvHD.
I've been comparing studies in Rux for SR acute and chronic GvHD with the landmark study by Zeiser et al. I found two further studies in addition to the ones I referenced in a previous post:
https://hotcopper.com.au/threads/ann-msb-to-host-virtual-symposium-with-kol-on-gvhd.4812922/page-12?post_id=39344078
Vicent et al (2019) reported on a study in 22 children with SR acute and chronic GvHD. in 13 and 9 patients respectively. The dose for Rux has not been established for paediatrics.
Patients were scored for their best response at any time afterbeginning ruxolitinib, with follow-up censored at onset of any moreimmunosuppressive treatment. There were 54% infections caused by virus, 18% by bacteria and 13% by fungi. Bacterial infections were not serious in any case.
Acute GvHD was severe (grades 3 & 4 of gut and skin) and cohort was heavily pre-treated. CR,PR and non-response was achieved in four (31%), six (46%) and three(23%) patients, respectively.
For chronic GvHD 7/9 patients were classified as severe. CR, PR and non response was achieved in two (22%), 6.(67%) and 1 (11%) patient respectively. "Our CR rates are somewhat lower (22%).Since the lung is affected in most cases, with the severity that this supposes. Thus, it emphasizes that practically all of our patients with lung involvement have some degree of response."
"Thirteen of 22 patientswere alive at a median follow-up of 716 days (range, 131-4775) afterHSCT. Five of these 13 patients were free of GvHD symptoms, and2 patients were off all immune suppression."
There were no deaths for chronic gvhd; therefore 4/13 patients were still alive in the acute cohort at follow up after two years:
"If we analyze separately patients with acute and chronic GvHD,OS was 30 ± 15% and 100%, respectively"
Toama et al (2019) performed a retrospective chart review to identifypatients treated with Rux 2015-2016 at their center. Thirty six patients were included in the analysis. The overall response rate was 58% with 25% obtaining a CR.RUX was well tolerated. The majority of patients discontinueddue to treatment failure or clinical deterioration. Four patients discontinued for toxicity and six for issues in obtaining RUX.
My conclusion is that out of nine studies of Ruxolitinib in SR acute and chronic GvHD, only one reflects the results of the landmark study by Zeiser et al. This is the small study by Maldonado et al. They provide an impressive photo of a scope in severe GI GvHD; however all patients continue on the drug and being off immune suppression is the key to long term survival. I think RUX is an option but it's not the best option.
Chronic GvHD of the lung (like sclerodermatous GvHD of the skin) can be difficult and costly to treat; if cases become severe only some degree of improvement is possible, which is why prevention is better than cure.
PULMONARY COMPLICATIONS
Khurshid et al (2002) "Pulmonary complications, including infectious and non-infectious, occur in 40%–60% of all BMT recipients, which accounts for a considerable morbidity and mortality.The incidence of noninfectious pulmonary complications has been reported as high as 65% in allogeneic BMT recipients"
Authors say such complications are not common in acute GvHD but that there's a distinct association with chronic GvHD:
"Pulmonary complications of acute GVHD are minimal. Chronic GVHD occurs in 20%–45% of BMT recipients who survive six months after transplantation and pulmonary involvement is common in these patients."
Yoshihara et al (2007)"In particular, pulmonary complications occur in 25%-50% of allo-HSCT recipients, and can account for approximately 50% of transplant related deaths."
Saval et al (2018) "Despite these advancements, pulmonary complications still develop in 30%-60% of HSCT recipients and can account for approximately 50% of transplant-related mortality."
GUT LUNG AXIS
Gut barrier and the microbiome have long been studied in GvHD and IBD but interest in the past few years has expanded to RA, CHF and also lung diseases such as asthma and cystic fibrosis. In the Journal of Cystic Fibrosis,Hery-Arnaud et al (2019) say the "microbiome has emerged as a blockbuster theme in clinical microbiology." Rogers et al: "However, while the bulk of the illness and shortened life expectancy conferred by cystic fibrosis (CF) is attributable to respiratory disease, many of the earliest and most severe manifestations of CF afflict the gastrointestinal (GI) tract."
Nalle et al (2015) have reported on research in restoring the intestinal barrier in GvHD: "What is perhaps most striking about the loss of both barrier function and microbial diversity in GVHD is that, in addition to amplifying intestinal disease and reducing survival, these factors impact disease in other target organs, including the liver, skin, and lungs."
IL-22
There is a large number of research papers on IL-22 and its role in potentially restoring the epithelial barrier and homeostasis. Nalle et al (2015) published on this in IBD and GvHD:" IL-22 has been implicated in epithelial barrier homeostasis, and exogenous application of IL-22 is currently being evaluated as a means to treat several diseases, including IBD, GVHD, and psoriasis".
Obviously stem cells are a complex area but I would think MSCs do regulate this? I think they signal to ISCs but I haven't been able to find much on MSCs and IL-22 specifically. I found a study by Van Hoeven et al (2018) Authors say: "Thus, in addition to inhibiting the proliferation of alloreactive T cells, MSCs also promote the expansion and IL-22 production of ILC3s, which may contribute to healthy homeostasis and wound repair in the treatment of various inflammatory conditions in the intestine, including GvHD."
I spent a lot of time up wrong alleys thinking our cells might have anti microbial action, but if they have a positive effect on the microbiome then maybe they do indirectly? I don't know. It's very complex for a non scientist like me. You can change the microbiome quickly, as my daughter tells me, but the problem is making it stick. It's looking like restoring the epithelial barrier is the better way to go.
GI GVHD: RELEVANCE TO CROHN'S DISEASE
At the AGM the potential application for Remestemcel-L in Crohn's Disease was mentioned. I've been droning on here about the lack of information on this p3 candidate for a couple of years. When SI mentioned this in his speech I sat up and took notice. If results for CD are positive, it will have imo an immediate benefit in that it will further reinforce Remestemcel-L's good action on gut inflammation and support off label use in both children and adults who are refractory to the biologics.
The connection between GI-GvHD and CD is well known to doctors who work in acute medicine in these disciplines. Nalle et al say there are differences but more similarity than previously thought. Seattle CH is running a trial comparing the two, which gives an indication of some of the severe cases of IBD they must see. Our cells were successfully used at Seattle CH for a child called London who had grade 4 intestinal hemorrhaging her father said it would take a miracle to cure. Intestinal bleeding is not that common in CD but is a feature of ulcerative colitis. Doctors treating severe UC refractory to biologics would be very interested in this.
The market is bigger than CD because it would encompass ulcerative colitis. IBD is a fast growing market with increasing incidence in young children in north America where it often takes an more aggressive course. Severe UC can lead to sclerosing cholangitis, which can result in liver transplant. Severe disease can also result in short gut syndrome requiring intestinal transplant. I've been unable find on data on the incidence of short gut syndrome caused specifically by IBD.
Mucosal healing is the goal in IBD. Full mucosal healing leads to long-term remission. The current thinking is that when a patient with severe disease has failed multiple lines of therapy only 50% mucosal healing is possible. I've provided evidence of quality data that disputes this. The success of the low FODMAPs (by Monash University) for IBS and the Specific Carbohydrate Diet used by Suskind at Seattle CH for IBD is imo that it's difficult to eat high carb. This supports the work of Lutz MD. Lutz was no naturopath; he used drugs when necessary and treated 200 IBD patients with low carb nutrition who had failed conventional medicine. He published in five peer-reviewed journals and wrote to every Crohn's Colitis society in the world.
I'm not recommending doing such therapies alone, particularly as compliance can be poor; however, there is evidence of superior mucosal healing achieved by relatively gentle therapies (also FMT in SR-GvHD) when all else has failed .I don't think there's anything natural about putting donor stem cells into patients; I'm saying there's a natural process and stem cells,that are not drugs, are imo most likely to be able to achieve that, to boost this process, however it is they do it.
The primacy of the gut is not a new idea. It was known in the time of Hippocrates. It's observable if medicine talked more across disciplines. Re. GvHD, evidence is converging we should lead with the best option for healing the gut, regardless of the organ affected You don't let it get to the second location because it's a much tougher battle. I think this is just common sense. It also makes economic sense.
I question the rhetoric of the slow careful consideration by the FDA because of getting to grips with an entirely new therapy. Remestemcel-L has been in EAP and two very impressive KOLs are familiar with it; also we're in the unique position of having data from Temcell , as has been pointed out on this forum. SI affirmed safety at the AGM, and the company is beaming out its message that it's confident about manufacturing and supply. I firmly believe that Remestemcel-L is a multi organ rescuer with an excellent safety profile that should be available in every hospital in the world.
All IMO GLTAH
(20min delay)
