Understanding the burden of pediatric steroid-refractory acute GvHD

You know, I’m a pediatrician, so when we counsel parents and children for transplant, we explain that one of the possible complications is GvHD.

Understanding the burden of pediatric steroid-refractory acute graft-versus-host disease (SR-aGvHD).

Families have heard that before, but hope that it wouldn’t happen to them. And then when they hear that it’s GvHD, usually they panic and just get very worried that maybe their child’s going to die from this, and they’re disappointed in a way that now there’s another complication to deal with, and that it could be serious.

No family goes into transplant expecting they’re going to get that worse complication. Usually they’re expecting if they get a little bit of GvHD, it’s going to be a little skin rash, maybe a little nausea. We’ll give them some Prednisone and it’ll all get better.

The standard of care is to give steroids, but only half the children who get steroids respond. And for the half who do not respond to steroids, there are really no good therapies and most therapies aren’t approved in children.

When they fall into the category of a non-responder, it’s kind of pretty scary for them because they’ve heard that that’s one of the life-threatening conditions that can, you know, hasten their demise. And, you know, we’ll need to treat it very aggressively to get it under control.

It’s really rough on families. It often leads to prolonged hospital stays. They’re having to go on additional agents, many of which are not approved for children. And when it doesn’t get better with therapy, that misery, that suffering is prolonged.

And there’s a lot of reasons that acute GvHD, particularly acute GvHD that doesn’t respond to steroids, really impacts just how patients are feeling and the quality of life. In fact, if you look historically in the literature, roughly half of patients that don’t respond to steroids will die as a result of their steroid-refractory aGvHD.

The amount of stress the child and parents have to go through is unexplainable. Patients have to be in the hospital for a long time, but parents as well, because then they have to be with the child in the hospital. Frequent hospital visits, dealing with multiple infections back-to-back, and it just…it’s probably one of the worst things we deal with.

Steroid-refractory aGvHD is the Achilles heel of bone marrow transplantation because it not only affects the survival of the patient, but it also causes significant morbidity. We clearly are in need for drugs which can be given to younger children. Sometimes we have to go beyond Prednisone to newer agents.

Discover a different path forward for pediatric patients with steroid-refractory acute GvHD.

So here in the United States, the only medication that we have that’s approved is RYONCIL for the steroid-refractory acute GvHD in these very young patients.

RYONCIL is the first and only FDA-approved steroid-refractory acute GvHD treatment for pediatric patients two months of age and older, and the only approved option for patients under 12 years of age.

Important Safety Information.

Do not use RYONCIL in patients with known hypersensitivity to dimethyl sulfoxide (DMSO) or porcine and bovine proteins. Serious hypersensitivity reactions, including anaphylaxis, may occur due to DMSO and trace amounts of porcine or bovine proteins. Premedicate with antihistamines and corticosteroids and monitor closely. Interrupt infusion if hypersensitivity or a serious reaction occurs. Do not administer RYONCIL in patients who experience serious or life-threatening reactions.

RYONCIL may transmit infectious agents because it contains cells from human donors and uses human, porcine, and bovine-derived materials. Ectopic tissue formation may occur following treatment with RYONCIL due to the differentiation potential of mesenchymal stromal cells.

The most common non-laboratory adverse reactions ≥20% are: viral and bacterial infectious disorders, infection—pathogen unspecified, pyrexia, hemorrhage, edema, abdominal pain, and hypertension. Please see full Prescribing Information for complete safety information.

For our patients that are under 12 years of age, I think it’s really going to be the go-to agent as second-line therapy for steroid-refractory acute GvHD. But it certainly gives us another much-needed tool in our toolbox for treating patients that are 12 and up with steroid-refractory acute graft-versus-host disease as well.

Indication. RYONCIL is indicated for the treatment of steroid-refractory acute graft-versus-host disease (SR-aGvHD) in pediatric patients 2 months of age and older.

Important Safety Information.

Contraindications. Do not use RYONCIL in patients with known hypersensitivity to dimethyl sulfoxide (DMSO) or porcine and bovine proteins.

Warnings and precautions.

Hypersensitivity and acute infusion reactions. Hypersensitivity reactions, including acute infusion reactions, have occurred with RYONCIL administration. Serious hypersensitivity reactions, including anaphylaxis, may occur due to DMSO and trace amounts of porcine or bovine proteins. Signs and symptoms may include fever, dyspnea, and hypotension during or after RYONCIL infusion. Premedicate patients with antihistamine and corticosteroids and monitor closely for signs and symptoms of hypersensitivity or acute infusion reactions. If a hypersensitivity or infusion reaction occurs, interrupt RYONCIL infusion. Do not administer RYONCIL in patients who experience serious or life-threatening reactions.

Transmission of Infectious Agents. Transmission of infectious disease or agents may occur with RYONCIL administration because it contains cells from human donors and is manufactured using human, porcine, and bovine derived reagents. Donors are screened and tested for Human Immune-deficiency Virus 1 (HIV-1); Human Immune-deficiency Virus 2 (HIV-2); Hepatitis B Virus (HBV); Hepatitis C Virus (HCV); Human T-cell Leukemia-lymphoma Virus 1 (HTLV-1); Human T-cell Leukemia-lymphoma Virus 2 (HTLV-2); West Nile Virus (WNV); Cytomegalovirus (CMV); Epstein-Barr Virus (EBV); and Syphilis (Treponema pallidum). Screening was performed for Creutzfeldt-Jakob disease (CJD) and communicable disease risks associated with xenotransplantation.

RYONCIL cell banks are tested for human and animal viruses, retroviruses, bacteria, fungi, yeast, and mycoplasma. Human and animal-derived reagents are tested for human and animal viruses, bacteria, fungi, and mycoplasma before use. These measures do not eliminate the risk of transmitting these or other infectious diseases or agents.

Ectopic Tissue Formation. Ectopic tissue formation may occur following treatment with RYONCIL due to the ability of human mesenchymal stromal cells to differentiate into mesenchymal lineage cells such as bone, cartilage, and fat cells.

Adverse reactions — Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety data described in this section reflect exposure to RYONCIL in 54 patients in study MSB-GVHD001 for the treatment of SR-aGvHD. Patients received intravenous infusion of RYONCIL at a dosage of 2 × 10⁶ MSCs per kilogram twice a week for four consecutive weeks for a total of eight infusions. Patients with partial or mixed response at Day 28 received additional infusions of RYONCIL 2 × 10⁶ MSCs per kilogram once a week for an additional 4 weeks. The median number of doses administered were 10 (range 1 to 16) and the treatment was administered over a median of 43 days (range 1 to 104 days).

Serious adverse reactions occurred in 35 patients (65%) including pyrexia (n=5; 9%), respiratory failure (n=5; 9%), pneumatosis intestinalis (n=4; 7%), and staphylococcal bacteremia (n=2; <5%). Eight patients had discontinuation of RYONCIL treatment due to the following: acute infusion reactions (n=3), hypotension (n=1), gastroenteritis (n=1), and death (n=3).

Adverse reactions ≤grade 3 occurring in ≥10% of patients in study MSB-GVHD001 up to day 100 after RYONCIL treatment included viral infectious disorders, bacterial infectious disorders, infections—pathogen unspecified, pyrexia, hemorrhage, abdominal pain, hypertension, vomiting, arrhythmia, diarrhea, rash, arthralgia, fungal infectious disorders, hypotension, cough, and respiratory failure. No grade 4 or 5 adverse reactions occurred in the study.

Grade 3 or 4 laboratory abnormalities that worsened from baseline in ≥10% of patients in study MSB-GVHD001 included elevated Gamma-glutamyl transferase, thrombocytopenia, and elevated bilirubin.

Use in specific populations.

Pregnancy. There are no available data for RYONCIL use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with RYONCIL to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known if RYONCIL has the potential to be transferred to the fetus. Therefore, RYONCIL is not recommended for women who are pregnant. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 10-20%, respectively.

Lactation. There is no information regarding the presence of RYONCIL in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RYONCIL and any potential adverse effects on the breastfed infant from RYONCIL or from the underlying maternal condition.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Mesoblast at toll-free phone number 1-844-889-MESO (6376). Please see the RYONCIL full Prescribing Information for additional Important Safety Information.

In the treatment of pediatric steroid-refractory acute GvHD, redefine what’s possible with RYONCIL.