Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients.
Severe steroid-refractory acute graft-versus-host disease (aGVHD) is related to significant mortality and morbidity after allogeneic stem cell transplantation. Early clinical trials of therapy with human mesenchymal stem cells (hMSCs) in pediatric patients with severe aGVHD resistant to multiple immunosuppressive agents showed promising results. In this study, we evaluated the risk/benefit profile of remestemcel-L (Prochymal), a third-party, off-the-shelf source of hMSCs, as a rescue agent for treatment-resistant aGVHD in pediatric patients. Children with grade B-D aGVHD failing steroids and, in most cases, other immunosuppressive agents were eligible for enrollment. Patients received 8 biweekly i.v. infusions of 2 × 10(6) hMSCs/kg for 4 weeks, with an additional 4 weekly infusions after day +28 for patients who achieved either a partial or mixed response. The enrolled patients compose a very challenging population with severe disease that was nonresponsive to the standard of care, with 88% of the patients experiencing severe aGVHD (grade C or D). Seventy-five patients (median age, 8 yr; 58.7% male; and 61.3% Caucasian) were treated in this study. Sixty-four patients (85.3%) had received an unrelated hematopoietic stem cell graft, and 28 patients (37.3%) had received a cord blood graft. At baseline, the distribution of aGVHD grades B, C, and D was 12.0%, 28.0%, and 60.0%, respectively. The median duration of aGVHD before enrollment was 30 d (range, 2 to 1639 d), and patients failed a median of 3 immunosuppressive agents. Organ involvement at baseline was 86.7% gastrointestinal, 54.7% skin, and 36.0% liver. Thirty-six patients (48.0%) had 2 organs involved, and 11 patients (14.7%) had all 3 organs involved. When stratified by aGVHD grade at baseline, the rate of overall response (complete and partial response) at day +28 was 66.7% for aGVHD grade B, 76.2% for grade C, and 53.3% for grade D. Overall response for individual organs at day +28 was 58.5% for the gastrointestinal system, 75.6% for skin, and 44.4% for liver. Collectively, overall response at day +28 for patients treated for severe refractory aGVHD was 61.3%, and this response was correlated with statistically significant improved survival at day +100 after hMSC infusion. Patients who responded to therapy by day +28 had a higher Kaplan-Meier estimated probability of 100-d survival compared with patients who did not respond (78.1% versus 31.0%; P < .001). Prochymal infusions were generally well tolerated, with no evidence of ectopic tissue formation.
Pediatric Blood and Bone Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina.
Joanne
J
Kurtzberg
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
Susan
S
Prockop
Hematology-Oncology Division, Charles Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada.
Pierre
P
Teira
Hematology-Oncology Division, Charles Bruneau Cancer Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada.
Henrique
H
Bittencourt
Pediatric Oncology, Blood and Marrow Transplantation, Alberta Children's Hospital, Calgary, Alberta, Canada.
Victor
V
Lewis
Pediatric Blood and Marrow Transplant Program, Texas Transplant Institute, Methodist Children's Hospital of South Texas, San Antonio, Texas.
Ka Wah
KW
Chan
Blood and Marrow Transplant Program, Benioff Children's Hospital, University of California, San Francisco, California.
Biljana
B
Horn
Bone Marrow Transplant Program, Children's Hospital, Louisiana State University Health Science Center, New Orleans, Louisiana.
Lolie
L
Yu
Department of Pediatric Hematology Oncology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin.
Julie-An
JA
Talano
Pediatric BMT Program, Oregon Health & Science University, Portland, Oregon.
Eneida
E
Nemecek
Osiris Therapeutics, Columbia, Maryland. Electronic address: rmills@osiris.com.
Charles R
CR
Mills
Division of Pediatric Hematology, Oncology, Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
Sonali
S
Chaudhury
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007223:Infant; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D011446:Prospective Studies; D014184:Transplantation, Homologous / Q000009:adverse effects* / Q000379:methods
Acute graft-versus-host disease; Allogeneic hematopoietic stem cell transplantation; Human mesenchymal stem cells; Pediatric; Steroid refractory