Clinical deep dive 

Disease state overview 
GVHD is a potentially life-threatening complication that may arise following an allogeneic hematopoietic cell transplantation (HCT). GVHD can present as two main types: acute or chronic disease, each with different clinical presentations. GVHD is classified based on timing and clinical manifestations. The most significant risk factor for developing aGVHD is HLA mismatch. GVHD onsets when immunocompetent T cells in the donated graft recognize the recipient’s tissues as foreign and subsequently develop an immune response. Donor T cells are activated and attack the recipient tissue to remove foreign cells. The skin, gastrointestinal (GI) tract, and liver are the three most commonly affected areas by aGVHD with common symptoms being maculopapular rash, hyperbilirubinemia with jaundice, nausea, vomiting, anorexia, watery or bloody diarrhea, and crampy abdominal pain. The grade of aGVHD is helpful to understand the patient’s prognosis as the risk of mortality is generally greater with moderate to severe disease. Different grading tools exist to evaluate disease severity of aGVHD; extent of organ involvement is used to determine an overall severity grade, with well-known tools using scales from I-IV or A-D ranging from milder to most severe forms of disease. It is important to note that mortality rates are high in patients with steroid-refractory disease, which thus highlights the need for additional treatment options in this patient population.

Epidemiology 
Recent data shows there are approximately 9,000 allogeneic HCT each year in the United States with about 15% of these being pediatric cases. The rate of developing aGVHD is dependent on donor, transplant technique, and other factors; therefore, the frequency is difficult to measure due to variance among populations. Even with prophylaxis regimens, 20 to 80% of patients who undergo an allogeneic HCT develop aGVHD. Additionally, approximately 40% to 50% of patients with aGVHD are refractory to steroids; the SR-aGVHD patient population has mortality rates exceeding 90%. Acute GVHD remains a substantial cause of morbidity and mortality following allogeneic stem cell transplantation; one-year overall survival rates have shown to be 70% in patients with grade II aGVHD and 40% in patients with grade III-IV disease.

Treatment 
Treatment of Grade I aGVHD includes administering or restarting the original immunosuppressive agent(s) and topical options (corticosteroids and/or tacrolimus). Grades II-IV are also treated with restarting, continuing, or escalating the dose of immunosuppressive agent(s) as well as with systemic corticosteroids (e.g., 1-2 mg/kg/day methylprednisolone or prednisone equivalent with regimen dependent on factors such as grade/affected area) with or without topical steroids. Currently, ruxolitinib (Jakafi) is the only FDA approved treatment for the treatment of steroid-refractory acute graft-versus-host-disease in adult and pediatric patients 12 years and older. Other treatments are used off-label for SR-aGVHD such as: alemtuzumab, alpha-1 antitrypsin, anti-thymocyte globulin, basiliximab, calcineurin inhibitors, etanercept, extracorporeal photopheresis, infliximab, mTOR (mammalian Target of Rapamycin) inhibitors, mycophenolate mofetil, pentostatin, tocilizumab, and vedolizumab. Patients with SRaGVHD are encouraged to enroll in a clinical trial as this patient population is at a high risk for mortality, and no standard and effective treatment has been recognized in this patient population. As a result, choice of treatment in SR-aGVHD is dependent on a host of factors such as institutional preferences, side effect profile, drug interactions, prior treatments and response, physician experience, and patient tolerability.

Drug and clinical trial overview 

Remestemcel-L was evaluated in a phase 3, single-arm, open-label, prospective study (MSB-GVHD001) in 54 children at 20 facilities in the United States. Additionally, a follow-up extension study through 180 days was completed (MSB-GVHD002). Patients were eligible for inclusion if they were 2 months to 17 years of age with steroid-refractory grade B to D aGVHD. Additionally, patients were required to have an inadequate response to systemic steroid first-line treatment, which was defined as disease progression within three days or lack of improvement within seven days of therapy with 2 mg/kg/day of methylprednisolone or equivalent. The trial excluded patients who had received any other systemic first-line or any second-line therapy for aGVHD as well as patients with skin-only grade B disease. Patients received remestemcel-L intravenously at a dose of 2 x 10⁶ MSC/kg twice weekly for four weeks. Patients who experienced a partial response (PR) or mixed response (MR) at day 28 were eligible for additional therapy which consisted of 4-once weekly infusions at the same dose (N = 25). Additionally, patients who achieved a complete response (CR) and then subsequently had a flare of grade B to D progression were eligible for twice weekly dosing for four more weeks (N = 5). The primary efficacy endpoint was OR at day 28. At the primary endpoint, 70.4% (38/54) of patients reached an OR which was statistically superior compared to the derived control group which was 45%. At days 56 and 100, 59.3% (32/54) and 70.4% (38/54) achieved an OR, respectively. The median duration of response was 146 days. The key secondary endpoint of overall survival was 74.1% (40/54) through day 100 and 68.5% (37/54) at day 180. At day 28 through day 180, responders (those who achieve an OR) demonstrated a statistically superior survival as compared to nonresponders, which demonstrates the predictive nature of day 28 response with outcomes. All participants in the trial reported at least one treatment-emergent adverse event (TEAE), but many reported TEAEs were deemed unrelated to the investigational product. Infections occurred in 83.3% of patients and were the most common TEAE. Fourteen deaths occurred during the 100-day follow-up, but none were a result of treatment with remestemcel-L. Thirty-two patients continued in the follow-up study through 180 days; by the end of the trial, 46.9% (15/32) were able to discontinue systemic corticosteroids, and 87.5% (28/32) were GVHD immunosuppressive therapy (IST) free. Eight patients developed chronic GVHD in the follow-up study with most cases being mild in nature.