Browsing by Author "Prasad, Vinod"

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    A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease.
    (Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020-05) Kurtzberg, Joanne; Abdel-Azim, Hisham; Carpenter, Paul; Chaudhury, Sonali; Horn, Biljana; Mahadeo, Kris; Nemecek, Eneida; Neudorf, Steven; Prasad, Vinod; Prockop, Susan; Quigg, Troy; Satwani, Prakash; Cheng, Annie; Burke, Elizabeth; Hayes, Jack; Skerrett, Donna; MSB-GVHD001/002 Study Group
    Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well tolerated, and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single-arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies for aGVHD treated with MSC product (remestemcel-L) dosed at 2 × 106 cells/kg twice weekly for 4 weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared with the prespecified control OR value of 45% (70.4% versus 45%, P = .0003). The statistically significant OR (70.4%) was sustained through day 100, including an increase in complete response from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days, and survival was significantly greater in day 28 responders compared with nonresponders through day 100 (86.8% versus 47.1% for responders and nonresponders, respectively, P = .0001) and through day 180 (78.9% versus 43.8%, P = .003). Remestemcel-L was well tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability, and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.
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    Effect of HLA-matching recipients to donor noninherited maternal antigens on outcomes after mismatched umbilical cord blood transplantation for hematologic malignancy.
    (Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2012-12) Rocha, Vanderson; Spellman, Stephen; Zhang, Mei-Jie; Ruggeri, Annalisa; Purtill, Duncan; Brady, Colleen; Baxter-Lowe, Lee Ann; Baudoux, Etienne; Bergamaschi, Paola; Chow, Robert; Freed, Brian; Koegler, Gesine; Kurtzberg, Joanne; Larghero, Jerome; Lecchi, Lucilla; Nagler, Arnon; Navarrette, Cristina; Prasad, Vinod; Pouthier, Fabienne; Price, Thomas; Ratanatharathorn, Voravit; van Rood, Jon J; Horowitz, Mary M; Gluckman, Eliane; Eapen, Mary; Eurocord-European Blood and Marrow Transplant Group and the Center for International Blood and Marrow Transplant Research
    Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces T regulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non-NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation-conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA-matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P = .05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P = .04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT.
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    Expanded Access Protocol of Umbilical Cord Blood Infusion for Children with Neurological Conditions: An Update.
    (Stem cells translational medicine, 2021-09) McLaughlin, Colleen; West, Tara; Hollowell, Rachel; Skergan, Natalie; Giguere, Paige; Vinesett, Richard; Arbuckle, Erin; Cash, Jayne; Hoyle, Kerry; Crane, Sydney; Moore, Lettie; Waters-Pick, Barbara; Hawkins, Tiffany; Prasad, Vinod; Sun, Jessica; Kurtzberg, Joanne
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    Late Effects after Umbilical Cord Blood Transplantation in Very Young Children after Busulfan-Based, Myeloablative Conditioning.
    (Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2016-09) Allewelt, Heather; El-Khorazaty, Jill; Mendizabal, Adam; Taskindoust, Mahsa; Martin, Paul L; Prasad, Vinod; Page, Kristin; Sanders, Jean; Kurtzberg, Joanne
    Infants and young children who undergo allogeneic cord blood transplantation (CBT) are at increased risk for late effects because of exposure of developing organs to chemotherapy and radiation therapy typically used in transplant conditioning regimens. Busulfan (Bu)-based myeloablative regimens were developed to eliminate radiation exposure in these young children with the hope that late effects would be minimized. We now describe the late effects in 102 consecutive patients surviving a minimum of 5 years (median follow-up, 12.9 years) post-CBT. Patients were conditioned with high-dose chemotherapy using Bu-containing regimens. No patient received total body irradiation. The median age at transplant was 1 year (range, .1 to 2). Diagnoses included inherited metabolic diseases (59.8%), leukemia (17.6%), congenital immune deficiency (20.2%), bone marrow failure/myelodysplastic syndrome (3.9%), and hemoglobinopathy (2%). Among patients surviving 5 years, the overall survival rate at 10 years post-CBT was 93% (95% CI, 84.9 to 96.8). Virtually all patients (98%) experienced at least 1 significant late effect. Most (83.3%) experienced 2 or more late effects, and more than half of the patients (64.7%) experienced 3 or more late effects. The most commonly observed late effects included dental problems (92.2%), short stature (55.9%), cognitive deficits (53.6%), pulmonary dysfunction (18.6%), and abnormal pubertal development (27.9%). This is the first report of late effects of Bu-based conditioning in a cohort of very young patients at the time of transplant. These results will inform clinical care guidelines for long-term follow-up and add to the growing information regarding outcomes of hematopoietic stem cell transplantation.
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    Study 275: Updated Expanded Access Program for Remestemcel-L in Steroid-Refractory Acute Graft-versus-Host Disease in Children.
    (Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2020-05) Kurtzberg, Joanne; Prockop, Susan; Chaudhury, Sonali; Horn, Biljana; Nemecek, Eneida; Prasad, Vinod; Satwani, Prakash; Teira, Pierre; Hayes, Jack; Burke, Elizabeth; MSB-275 Study Group
    Clinical outcomes in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD) are generally poor, with a high mortality rate and limited therapeutic options. Here we report our updated investigational experience with mesenchymal stromal cell (MSC) therapy with remestemcel-L in a multicenter expanded access protocol (ClinicalTrials.gov identifier NCT00759018) in 241 children with aGVHD who failed to respond to steroids with or without other secondary and tertiary immunosuppressive therapies. A total of 241 children with grade B-D SR-aGVHD were enrolled at 50 sites in 8 countries and received 8 biweekly i.v. infusions of human MSCs, 2 × 106 per kg for 4 weeks, with an option for an additional 4 weekly infusions after day +28 for subjects who achieved either a partial response (PR) or mixed response. The mean age of the subjects was 9.6 years; 39% were female, and 60% were white. Most of the subjects had grade C (30%) or grade D (50%) disease, and in most cases, the subjects had failed to respond to other immunosuppressive agents after failing steroids. The primary endpoint was overall response (OR; the sum of complete response [CR] and PR) at day +28. Across all subjects, a 28-day OR was observed in 157 patients (65.1%), with 34 (14.1%) achieving CR and 123 (51.3%) achieving PR. Stratified by aGVHD grade at baseline, the OR rate at day +28 was 72.9% for patients with aGVHD grade B, 67.1% for those with aGVHD grade C, and 60.8% for those with aGVHD grade D. Survival through day +100, a secondary endpoint of the study, was 66.9% (n = 160 of 239). Importantly, survival through day +100 was significantly greater in subjects who achieved a day +28 OR compared with nonresponders (82.1% versus 38.6%; P < .001, log-rank test). Remestemcel-L safety was generally well tolerated, with no infusional toxicity and no identified safety concerns. In summary, this update to the remestemcel-L expanded access program confirms the reported clinical and survival benefits of remestemcel-L therapy in children with aGVHD who have exhausted all conventional therapeutic options.
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    Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation.
    (Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2019-03) Raymond, Gerald V; Aubourg, Patrick; Paker, Asif; Escolar, Maria; Fischer, Alain; Blanche, Stephane; Baruchel, André; Dalle, Jean-Hugues; Michel, Gérard; Prasad, Vinod; Miller, Weston; Paadre, Susan; Balser, John; Kurtzberg, Joanne; Nascene, David R; Orchard, Paul J; Lund, Troy
    Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P = .01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE+) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE+ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE+ status is a strong predictor of disease progression in untreated patients.‎ This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.
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    Use of Letermovir for Salvage Therapy for Resistant Cytomegalovirus in a Pediatric Hematopoietic Stem Cell Transplant Recipient.
    (Journal of the Pediatric Infectious Diseases Society, 2019-07-31) Kilgore, Jacob T; Becken, Bradford; Varga, Matthew G; Parikh, Suhag; Prasad, Vinod; Lugo, Debra; Chang, Yeh-Chung
    We present here the first published use of letermovir for the treatment of resistant cytomegalovirus (CMV) in a pediatric patient. A 14-year-old girl underwent a double unrelated umbilical cord blood transplantation to treat her sickle cell disease (hemoglobin SS) and developed ganciclovir-resistant CMV DNAemia with end-organ involvement that was treated successfully with a combination of foscarnet and letermovir. After she was transitioned to letermovir monotherapy for secondary prophylaxis, she developed recurrent DNAemia with laboratory-confirmed ganciclovir, foscarnet, and letermovir resistance.