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Shea T.C.,University of North Carolina at Chapel Hill | Walko C.,DeBartolo Family Personalized Medicine Institute | Chung Y.,University of North Carolina at Chapel Hill | Ivanova A.,University of North Carolina at Chapel Hill | And 9 more authors.
Biology of Blood and Marrow Transplantation | Year: 2015

Intensive chemotherapy or chemotherapy plus irradiation and allogeneic stem cell transplantation can be curative for patients with hematologic diseases. Reduced-intensity transplants can also achieve cure and result in less treatment-related mortality but higher relapse rates. Thus, optimizing the conditioning regimens used in allogeneic transplantation remains an important goal. We conducted a phase I/II trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a continuous infusion of busulfan over 90 hours in conjunction with fludarabine followed by allogeneic related or unrelated donor transplant. Fifty-four patients with advanced hematologic malignancies were enrolled on this study. The MTD was identified as a 24-hour area under the curve (AUC) of approximately 7095 μM/min, which represents a 43% increase over the standard total daily AUC dose of 4800 μM/min given by intermittent schedules. DLTs at doses over 8000 μM/min were identified by a desquamative skin rash and mucositis. No dose-related increase in hepatic, pulmonary, or other organ toxicities were seen, whereas efficacy appeared to be improved at higher dose levels. Continuous-infusion busulfan with intermittent fludarabine provides an alternative treatment strategy that is generally well tolerated and permits an increase in total busulfan dose with encouraging efficacy. (NCI study no. NCT00448357.). © 2015 American Society for Blood and Marrow Transplantation. Source


Richardson P.G.,Dana-Farber Cancer Institute | Riches M.L.,University of North Carolina at Chapel Hill | Kernan N.A.,Sloan Kettering Cancer Center | Brochstein J.A.,Cohen Childrens Medical Center | And 28 more authors.
Blood | Year: 2016

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS withmulti-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day 1100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8; P =.0109, using a propensityadjusted analysis). Observed day 1100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6; P =.0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8%and 9.4%])was similar between the defibrotide and control groups, respectively.Defibrotide was associated with significant improvement in day 1100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00358501. © 2016 by The American Society of Hematology. Source


Prasad V.K.,Duke University | Lucas K.G.,Pediatric Stem Cell Transplantation | Kleiner G.I.,University of Miami | Talano J.A.M.,Medical College of Wisconsin | And 4 more authors.
Biology of Blood and Marrow Transplantation | Year: 2011

Preliminary studies using directed-donor ex vivo expanded human mesenchymal stem cells (hMSCs) have shown promise in the treatment of acute graft-versus-host disease (aGVHD). However, their production is cumbersome and standardization is difficult. We describe the first experience of using a premanufactured, universal donor, formulation of hMSCs (Prochymal) in children (n = 12; 10 boys; 9 Caucasian; age range: 0.4-15 years) with treatment-resistant grade III and IV aGVHD who received therapy on compassionate use basis between July 2005 and June 2007 at 5 transplant centers. All patients had stage III or IV gut (GI) symptoms and half had additional liver and/or skin involvement. Disease was refractory to steroids in all cases and additionally to a median of 3 other immunosuppressive therapies. The hMSCs (8 × 106cells/kg/dose in 2 patients and 2 × 106cells/kg/dose in the rest) were infused intravenously over 1 hour twice a week for 4 weeks. Partial and mixed responders received subsequent weekly therapy for 4 weeks. HLA or other matching was not needed. The hMSCs were started at a median of 98 days (range: 45-237) posttransplant. A total of 124 doses were administered, with a median of 8 doses (range: 2-21) per patient. Overall, 7 (58%) patients had complete response, 2 (17%) partial response, and 3 (25%) mixed response. Complete resolution of GI symptoms occurred in 9 (75%) patients. Two patients relapsed after initial response and showed partial response to retreatment. The cumulative incidence of survival at 100 days from the initiation of Prochymal therapy was 58%. Five of 12 patients (42%) were still alive after a median follow-up of 611 days (range: 427-1111) in surviving patients. No infusional or other identifiable acute toxicity was seen in any patient. Multiple infusions of hMSCs were well tolerated and appeared to be safe in children. Clinical responses, particularly in the GI system, were seen in the majority of children with severe refractory aGVHD. Given the favorable results observed in a patient population with an otherwise grave prognosis, we conclude that hMSCs hold potential for the treatment of aGVHD, and should be further studied in phase III trials in pediatric and adult patients. © 2011 American Society for Blood and Marrow Transplantation. Source


News Article
Site: http://news.yahoo.com/science/

A gene-editing technology that made headlines recently for successfully treating a baby with leukemia may one day be used to treat other types of cancers, experts say. Layla Richard was just 14 weeks old when she was diagnosed with acute lymphoblastic leukemia (ALL), according to the Great Ormond Street Hospital in London, where she was treated. Though doctors had previously tried several treatments, nothing had worked. The hospital offered Layla's family the chance to try out an experimental treatment that had only been used in mice. The researchers took blood that had been donated, and separated out the white blood cells called T-cells, which normally help to fight infections in the body. Then, they edited the cells' genes, which gave the cells the ability to attack the cancer, and injected the cells into Layla. In the future, this same technique could be used to treat people with other blood cell cancers, such as chronic lymphocytic leukemia and myeloma, Dr. Waseem Qasim, one of the doctors at the hospital who worked on Layla's case, told Live Science. And although it will be more difficult to use the treatment for cancers that form solid tumors, researchers are looking at the possibility of using it to treat people with one such cancer, called neuroblastoma, which begins in the nerve cells, according to the American Cancer Society.  [5 Amazing Technologies That Are Revolutionizing Biotech] What made Layla's case special was the use of the designer T-cells, said Dr. Madan Jagasia, of the Outpatient Stem Cell Transplant Program at Vanderbilt-Ingram Cancer Center, who was not involved in treating Layla. The genetic technique that researchers used to treat Layla is nicknamed TALEN (which stands for transcription activator-like effector nuclease). It involves an enzyme that works like tiny scissors, and cuts genes. In Layla's case, the researchers cut specific sequences out of the DNA of the donated cells, and corrected broken genome sequences. This gene editing reprogrammed the cells to fight leukemia cells. It is still unclear how long the treatment will keep Layla's leukemia at bay. "We don't know if this translates into a cure," but the treatment put her in remission long enough for doctors to perform a bone marrow transplant, which can hold cancer at bay for a long time, Jagasia said. For Layla, the treatment itself took only about 10 minutes — the genetically edited cells were given through an IV line. But after the cells were delivered, she spent several months in isolation to stay protected from infection while her immune system was weak, according to a statement from the hospital. Once the genetically edited cells had finished their job of killing all of the leukemia cells, Layla received a bone marrow transplant to replace her entire immune system with healthy cells. Now recovering at home, Layla still returns for regular checkups so that doctors can look at her bone marrow cells and blood cell counts, according to the hospital. The doctors who treated Layla, along with investigators at University College London and biotech company Cellectis, had been working to refine these T-cells. The cells are collected from donors, edited and frozen in doses that can be thawed and provided on demand for patients who need T-cells. Jagasia said that the main advantage of having these "off-the-shelf" (i.e., ready-to-use) treatments is that less time is needed to administer the treatment to the patient. "It's really a game-changing technology, because you could have these T-cells sitting in a lab everywhere, and you wouldn't have to collect a patient's T-cells," Jagasia told Live Science. "It really changes the cancer therapy field completely." Though more research is needed, clinical trials funded by Cellectis are currently being planned to test the genetically edited T-cells in larger groups of adults and children who have blood cell cancers. The trials are set to begin in early 2016. Copyright 2015 LiveScience, a Purch company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

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