Use of Mesenchymal Stem Cells (Prochymal™) to Treat Pediatric Patients with Severe (Grade III-IV) acute Graft Versus Host Disease Refractory to Steroid and Other Agents
Vinod K. Prasad, MD, MRCP, Blood and Marrow Transplant Program, Dept. of Pediatrics, Duke University Medical Center, Durham, NC; Kenneth G. Lucas, MD, Pediatric Stem Cell Transplantation, PennState Children’s Hospital, Hershey, PA; Gary I. Kleiner, MD, PhD, Dept. of Pediatric Immunology, University of Miami, Miami, FL; Julie-An Talano, MD, Pediatric Hematology Oncology and BMT, MedicalCollege of Wisconsin, Milwaukee, WI; David Jacobsohn, MD, Stem Cell Transplant Program, Children’s Memorial Hospital, Chicago, IL; Paul Szabolcs, MD, Blood and Marrow Transplant Program, Dept. of Pediatrics, Duke University Medical Center, Durham, NC; Rod Monroy, PhD, Osiris Therapeutics, Inc., Columbia, MD; Joanne Kurtzberg, MD, Blood and Marrow Transplant Program, Dept. of Pediatrics,Duke University Medical Center, Durham, NC
Data was presented at the December 2007 American Society of Hematology meeting Background Patient Transplantation History
Severe acute Graft versus Host Disease (aGvHD) that fails to respond to steroids and
Conditioning Stem cells Donor/match
other immunosuppressive agents is associated with 180 day survival of less than 20%.
Preliminary studies have shown that human mesenchymal stem cells (hMSCs,
Prochymal™, Osiris Therapeutics, Inc.) have immunomodulatory and tissue regenerative
properties. This report summarizes the safety and efficacy of Prochymal for the
compassionate treatment of severe (Grades III/IV) acute GvHD in pediatric patients
who failed steroids and multiple 2nd line immunosuppressive therapies. Patients
ALD: adrenoleukodystrophy; HLH: hemophagocytic lymphohistiocytosis; APML: acute promyelocytic leukemia;
• 12 pediatric patients with severe aGvHD (Grade III, n=6 and IV, n=6) were treated
AML: acute myeloid leukemia; ALL: acute lymphocytic leukemia; MPD/eos: myeloproliferative disease/eosinophilia;ANLL: acute non-lymphocytic leukemia; Hurler’s: Hurler’s syndrome; M Osteopet: malignant osteopetrosis;
Red Int: reduced intensity; BM: bone marrow; UCB: umbilical cord blood cells; PBSC:peripheral blood stem cells; haplo PBSC:CD34 selected cells;RD: related donor; UD: unrelated donor;
• To be eligible for compassionate use, patients must have exhausted all reasonable
• Patients had failed an average of 3.2 lines of therapy prior to treatment with Prochymal
• Patients suffered with aGvHD for a median of 30 days (16-181days) prior to
• Patients from 5 different centers were enrolled
Patient GvHD History
• Median patient age was 6 years (range 0.4-15 years)
Onset aGvHD GvHD Severity GvHD Therapies
• Each treatment plan received IRB and FDA approval
Post Transplantation Before Prochymal at start of Prochymal Infusion prior to Prochymal (Number) Agent
(4) Solumedrol, cellcept, infliximab daclizumab
Prochymal Therapy Treatment Plan: Infusion: Cells were given IV over 1 hour for patients under 35kg and at a rate of
(4) Solumedrol, cellcept, infliximab, OKT3
4-6mL/min for patients ≥35kg. Patients received hydrocortisone and diphenylhydramine
30 minutes prior to infusion of Prochymal. Induction therapy: 2 x 106 MSC/kg/infusion, twice a week for 4 weeks. Patients #’s 1
and 2 received 8 x 106 MSC/kg/infusion under a different treatment plan (see Table). Maintenance therapy: Option for additional infusions of 2 x 106 MSC/kg/infusion,
once a week for the subsequent 4 weeks. Therapy was provided to patients who did
not achieve a CR during the induction therapy. GvHD Severity and Prochymal Prochymal™ (ex vivo cultured human mesenchymal stem cells) Treatment Plan
The product was manufactured by Osiris and consists of a population of homogeneous
MSCs characterized by cell surface phenotype. hMSCs are isolated from an unrelated,
GI/Skin/Liver Grade GvHD No. Infusions Treatment Plan
unmatched donor-derived BM aspirate after donor screening and testing according to
(stages) /Infusion
8 x 106; 2 x 106 2/wk for 4 wk; 1/wk 13 wk
FDA requirements. The cells are expanded in culture to permit up to 5,000 doses to
be obtained from a single donation. The hMSCs are tested for potential pathogens,
mycoplasma, sterility, endotoxins and potency. The cells are formulated in Plasmalyte
A containing 5% human serum albumin and 10% DMSO and aseptically packaged
Preparation. Cells were thawed and resuspended in Plasmalyte A. The final product
had a cell concentration of 2.5 x 106 MSC/mL and a DMSO concentration of 3.75%.
All products had a cell viability ≥70%. The volume administered was dependent upon
a 11 infusions were administered at 8 x 106 hMSC/kg and 10 infusions were administered at 2 x 106 hMSC/kgb Patient was discontinued at parents’ requestc Patient was continued on therapy to allow for removal of steroids
Use of Mesenchymal Stem Cells (Prochymal™) to Treat Pediatric Patients with Severe (Grade III-IV) acute Graft Versus Host Disease Refractory to Steroid and Other Agents
Vinod K. Prasad, MD, MRCP, Blood and Marrow Transplant Program, Dept. of Pediatrics, Duke University Medical Center, Durham, NC; Kenneth G. Lucas, MD, Pediatric Stem Cell Transplantation, PennState Children’s Hospital, Hershey, PA; Gary I. Kleiner, MD, PhD, Dept. of Pediatric Immunology, University of Miami, Miami, FL; Julie-An Talano, MD, Pediatric Hematology Oncology and BMT, MedicalCollege of Wisconsin, Milwaukee, WI; David Jacobsohn, MD, Stem Cell Transplant Program, Children’s Memorial Hospital, Chicago, IL; Paul Szabolcs, MD, Blood and Marrow Transplant Program, Dept. of Pediatrics, Duke University Medical Center, Durham, NC; Rod Monroy, PhD, Osiris Therapeutics, Inc., Columbia, MD; Joanne Kurtzberg, MD, Blood and Marrow Transplant Program, Dept. of Pediatrics,Duke University Medical Center, Durham, NC
Data was presented at the December 2007 American Society of Hematology meeting GvHD Response Survival and Response All patients responded to Prochymal therapy; 7 (58%) patients achieved a CR After Completion of Prior to Prochymal Treatment Prochymal Treatment Response GI/Skin/Liver GI/Skin/Liver (stages) (stages) Response by Organ System Current Status
• All patients tolerated treatment and there were no SAEs related to
Overall response
• 100 day survival (from initiation of Prochymal) is 58% (7/12)
Complete response
• By publication (median follow up 229 days), 7 patients had died• Patient survival and response status
Death post 1st infusion Response GI SKIN 2 pts increased LIVER 2 pts increased: stage 0 to 1
* Patient received a liver transplantation for severe hepatitis on day 19 after starting induction therapy. Use of Mesenchymal Stem Cells (Prochymal™) to Treat Pediatric Patients with Severe (Grade III-IV) acute Graft Versus Host Disease Refractory to Steroid and Other Agents
Vinod K. Prasad, MD, MRCP, Blood and Marrow Transplant Program, Dept. of Pediatrics, Duke University Medical Center, Durham, NC; Kenneth G. Lucas, MD, Pediatric Stem Cell Transplantation, PennState Children’s Hospital, Hershey, PA; Gary I. Kleiner, MD, PhD, Dept. of Pediatric Immunology, University of Miami, Miami, FL; Julie-An Talano, MD, Pediatric Hematology Oncology and BMT, MedicalCollege of Wisconsin, Milwaukee, WI; David Jacobsohn, MD, Stem Cell Transplant Program, Children’s Memorial Hospital, Chicago, IL; Paul Szabolcs, MD, Blood and Marrow Transplant Program, Dept. of Pediatrics, Duke University Medical Center, Durham, NC; Rod Monroy, PhD, Osiris Therapeutics, Inc., Columbia, MD; Joanne Kurtzberg, MD, Blood and Marrow Transplant Program, Dept. of Pediatrics,Duke University Medical Center, Durham, NC
Data was presented at the December 2007 American Society of Hematology meeting • All patients achieved a clinical response in at least one organ system after Prochymal infusions • 58% (7/12) of the patients achieved a complete response at the end of Prochymal therapy • Best responses were seen in patients with severe (stages 3/4) GI GvHD:
– 75% (9/12) achieved a complete resolution of GI symptoms
• 42% (5/12) of the patients are alive with a median follow up of 229 days • All surviving patients had achieved a complete response • The infusion of Prochymal was safe and well tolerated. No infusional toxicities were observed Conclusions • The administration of Prochymal to patients who had failed steroids and multiple other therapies for their severe acute GvHD resulted in significant clinical responses and survival • Prochymal represents a very promising new treatment option • Phase III placebo-controlled clinical trials are underway
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