This post contains confronting information about GvHD.
I don't know what the landscape of the ARDS trial will look like but I've long thought that results would inform GvHD, as they have many features in common. This post is about GvHD with reference to ARDS in the light of biomarkers that I hope has some relevance to Dr Galipeau's paper.
In this post I discuss and provide evidence for:
- Why I think a RCT in GvHD could not have taken place, not only for ethical reasons
- The truth about GvHD, that's similar to ARDS, that no one wants to talk about
- Biomarkers, a move to personalised medicine, a better way to prove efficacy?
- ARDS: a potential way out of 1967
- GvHD: a potential way out of Catch 22
A RCT against Ruxolitinib
I'm no expert on clinical trials so please feel free to make any corrections. I know the basics in that doctors have to agree to run them, patients have to agree to participate and ethics committees have to approve them. There's particular difficulty in running a RCT in acute GvHD because treatment would be trialled against SOC and there's nothing effective for SR cases. Rux was the first approved in 50 years.
Westin et al (2011) say:
“Patients with steroid-resistant acute graft versus host disease (aGVHD) have a dismal prognosis, with mortality rates in excess of 90%”
A multi centre RCT in Rux in Germany was recently cancelled due to impossibility of recruiting in the BAT arm. Reach2 had a crossover, which is not advised, but Zeiser et al said investigators would not have agreed to run it otherwise. Editorial in NEJM calls Reach2 finally 'a successful' randomized trial in GvHD. That in itself speaks volumes.
I wrote about two therapies for SR GvHD here a few years ago. I identified Infliximab as the worst and I thought Sirolimus was doing a reasonable job. In Reach2, 17 patients got Infliximab as BAT and 3 got Sirolimus. Despite such favourable odds, rux failed to show any difference in survival.
Rux met its PE in Reach2 which is why it's still being given to adults with severe diarrhea in ICU and also very young children on compassionate grounds. It's no more effective than any other second line therapy (hence a dire prognosis).
It has been mentioned to have a quick trial or a quick crossover. Acute GvHD is a lot about timing. Decisions are made quickly, things can escalate quickly and there's growing awareness of a window in which to act. GvHD is profoundly immune suppressive in itself and there's an extremely high risk of infections, particularly bacterial, which usually occur within the first 6 weeks. Rux raises the risk of infections. Also, jak inhibitors affect the IL-6 pathway our cells respond to.
Garbers et al (2013) discuss how IL-6 and IL-11 are the same but different and the effect of jak inhibitor rux:
"Both cytokines (and numerous other cytokines and growth factors) trigger activation of jaks, and all these beneficial and/or destructive effects are simultaneously gone when the mentioned inhibitors are applied".
Kim et al's (2009) research was cited by Dr Galipeau: "Although in many inflammatory conditions IL-6 is induced along with other pro-inflammatory cytokines, endogenous IL-6 from tissue macrophages [61], can also play a significant anti-inflammatory role in both local and systemic inflammatory responses [62]. Furthermore, several animal models have shown the importance of IL-6 for wound repair"
In another post I cited research that IL-6 plays an important role in gut homeostasis, the key to shutting down the inflammatory cascade.
This is MSB we're talking about, the company that has to jump through hoops. We likely wouldn't be able to have crossover. As Zeiser et al acknowledge, a crossover makes it difficult to analyse data on overall survival. Some patients would draw the short straw and get the tablet. Our cohort is high risk: GI GvHD that can cause severe diarrhea and even hemorrhaging. Effective pain killers can't be given because volume of diarrhea needs to be monitored. Patients wouldn't have much idea of what was involved until they were right in the thick of it. I posted a link to two public blogs that describe the reality of the literal torture of gut GvHD.
I think most posters here who are real human beings and not robots didn't like the idea of patients in the ARDS trial getting a placebo because we believe Ryoncil/Remestemcel-L works but we knew that doctors treating ARDS wouldn't know that yet; a RCT would be necessary if our therapy was to go on to save countless lives and prevent disability. Investigators in an acute GvHD trial, however, know Ryoncil works and its safety profile. They know what can be the reality of GI GvHD. Our focus is on the patients and their suffering, just as it should be, but I also wonder how relatives and clinicians could recover psychologically from the reality of a RCT in high risk disease against rux.
A RCT against Steroids?
I wondered if a trial could be run against steroids. It's taken a lot of reading and careful listening to find out the truth of the job they do in GvHD. The Reach2 editorial in NEJM says first-line therapy glucocorticoids are 'effective in approximately half the patients'. I've read this a lot but it doesn't mean they work in 50% of cases. The doctors I identified as my horse's mouth experts are very specific about the job steroids do. According to Carpetenter et al (2010), approximately one third of patients get a durable response. @Bazsa provided a ref to a study by Bacigalupo et al (2017) that steroids are effective in only mild cases and do a particularly poor job in higher grades C/D, more harm actually than good because they cause infections and other adverse effects.
There's clearly a need for a steroid-sparing therapy. Levine et al write:
"The primary treatment of GVHD is immunosuppression with high-dose systemic glucocorticoids, usually lasting for a minimum of several months. Even when steroid therapy results in complete resolution of GVHD symptoms, intensive immunosuppression leads to significant morbidity and mortality, including opportunistic infections, avascular necrosis, osteopenia, osteoporotic fractures, metabolic disturbances, and neuropsychiatric abnormalities".
AVN is not uncommon in chronic GvHD and it's not uncommon for a person in their twenties to have to undergo a hip replacement. It's not uncommon to have to undergo a second transplant. Broad immune suppression can affect graft v tumour effect.
Dr Levine mentioned a small trial in Itacitinib in lieu of steroids in low risk patients who were identified as likely to respond well to steroids. Results are due this year.
I confirmed with a transplant physician who has nothing to do with MSB and whose research area wasn't MSCs who said MSCs would need to prove themselves in SR GvHD if they were to be used in lieu of steroids. Currently they're in SR position where they're showing good efficacy but can't do their best work because steroids are harmful to MSCs. Also, against us is the perception that steroids work in 50% of cases and they do have a reputation for getting things under control very quickly.
Perhaps, however, if a patient was informed that new biomarkers indicate refractoriness, they'd be willing to forgo steroids first line. There could be a crossover to steroids; patients would know they could drop out any time and have to be treated with steroids anyway, but I still think what our therapy suffers from most are scepticism and ignorance. I mentioned MSCs recently to a specialist in another area who said MSCs had only been trialled in rats! That's why imo we badly needed our Covid ARDS trial to be a success.
The posters @Southoz @Davisite appear to know a lot about clinical trials and FDA procedure. Southoz states as a fact and Davisite expresses the opinion the FDA wanted MSB to run a RCT that MSB has been avoiding:
@Southoz:"MSB doesn't want to go away at all - it knows the risks in meeting P3 primary endpoints and so will leave no stone unturned to avoid another trial"
@Davisite: "To me it looks like MSB thought they could bully the FDA into accepting a single arm study by getting support from the big name clinicians".
Southoz has said the FDA wanted matching at the patient level. I take it that means ensuring the characteristics are balanced between groups in a RCT? According to Dr Levine, clinical signs such as extent of rash or volume of diarrhea don't correlate to non relapse mortality. Magic consortium found REG3α and ST2 strongly correlate to NRM, which are endorsed by the FDA and NIH. Zeiser et al were criticised for not matching according to these biomarkers but they say these biomarkers are not standard and that multiple biomarkers have been associated with aGvHD outcomes.
I ask therefore if the above posters would kindly write out the design of RCT (against which SOC, how patients would be matched), a design for a trial they know for a FACT that doctors would have agreed to run and patients agreed to enrol in.
Our cohort is high risk adults with GI involvement, so it's highly likely patients not in the treatment group are going to die in a tortured way in order to prove something. What PE would be chosen for 'proof' and how valid would that proof be in terms of what all parties (patients, physicians, insurers) actually want?
Biomarkers
MSB is specifically looking for IL-6 and IL-8 in ARDS trial. Gorham et al (2020) found IL-6 is linked to non survivors of Covid ARDS. These two biomarkers have also been shown to predict treatment response and long term survival in GvHD.
Paczesny et al (2009) determined that a panel composed of 4 biomarkers (IL-2Rα, TNFR1, IL-8, and HGF) effectively discriminated between patients with and without GVHD. This biomarker panel was highly specific and predicted long-term survival independently of maximum GVHD grade.
IL-8 has also been identified as an indicator as to whether a patient with acute GvHD goes on to suffer chronic GvHD. Berger et al (2013) say, "The higher IL-8 serum concentration on day +28 was associated with a lower probability of chronic GVHD being 4% vs 29% (P=0.01) for patients with higher vs lower IL-8 serum concentration".
Levine et al (2019) report on a panel of biomarkers, specifically REG3α and ST2, that could more accurately predict treatment response in GvHD. Authors say "IL-6 also was observed to be elevated early post-transplant in patients who later developed GVHD, and its blockade has emerged as a potential prophylactic strategy".
Greco et al (2019) report on IL-6 as biomarker for longer survival in GvHD:
"Within this retrospective cohort of patients, the survival analysis confirmed a significantly decreased 2-year OS in patients with baseline IL6 levels higher than 2.5 pg/ml (40 vs. 77%; p = 0.001) and/or post-transplant IL6 concentrations higher than 16.5 pg/ml (36 vs. 81%; p 0.001)."
"Rates of grades III–IV acute GvHD were higher in patients with post-transplant IL6 levels higher than 16.5 pg/ml (19 vs. 4%; p = 0.05).High levels of post-transplant IL6 achieved a statistically significant association with worse TRM at 2-year (35 vs. 4%; p = 0.009)."
It's about long-term survival in GvHD, 3-5 years giving the best indication.
ARDS: Stuck in 1967?
Robert P Dickson (2018) discusses ARDS' mid life crisis:
"The original 1967 report of the disease (1) is both impressive in its prescience and deflating in its familiarity: At the dawn of the disease, the authors debated the efficacy of corticosteroids, conservative fluid management, positive-end expiratory pressure, and recruitment maneuvers. A half-century later, these same supportive therapies remain the subjects of clinical study and bedside debate. Intensivists, investigators, and patients are justified in asking the question behind all midlife crises: Is this all there is?"
"Our research group recently demonstrated that sepsis, the most common etiology of ARDS, results in an altered lung microbiome, selectively enriched with gut-associated bacteria (9). In the current study, the authors report that development of ARDS was most strongly correlated with lung enrichment of Enterobacteriaceae spp., a prominent gut-associated bacterial family. This represents more than just an independent confirmation of our previous findings: it is the first temporal evidence to date suggesting that enrichment of lung communities with gut-associated bacteria may precede the inflammation and injury of ARDS"
I read the paper by Dr Galipeau posted by @Chau165. I don't know whether I understood correctly but this is my question for experts: Does this have to do with MSCs' ability to polarise macrophages from M1 (pro-inflammatory) to M2 (anti-inflammatory) with IL-10 being a marker of anti-inflammatory? Also, M2 macrophages have a high phagocytosis capacity and according to Dr Matthay's YT presention in ARDS, MSCs have direct action on bacteria through secretion of peptides but also enhance phagocytosis of the bacteria by monocytes and alveolar macrophages.
If data from early stage of ARDS trial show consistent changes in IL-6 and IL-8, upregulation of IL-10 with temporal association, if there's a corresponding improvement in clearance of edema in lungs, that speaks to restoration of epithelial and endothelial integrity, which is vital to any cytokine storm. If there's a corresponding clearance in bacteria, that's highly relevant to both ARDS and GvHD. In GvHD it's so important to avoid giving antibiotics for infections because more diverse gut flora is strongly lito long-term survival. In Covid ARDS, SOC is currently steroids, which poses a difficult problem of timing with a viral cause of ARDS because of the risk of infection. Positive results in both these effects and superior results in overall mortality would be the key imo to putting our therapy ahead of ventilators where steroids showed no mortality benefit.
The Truth about GvHD
With GvHD, as with ARDS, the issue is about bad survival.
In Thorax (2017), Dr Brown says:
"If you had ARDS 25 years ago, we thought we saved your life in the intensive care unit, so we'd say, 'All is well, off you go -- you'll be fine,'" said Dr. Brown. "We had no idea as doctors how wrong we were about life after ARDS".
Quality of life of survivors of GvHD has begun to be discussed just in the past five years or so. Many sufferers of chronic GvHD feel they've been given a disease that's as bad or worse than the original condition.
Chronic GvHD of skin and lungs are very common and require a multi-disciplinary approach of physiotherapy, gastroenterology, gynaecology. Despite a drug approved for chronic GvHD, this hasn't reduced use of expensive in-hospital therapy such as ECP for skin. Lung GvHD causes repeated hospitalizations for pneumonia and can even lead to lung transplant.
With chronic skin and lung GvHD being so common, I would think what's most externally valid in GvHD is knowing whether patients treated with MSCs for acute GvHD have a reduced rate of chronic GvHD and because there's so much data sharing and AI to analyse it surely that's best shown by years of real-world data from Temcell and the EAP. Mount Sinai itself has a huge database.
Could Biomarkers Replace RCTs?
The Magic algorithm probability (MAP) was developed by Mount Sinai:
"The MAP also predicts response to treatment and maximum GVHD severity, and is now commercially available and widely used among scores of centers in clinical practice. Both academic and commercial laboratories have demonstrated that MAPs are highly reproducible, with 92% of samples receiving the same risk category assigned by different laboratories".
What Mount Sinai are doing is cutting edge, leading the field. We're moving into the era of personalised medicine; there are biomarkers to accurately predict treatment response and perhaps in the future we will also have biomarkers that measure response, as in change from baseline, that could ultimately replace a RCT and give a more accurate and valid result?
If we have some good data from the first part of the ARDS trial, then we see the cells working less well or not working at all in the later stage, it's easy to see what's happened when we know the cells respond to peak inflammation and when the treatment paradigm changed. I don't know how you could get any more cast iron proof of efficacy and MOA. Surely this would be enough to spare GvHD patients from a placebo? Also, surely it's enough for an EUA in Covid ARDS. Of all the conditions I've researched, I never read such frank and honest admission of the inadequacy of SOC and that was before the pandemic.
ALL IMO GLTAH
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893923/
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244628
https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/stem.3380
https://www.degruyter.com/document/doi/10.1515/hsz-2013-0166/htmlhttps://pubmed.ncbi.nlm.nih.gov/19772890/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227683/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709112/https://www.sciencedirect.com/science/article/pii/S0006497120378745https://www.nature.com/articles/bmt201341https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779849/https://www.atsjournals.org/doi/full/10.1164/rccm.201710-2096ED
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