Ann: MSB to Host Virtual Symposium with KOL on GvHD, page-12

Imo this comment from Dr Prockop was the most important thing in the symposium:

"While there is the potential that a graft versus tumour effect could help maintain remission in the setting of malignant disorders, in non malignant disorders there's absolutely no advantage for even mild GvHD."

My own inference from the three qualifiers is in keeping with my prior view based on my research, that even for malignant disorders the GvHD advantage is overstated (The Fred Hutchinson article (2/4/18) on GvHD that I posted on another thread doesn't specify malignant or non.)

The focus recently seems to be on GvHD prevention.

Our cells have shown benefit in endothelial dysfunction. Endothelial dysfunction is also implicated in rheumatic autoimmune disorders such as SLE and also in IBD.

Luft et al report on endothelial dysfunction in SR-GvHD (Blood, 2016):

"These results suggest that endothelialcell vulnerability and dysfunction, ratherthan refractory T-cell activity, drives treatment refractoriness of GVHD and opensnew avenues for prediction and control ofthis devastating condition."
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I posted earlier in the year on evidence that loss of intestinal integrity is the driver of chronic disease. In terms of the gut barrier Assimokoupos et al (2018) explain:

"The mechanical barrier, consisting of the closed-lining intestinal epithelial cells and by the capillary endothelial cells. The epithelial and endothelial cells come into the closest possible contact in the most apical part of the lateral cell membranes (“kissing points”) by specific structures named “tight junctions” (TJs), which interconnect the cells and restrict the passage of ions, molecules and cells through the paracellular space."

My layperson's understanding is that maintaining tight junctions stop toxins leaking into the blood stream?

The idea that maintaining intestinal integrity could reduce GvHD severity has long been proposed: Johanson et al (2007);Hill et al (2007) Nalle et al (2014) and more recently, Tsai et al (2017); Lounder et al (2018) have published research on the role of IL-22 in increasing permeability of tight junctions.

Nalle et al published a study in the Journal of Clinical Investigation (2019):

"Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355225/

In this study researchers harvested tissue from the jejunum, liver and skin. Mice which underwent BMT and were shown to have preserved intestinal barrier showed less GvHD effect including fewer skin ulcers and less hair loss.

Clinicians are well onto the importance of intestinal barrier. Dr Paul carpenter ( who called in our product on compassionate ground for a child with grade 4 GI-GvHD ) has published on the role of vitamin A in reducing intestinal permeability. Lounder et al (2019) also published on vitamin A.

MSCs have long been studied for intestinal ischemia. Yabana et al (2009) found MSCs were implicated in maintaining tight junctions. Menge et al (2012) reported in Science Translational Medicine that MSCs were found to inhibit blood brain barrier permeability in traumatic brain injury by maintaining tight junctions.

Regarding GvHD, I quoted this in a post earlier this year but imo it's worth repeating because, while work is still in the experimental stage, the international research team was at MSKCC and we have the idea that there could be an optimal window in which to act. According to team leader Hendrik Peoeck of the Technical University of Munich:

"The intestine is believed to be the key organ where GVHD starts... If the epithelium could be protected or quickly restored, the risk of an immune response would be much lower."

GI-GvHD has the highest death rate and the focus is naturally on this in the acute stage, but further down the track lung and skin GvHD can develop into major problems that are difficult and expensive to treat. In IBD there can be later involvement of lung and connective tissue ( evidence of heart too but it's still considered controversial) The secondary stage can be a major battle, which is why prevention is better than cure.

I question the premise of skin only GvHD. If there are ongoing issues with skin, that likely comes from not healing the gut properly in the first place. There's evidence our cells are capable of structural repair of gut, in contrast to steroids which are not known for healing the gut well.

Jafaki is used in chronic GvHD to reduce steroid dependency; its approval for aGvHD was discussed in the symposium. Dr Prockop said, based on her experience of RUX with three patients, she wouldn't participate in a clinical trial.

Ruxolitinib Studies

Acute and Chronic

The study by Zeiser et al is highly cited. This is considered a landmark study as it's multi-centre and real world data. Importantly, the study included 95 patients with moderate and severe SR-GvHD who had failed multiple lines of therapy. I referred to this study before but I have a few more details to add since reading up on skin GvHD.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854652/

Khandelwhal et al say of Zeiser et al's study: "this above-mentioned study mandated that a response needed to last for 3 weeks, and patients were scored for their best response at any time after starting treatment with ruxolitinib, with follow-up censored at the onset of any subsequent systemic immunosuppressive therapy".

Zeiser et al say the two photos of skin GvHD are 'representative'. I'm not saying these are not skin GvHD. I assume biopsies would have been done but I couldn't find mention of them in the discussion, also not of sclerodermatous GvHD, which is the most challenging. The photos don't show the extent of skin GvHD that I've seen in other journals.

What I read of skin GvHD is that the hallmark is the soles of feet and palms of hands are affected. It can be lichenoid, scleredermatous, covering the entire body, raw ulceration and the epidermis can even detach. Dermatologists, however, report a wide variation of skin GvHD including a type that resembles atopic eczema.

In another thread I mentioned red skin syndrome (RSS) caused by over use of topical steroids. The hallmark of RSS is that it doesn't affect palms and soles of feet. There is a distinctive demarcation line at wrist but more fudgy on top of foot. I asked if you could suffer from skin GvHD and RSS at same time. The study by Creamer et al in which they report on a 'novel' form of eczematoid GvHD made me wonder. The symptoms they describe are exactly those of RSS. I sure see a use for steroids as it's dangerous for the skin not to be a barrier but in my relative's case every time the oral steroids were stopped the RSS came roaring back. Rux is prescribed most commonly for skin GvHD to reduce dependence on steroids.

In the study by Zeiser et al:

A The lower leg looks exactly RSS because of edema and demarcation on top of foot; that's a very good result to get in a week but the edema looks still there.

B The arm looks rather similar to RSS, the ripples above the elbow but the thick scaling is not familiar. Fine scaling is a feature of RSS. The skin is light pink and not angry red. From the enlarged photo, there doesn't appear to be ulceration.

C The photo of the colonoscopy was impressive; the patient had grade 4 intestinal GvHD and histological evaluation showed significant epithelial regeneration after Rux initiation. Neumann et al; Khandelwal et al (whose study Dr Prockop referred to) however, report poor results for GI-GvHD in their respective studies.

Zeiser et al reported on a follow up study: "The median follow-up was 19 and 24 months for aGVHD and cGVHD, respectively. At follow-up, 22/54 (41%) of SR-aGVHD patients and 10/41 (24%) of SR-cGVHD patients have an ongoing response and are free of any immunosuppression". Only 7.3% of cGvHD achieved remission. Graft versus tumour loss was 9.3% in acute and 2.4% in chronic, which authors say is low; however, according to Arai et al, 3-5 year survival data is important.

Maldonado et al (2017) reported on a small study of 8 patients. There are impressive photos of soles of feet and palms in sclerodermatous skin GvHD. In one case of extensive scleroderma there was significant ambulatory improvement: " After 11 months of ruxolitinib, sclerodermic form persists but in lower grade and normalization of skin changes". Case of of grade 3 GI showed complete resolution. Authors say all patients continue to use the drug without major adverse effects.

Neumann et al (2019) reported poor results for Gi-GvHD in a study of 8 patients. Tablets were finely ground to enable absorption but 4 patients with severe diarrhea did not respond to Ruxolitinib and died.

Acute

Assouan et al (2017) reported a study on Ruxolitinib in 10 patients with SR-aGvHD, 8 with acute, 2 with overlap. 6 patients had grades 3 and above, 7 with GI and 3 with liver. 5/10 had complete response, 2/10 partial response. Out of 7 responders, 4 patients were alive at longest follow up of 135 days. In this study RUX success for OS was 40%. Two patients died from septic shock that authors say was due to high doses of steroids.

Khandelwhal.et al's study on Rux in pediatric SR-GvHD is highly cited. They reported 45% response, only one complete responder. Seven of 13 patients were alive at median follow up of 401 days. High rate of reversible infections were observed. Poor results for GI.

Chronic

Hurabrielle et al (2017)report:

"In our cohort of heavily pretreated patients with severe sclerodermaous cGvHD of the skin, ruxolitinib led to a partial improvement in skin softness in the majority of cases (eight of twelve patients), but the total surface area affected by sclerosis remained the same. No complete response was observed in our study and the overall response rate was slightly lower compared with the study by Zeiser et al... We observed severe bacterial infections in one-quarter of the patients (one patient died)"

It was hard to see much difference in the after photo, which is why it's important to prevent such morbidity. ECP was mentioned in the symposium as a costly treatment. Patients need to spend hours at the hospital, sometimes more than once a week, monthly and for years. From what I gather in clinical practice, ECP is still used widely for cGvHD of skin and Jakafi is added to kick things on. Patients need to see specialist dermatologists, physiotherapists (as it can restrict movement) and gynaecologists as it can affect the vagina. There is also risk of infection.

Modi et al (2018) published a study in the largest cohort for SR-cGvHD. Of 46 patients, 13% had complete response and 30.4% had partial response. Rux use was associated with a reduction in prednisone. There were a high number of infections that contributed to overall mortality.

Ferreira et al reported similar results to Modi et al in 20 patients. Most had moderate disease and were partial responders. The majority had skin involvement. Rux could not be ruled out as contributing to 3 deaths from infections. Only 3/20 patients achieved remission. RUX was associated with reduction in steroid use and improvement in quality of life, although QOL wasn't formally evaluated. .

With approval for Remestemcel-L, MSB could fund itself because GvHD is not the tiny market our detractors would have us believe (Note the pharma source claiming we'd have the 15% of SR cases) and the urgent situation in cGvHD in US is not widely known. I suspected RUX would be approved and our candidate would be delayed, which is why I started writing about RUX over a year ago. I feared it would encroach into pediatrics. Now it seems likely in the 12-17 age group.

I don't see how Jakafi approval for aGvHD is in any sense good for patients or MSB. It makes the situation look less urgent, another reason for delay. Jakafi side effects have been extensively covered by Dr Prockop and others. I question its efficacy, including in skin where it's said to be most effective. I'm not saying it's ineffective, just that I think it's overstated.

But the problem isn't Jakafi; it's steroids that occupy a position in clinical practice they shouldn't have, blocking a critical window of opportunity. If Remestemcel-L was first in line and not steroids then it's likely Jakafi wouldn't have much place in either acute or chronic GvHD.



All IMO. GLTAH