Prospective study investigating a mesenchymal stem cells infusion, remestemcel-L, in pediatric patients with steroid-refractory acute GvHD

Acute graft-versus-host disease (aGvHD) refractory to steroid therapy is associated with poor prognosis. Currently, there is no safe and effective treatment approved for children under the age of 12 years.¹ The hallmark of aGvHD is systemic inflammation caused by alloreactive donor T cells attacking the patient’s tissues leading to tissue injury. The human leukocyte antigen (HLA) disparity between the hematopoietic stem cell (HSC) donor and the recipient is the key trigger of the immune activation.² In vitro studies and results from animal models demonstrated immunosuppressive and immunomodulatory function of bone marrow-derived mesenchymal stem cells (MSCs).^3,4 Initial clinical trials showed acceptable safety and promising clinical responses, including reduction of inflammatory biomarkers.^5-7

Previously, a multicentre expanded-access protocol study (NCT00759018) assessed remestemcel-L, an ex-vivo cultured adult human MSCs infusion, in 241 pediatric patients with steroid-refractory (SR) aGvHD. They demonstrated a 65% overall response (OR) at Day 28 and increased survival at Day 100 in responders compared with non-responders (82%  versus 39%, p < 0.001).⁷ A phase III study (NCT02336230) designed to further evaluate the efficacy and safety of remestemcel-L in pediatric patients with high-risk SR-aGvHD was recently reported by Joanne Kurtzberg, Duke University, Durham, US, and colleagues.⁸ The article below summarises key findings from the study.

Study design

• A phase III multicenter, prospective, single arm, open label study to evaluate the efficacy and safety of remestemcel-L in pediatric patients, aged 2 months to 17 years, with grade B–D primary SR-aGvHD (excluding skin-only grade B)
• Primary SR-aGvHD was defined as progression within three days, or no improvement within seven days of consecutive systemic treatment with 2mg/kg/d of methylprednisolone or equivalent
• Patients who received other first-line therapy or any second-line therapy were not eligible
• Remestemcel-L (healthy adult volunteer donor bone marrow-derived MSCs, cultured ex vivo and cryopreserved prior to administration) was administered intravenously at a dose 2 x 10⁶ /kg of body weight, twice a week for four consecutive weeks
• To assess efficacy and safety aGVHD assessments were performed at baseline and then weekly from Day 14 after the first infusion until Day 100 (± 7 days) in 54 patients (MSB GvHD001)
• A follow-up safety extension study through 180 days was conducted in 31 patients (MSB-GvHD002)
• Primary endpoint was aGvHD OR at Day 28. The study was powered to show a 20% improvement from a control OR of 45% for standard of care alone as supported by historical published findings and internal data
• Secondary endpoints included overall and responder survival (OS and RS), as well as response rates

Key findings

• In total, 55 patients were enrolled in MSB-GvHD001 and 54 patients received at least one infusion of Remestemcel-L
• After completing treatment, 40 patients were eligible to enrol in the follow- up study MSB-GvHD002 on day 100. Of these, 32 patients enrolled and 31 completed MSB-GvHD002 Baseline patient characteristics are presented in Table 1

Table 1. Selected baseline patient characteristics

aGvHD, acute graft versus host disease; min, minimum; max, maximum; PBSC, peripheral blood stem cells; SR-aGVHD steroid refractory aGvHD; HLA, human leukocyte antigen
Characteristics	Remestemcel-L (n= 55)
Median age (min, max)	7.0 (0, 17)
Male, %	63.6
HLA donor HLA frequency, % Matched/related Mismatched/related Unrelated	10.9 12.7 76.4
Type of transplant, % Bone marrow PBSC Cord blood	54.5 25.5 20.0
aGvHD at baseline, % Grade B Grade C Grade D	10.9 41.8 47.3
Organ involvement, % Single organ Multiple organ	63.6 36.4
aGvHD risk Standard-risk High-risk	27.3 72.7
aGVHD onset to first infusion, days Median (min, max)	12.0 (4, 142)
SR-aGVHD to first infusion, days Median (min, max)	3.5 (1, 10)

• The total number of infusions was 535, with 45.6ml ± 10.5 of mean volume administered at each infusion and 453.4ml ± 190.3 of mean total volume administered
  • 5.6% of patients received 1–4 infusions
  • 38.9% of patients received 5–8 infusions
  • 46.3% of patients received 9–12 infusions
  • 9.3% of patients received ≥13 infusions

Efficacy

• The primary efficacy endpoint was met with an OR of 70.4%. Further details are provided in Table 2
• Subgroup analysis showed consistent OR at Day 28 across different ages, races and gender subgroups
• Peripheral blood transplant recipients had lower Day 28 OR compared with bone marrow and cord blood transplant recipients (43% versus 83% and 73%, respectively)
• OS was 74.1% at Day 100 and 68.5% at Day 180
• Patients responding at Day 28 had significantly improved survival at Day 100 and Day 180 compared to non-responders (86.8% vs 47.1%, p = 0.0001 and 78.9% vs 43.8%, p= 0.001, respectively)
• The responses between patients who received the planned 8 infusions and those who received additional doses were comparable.

Table 2. Clinical response endpoints

CR, complete response; MR, mixed response; NR, no response; PD progressive disease; OR, overall response, PR, partial response; VGPR, very good partial response
Endpoint	Remestemcel-L (n = 54), %
Day 28 response
Responder (OR) CR PR VGPR Non-responder MR NR PD	70.4 29.6 40.7 9.3 31.5 9.3 14.8 7.4
Day 56 response
Responder (OR) CR PR VGPR Non-responder Missing	59.3 31.5 27.8 11.1 22.2 20.4
Day 100 response
Responder (OR) CR PR VGPR Non-responder Missing	70.4 44.4 25.9 7.4 11.1 20.4

Safety

• Infections were the most common treatment-emergent adverse events (TEAE), occurring in 83.3% of patients, including serious infections in 31.5% of patients
• Six serious TEAEs reported were possibly related to the remestemcel-L treatment and included: skin GvHD, adenovirus infection, BK virus infection, haemolytic uremic syndrome, hypermetabolism, and somnolence
• Fourteen deaths were recorded during the first 100 days, but none were attributed to the remestemcel-L
  • disease relapse (n= 4)
  • aGvHD progression (n= 4)
  • infection (n= 2)
  • multiple organ failure, pulmonary haemorrhage, cardiac arrest and lost to follow up (n= 1 each)
• There were two deaths between Day 100 and Day 180:
  • recurrent acute lymphocytic leukemia (n= 1)
  • lost to follow-up and presumed deceased (n= 1)
• Safety outcomes are summarised in Table 3

Table 3. Summary of safety outcomes

TEAE, treatment-emergent adverse events
TEAE	MSB-GvHD001 % (n = 54)	MSB-GvHD002 % (n = 32)
Any TEAE Possibly treatment-related Any infusion reaction Leading to discontinuation	100 16.7 5.6 14.8	84.4 0 0 0
Any serious TEAE Possibly treatment-related Leading to discontinuation Deaths	64.8 9.3 11.1 25.9	46.9 0 0 9.4
TEAE by system organ class Infections and infestations Gastrointestinal disorders General disorders Metabolism and nutrition disorders Laboratory investigations Respiratory, thoracic, and mediastinal disorders Immune system disorders	83.3 57.4 50.0 48.1 50.0 48.1 40.7	50.0 28.1 34.4 31.3 28.1 21.9 15.6
Serious TEAE by system organ class Infections and infestations Respiratory, thoracic, and mediastinal disorders General disorders Gastrointestinal disorders Immune system disorders	31.5 22.2 14.8 13.0 11.1	25.0 0 3.1 3.1 0

Conclusion

Study demonstrated remestemcel-L as a relatively safe and effective treatment option for pediatric patients with SR-aGVHD that induced a durable overall response rate of 70.4% with rates for complete responses improving from day 28 up to day 100. Moreover, a response at Day 28 indicated improved survival at Day 180.