Ryoncil, A Prophylactic for Chronic GvHD?
In Certain Conditions, Could Our Best Buddy Be Doing More Harm than Good?
I haven’t checked this myself but I trust Dr. Rapaport. He says eczema didn't persist beyond childhood until the advent of steroids, which have become increasingly potent, and that this fact can be found in medical textbooks.
If children can get easily addicted to topical steroids, then surely that can happen with systemic ones, as in the case of my daughter who had Crohn’s Disease?
The price for Ryoncil seems high because of positioning for SR but if I were in the shoes of insurers, I’d pay that amount first-line to avoid steroid dependence/addiction, which would increase survival (Most early deaths on GvHDOO1 were due to infection) and reduce severe AEs.
Carpenter and Macmillan (2010):
“aGVHD is by itself profoundly immunosuppressive as are the therapies used to treat it, leading to an extraordinarily high risk for opportunistic infections, and sepsis. Breakdown of skin and intestinal epithelia that occurs in more severe aGVHD forms adds to this risk. High dose prednisone increases the risk for cytomegalovirus (CMV) reactivation”
The best way to avoid steroid-dependence is not to give them in the first place. They don’t work for anything beyond mild GI GvHD. I emailed the company years ago with a suggestion to give a temporary steroid effect without giving steroids. IMO, re. malignant conditions, there’s a good chance of reducing the risk of relapse because of so much evidence supporting the metabolic theory of cancer.
A couple of years later, I came across a case study of a teenage boy able to come off TPN with this therapy. I think he had MSCs second-line though. I don’t know if it was our cells but it’s an obvious therapy. Seattle CH uses it for IBD, which is known to have similar features to GI GvHD.
Prior Acute: A Major Risk Factor for Chronic GvHD
Prior acute is known to be a major risk factor for developing cGvHD. Steroids are the mainstay treatment for cGvHD.
The Macmillan paper MSB cited at the 2022 AGM reported a large study in 370 children. It showed a very high death rate for aGvHD treated with steroids first-line and also a high incidence of cGvHD in survivors.
In the study by Zaidman et al. (2023) OP kindly posted a link to, the incidence of chronic GVHD was statistically significantly higher in the group of pediatric patients with severe aGvHD (a whopping 37.1%)
Maybe I overlooked it but I couldn’t find whether steroid responders were able to taper?
Lung: Target Organ of Acute GvHD
I’ve been waiting for some years for the lung to be officially acknowledged as a target organ of acute GvHD, so my attention was caught last year with the publication of a paper by Malard et al.Nature,June 2023 where the lung is stated as a target organ and also appears on p13 of MSB’s presentation later that same year (August 31 2023).
Emeritus Professor Robert Clancy is an expert in mucosal immunology and has explained the gut/lung axis for lay people. He speaks warmly of Prof Tom Borody (who was one of the researchers who worked on H pylori).
IMO the gut/lung axis is well acknowledged by physicians who know their immunology. (My eldest daughter was hospitalized with severe IBD (Crohn’s colitis) and had to have regular X- rays of the lung.
Relevant to us, I didn’t ask this publicly, so I’m just going to say that, based on a brief conversation at the 2022 AGM, it was my impression that treated under 65 survivors in Covid ARDS were doing better (in terms of function, which speaks to lack of fibrosis) than SoC + placebo. If I’m not in the UK and able to go to the next AGM, I’ll ask for more details publicly.
Most recipients of alloSCTs tend to be aged under 65.
Our long-term results in survivors from GvHD001 and data from the EAP may give a good indication of the rate of pulmonary complications, which are the most expensive to treat.
Lung GvHD and Pulmonary Complications Underreported
The Macmillan study covered 2 years, which would give a better indication of rates of cGvHD. You’d expect that incidence to be even higher in reality because there’s denial of cGvHD of the lung: it’s difficult to diagnose and its onset is insidious.
Hospitalisations and deaths are often recorded as due to other causes such as pneumonia (cGvHD of the lung can lead to frequent bouts of it), interstitial lung disease or bronchiolitis obliterans (BOS). A mother on the forum, for example, recently said her son (aged 11) had been diagnosed with BOS andchronic GvHD.
Patients suffer many AEs from the Immunosuppressive medications they’re taking. Fungal infections are common and some people report having spots on their lungs that have to be “scraped off”. One member’s husband was hospitalized 19 times for pneumonia. One member’s daughter has to have a lung transplant due to GvHD.
Broglie et al. (2019) say there has been limited evaluation of pulmonary complications in children and adolescents following allo- BMT. Their study of 5,022 children found pulmonary complications in 606 (12%) but the authors just looked at the first year; most cases start within two years but can be diagnosed later.
The overarching message by Helkar et al. (2023) is that more people are surviving long-term and therefore more are surviving badly. Authors say late cardiac events are “not uncommon”.
Re. pulmonary complications, Helkar et al. say:
“Arguably the most important and deadly late effects in HCT survivors are late-onset noninfectious pulmonary complications (LONIPC)...Most survivors developed their first episode of LONIPC within 36 months of HCT (23). One-year incidence of specific complications was 5% diffuse alveolar hemorrhage, 4% bronchiolitis obliterans (BOS), and 4% idiopathic pneumonia syndrome”.
The Real Cost of Poor Survival
Patients on the forum for sufferers of cGvHD are seldom on one drug. Many are on Prednisone. Ruxolitinib is still mentioned but less frequently than it used to be. Rezurock is mentioned increasingly frequently.
Rezurock costs around 137K a year for a tablet once daily (Sometimes doctors double the dose because of patients’ size or if they’re taking other medications.) It has known GI effects which sufferers have reported, along with joint pain, open wounds. Most report worsening GvHD or not seeing any results. Like Rux, it’s regularly combined with ECP, which sufferers do view as effective if kept up long enough.
ECP is mentioned with the same frequency (not often but regularly). This is an expensive in-hospital therapy requiring patients to attend all day for weeks, months or even years. It’s still considered an attractive therapy because, like MSCs, ECP is not immunosuppressive.
ECP is used for skin, gut, liver, lung, mouth, eyes but, as OP has said, does the best job with cutaneous skin GvHD. That’s the same conclusion I’ve come to after looking for a few years. It’s difficult to find studies on its efficacy for sclerodermatous (fibrotic) skin or lung GvHD.
Studies on sclerodermatous skin GvHD tend to report partial responses such as softening of the skin. It’s just common sense if you look at the photos. Once the skin has got that hide quality, it’s a hard ask for any therapy to reverse it.
Skin GvHD can restrict breathing (if across the torso) and movement (if affecting limbs). One mother on a UK forum said her little boy’s skin GvHD was being treated with Rux and ECP and he had to use a pusher to get around.
Afram et al. (2019) report on higher response with ECP for 34 patients with skin cGvHD. All patients with severe skin cGVHD had sclerodermatous presentation.
Median number of treatments was 22. One patient “was treated for117 weeksdue to hidebound scleroderma with skin cGVHD grade 3”.Only 5/34 got a complete response.
One patient with severe bronchiolitis obliterans had 61 weeks of ECP treatment but their symptoms got more severe when it was tapered to once a month and the patient ultimately died.
Consensus from studies and what patients say is that better results are gained with prolonged ECP treatment.
Ruxolitinib does the best job with skin. Check out the real world study by Zeiser et al. Neither photo of skin was sclerodermatous and the cGvHD (arm) couldn’t have fooled anyone with any knowledge of this condition. IMO it wasn’t intended to.
Penack et al. (Nature, Jan 2024) make the shocking statement:
“There is no published high-quality data from larger multicenter patient populations on the incidence of SR-cGVHD”.
Authors report on their study comparing ECP with Rux for cGvHD finding no statistical significance.
The authors are upfront with the limitations of their study (only 31 out of 227 centers responded!) but I thought this comment was very telling:
“The present results contribute to accumulating evidence on ECP as an effective treatment option in SR-cGVHD”.
Interesting to me that two recent papers published on the most prestigious platform clearly point to the inadequacy of Ruxolitinib in acute and chronic GvHD.
It’s not hard to see that the cost of a chronically surviving young person could run into the millions.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227683/
https://pubmed.ncbi.nlm.nih.gov/31477785/
https://pubmed.ncbi.nlm.nih.gov/31201861/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10130410/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526584/
https://www.nature.com/articles/s41409-023-02174-2
(20min delay)