Allogeneic human mesenchymal stem cell therapy (Remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients

Joanne Kurtzberg, Susan Prockop, Pierre Teira, Henrique Bittencourt, Victor Lewis, Ka Wah Chan, Biljana Horn, Lolie Yu, Julie An Talano, Eneida Nemecek, Charles R. Mills, Sonali Chaudhury

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Abstract

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 2×106 hMSCs/kg for 4weeks, 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, 8yr; 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 30d (range, 2 to 1639d), 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 3organs 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.

Original languageEnglish (US)
Pages (from-to)229-235
Number of pages7
JournalBiology of Blood and Marrow Transplantation
Volume20
Issue number2
DOIs
StatePublished - Feb 2014

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Graft vs Host Disease
Cell- and Tissue-Based Therapy
Mesenchymal Stromal Cells
Pediatrics
Immunosuppressive Agents
Steroids
Transplants
Choristoma
Skin
Survival
Liver
Stem Cell Transplantation
Standard of Care
Hematopoietic Stem Cells
Fetal Blood

Keywords

  • Acute graft-versus-host disease
  • Allogeneic hematopoietic stem cell transplantation
  • Human mesenchymal stem cells
  • Pediatric
  • Steroid refractory

ASJC Scopus subject areas

  • Transplantation
  • Hematology

Cite this

Allogeneic human mesenchymal stem cell therapy (Remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. / Kurtzberg, Joanne; Prockop, Susan; Teira, Pierre; Bittencourt, Henrique; Lewis, Victor; Chan, Ka Wah; Horn, Biljana; Yu, Lolie; Talano, Julie An; Nemecek, Eneida; Mills, Charles R.; Chaudhury, Sonali.

In: Biology of Blood and Marrow Transplantation, Vol. 20, No. 2, 02.2014, p. 229-235.

Research output: Contribution to journalArticle

Kurtzberg, Joanne ; Prockop, Susan ; Teira, Pierre ; Bittencourt, Henrique ; Lewis, Victor ; Chan, Ka Wah ; Horn, Biljana ; Yu, Lolie ; Talano, Julie An ; Nemecek, Eneida ; Mills, Charles R. ; Chaudhury, Sonali. / Allogeneic human mesenchymal stem cell therapy (Remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. In: Biology of Blood and Marrow Transplantation. 2014 ; Vol. 20, No. 2. pp. 229-235.
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abstract = "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 2×106 hMSCs/kg for 4weeks, 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, 8yr; 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 30d (range, 2 to 1639d), 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 3organs 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.",
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AU - Teira, Pierre

AU - Bittencourt, Henrique

AU - Lewis, Victor

AU - Chan, Ka Wah

AU - Horn, Biljana

AU - Yu, Lolie

AU - Talano, Julie An

AU - Nemecek, Eneida

AU - Mills, Charles R.

AU - Chaudhury, Sonali

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N2 - 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 2×106 hMSCs/kg for 4weeks, 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, 8yr; 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 30d (range, 2 to 1639d), 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 3organs 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.

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