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Nash R.A.,Colorado Blood Cancer Institute | Hutton G.J.,Baylor College of Medicine | Racke M.K.,Ohio State University | Popat U.,University of Houston | And 18 more authors.
JAMA Neurology | Year: 2015

IMPORTANCE Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS.OBJECTIVE To evaluate the safety, efficacy, and durability ofMS disease stabilization through 3 years after HDIT/HCT.DESIGN, SETTING, AND PARTICIPANTS Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled.INTERVENTIONS Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT.MAIN OUTCOMES AND MEASURES The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events.RESULTS Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4%(90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9%(90% CI, 73.7%-97.1%) and 86.3%(90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores.CONCLUSIONS AND RELEVANCE At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events. Copyright © 2015 American Medical Association. All rights reserved.


Vij R.,University of Washington | Kumar S.,Mayo Medical School | Zhang M.-J.,Medical College of Wisconsin | Zhang M.-J.,Institute for Health and Society | And 17 more authors.
Biology of Blood and Marrow Transplantation | Year: 2015

Patients with multiple myeloma (MM) who are eligible for autologous stem cell transplantation (ASCT) typically receive a finite period of initial therapy before ASCT. It is not clear if patients with suboptimal (less than a partial) response to initial therapy benefit from additional alternative therapy with intent to maximize pretransplant response. We identified 539 patients with MM who had an ASCT after having achieved less than a partial response (PR) to first-line induction chemotherapy between 1995 and 2010. These patients were then divided into 2 groups: those who received additional salvage chemotherapy before ASCT (n=324) and those who had no additional salvage chemotherapy immediately before ASCT (n=215). Additional pretransplant chemotherapy resulted in deepening responses in 68% (complete response in 8% and PR in 60%). On multivariate analysis there was no impact of pretransplant salvage chemotherapy on treatment-related mortality, risk for relapse, progression-free survival, or overall survival. In conclusion, for patients achieving less than a PR to initial induction therapy, including with novel agent combinations, additional pre-ASCT salvage chemotherapy improved the depth of response and pre-ASCT disease status but was not associated with survival benefit. © 2015 American Society for Blood and Marrow Transplantation.


Sharma M.,Thomas Jefferson University | Zhang M.-J.,Medical College of Wisconsin | Zhong X.,Medical College of Wisconsin | Abidi M.H.,Barbara Ann Karmanos Cancer Institute | And 35 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014

Autologous hematopoietic cell transplantation (AHCT) for plasma cell myeloma is performed less often in people >70 years old than in people ≤70 years old. We analyzed 11,430 AHCT recipients for plasma cell myeloma prospectively reported to the Center for International Blood and Marrow Transplant Research between 2008 and 2011, representing the majority of US AHCT activity during this period. Survival (OS) was compared in 3 cohorts: ages 18 to 59 years (n= 5818), 60 to 69 years (n= 4666), and >70 years (n= 946). Median OS was not reached for any cohort. In multivariate analysis, increasing age was associated with mortality (P= .0006). Myeloma-specific mortality was similar among cohorts at 12%, indicating an age-related effect on nonmyeloma mortality. Analyses were performed in a representative subgroup comparing relapse rate, progression-free survival (PFS), and nonrelapse mortality (NRM). One-year NRM was 0% for age >70 years and 2% for other ages (P= not significant). The three-year relapse rate was 56% in age 18 to 59 years, 61% in age 60 to 69 years, and 63% age >70 (P= not significant). Three-year PFS was similar at 42% in age 18 to 59 years, 38% in age 60 to 69 years, and 33% in age >70 years (P= not significant). Postrelapse survival was significantly worse for the older cohort (P= .03). Older subjects selected for AHCT derived similar antimyeloma benefit without worse NRM, relapse rate, or PFS. © 2014 American Society for Blood and Marrow Transplantation.


PubMed | University of Minnesota, Blood and Marrow Transplant Program and Core Informatics
Type: Clinical Trial | Journal: Blood | Year: 2015

Historically, alternative donor hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) patients resulted in excessive morbidity and mortality. To improve outcomes, we made sequential changes to the HCT conditioning regimen. A total of 130 FA patients (median age, 9.0 years; range, 1-48) underwent alternative donor HCT at the University of Minnesota between 1995 and 2012. All patients received cyclophosphamide (CY), single fraction total body irradiation (TBI), and antithymocyte globulin (ATG) with or without fludarabine (FLU), followed by T-cell-depleted bone marrow or unmanipulated umbilical cord blood transplantation. The addition of FLU enhanced engraftment 3-fold. The incidence of grades 2-4 acute and chronic graft-versus-host disease was 20% and 10%, respectively. Severe toxicity was highest in patients >10 years of age or those with a history of opportunistic infections or transfusions before HCT. Mortality was lowest in patients without a history of opportunistic infection or transfusions and who received conditioning with TBI 300 cGy, CY, FLU, and ATG. These patients had a probability of survival of 94% at 5 years. Alternative donor HCT is now associated with excellent survival for patients without prior opportunistic infections or transfusions and should be considered for all FA patients after the onset of marrow failure. These studies were registered at http://www.clinicaltrials.gov as NCT00005898, NCT00167206, and NCT00352976.


News Article | February 15, 2017
Site: www.eurekalert.org

OTTAWA, ON - Wednesday, February 15, 2017, 10 a.m. ET - BioCanRx, and its partners, today announced funding for 16 collaborative research projects in novel therapies to cure cancer including research aimed at developing clinical Chimeric Antigen Receptor modified T cell (CAR-T) manufacturing capabilities in Canada. CAR-Ts are a powerful new tool for treating cancer and have begun to provide hope to patients without other therapeutic options to treat and cure their disease. CAR-T cell therapy is on the cutting edge of cancer therapeutics and has shown promise in paediatric and adult patients with certain blood cancers such as acute lymphoblastic leukemia and lymphoma. CAR-T is a promising technology, involving sophisticated manufacturing and expertise. Canada has the basic laboratory infrastructure in place and this new funding will help to fully develop the expertise and capacity required to deliver this technology. BioCanRx is investing in research projects advancing several innovative engineered T cell designs, which will further benefit from this infrastructure and capacity investment, and accelerate delivery of these novel concepts into clinical testing in Canada. This Canadian capacity development will pave the way to enable Canadian patients to access this new technology, and will give Canadian researchers the necessary resources to deliver on their innovations in CAR-T and other engineered T cell platforms. This CAR-T manufacturing initiative is unique in that the Canadian academic community recognized a gap and stepped up to drive Canadian solutions to meet grassroots efforts taking place in the U.S., China and Europe. BioCanRx has established an extensive network of investigators and core facilities across the country and is well positioned to bring CAR-T cell treatment to patients in Canada who are in dire need. Leading this capacity building for CAR-T therapies in Canada are Dr. Robert Holt, distinguished scientist, BC Cancer Agency, Head of Sequencing and Head of Quality Systems, Canada's Michael Smith Genome Sciences Centre, Professor, Medical Genetics, University of British Columbia and Professor, Molecular Biology and Biochemistry, Simon Fraser University; Dr. John Bell, Sr. Scientist, Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Professor, Departments of Medicine and Biochemistry, Microbiology & Immunology, University of Ottawa and Scientific Director, BioCanRx; John Webb, Scientist and Project Leader, BC Cancer Agency Deeley Research Centre and Adjunct Associate Professor, University of Victoria; Brad Nelson, Director, Deeley Research Centre, BC Cancer Agency among other researchers. To help ensure CAR-T cell therapy is brought to patients safely and effectively, BioCanRx is funding a companion Clinical, Social, and Economic Impact project. It will review the existing base of knowledge and involve patient consultation to design a rigorous CAR-T clinical trial protocol ready to implement once the products are ready for a phase 1 clinical trial. Leading this project are Dr. Manoj Lalu, Associate Scientist, Assistant Professor, Clinical Epidemiology and Regenerative Medicine Programs, Ottawa Hospital Research Institute (OHRI), Department of Anesthesiology and Pain Medicine, University of Ottawa; Dr. Dean Fergusson, Director and Senior Scientist, Clinical Epidemiology Program, OHRI; Dr. Natasha Kekre, Assistant Professor, Associate Scientist, Hematologist, Blood and Marrow Transplant Program, OHRI, The Ottawa Hospital, University of Ottawa among other researchers. Cancer is the leading cause of death in Canada and is responsible for 30% of all deaths. Two out of five Canadians (45% of men and 42% of women) are expected to develop cancer during their lifetimes. One out of four Canadians (29% of men and 24% of women) is expected to die from cancer. (Canadian Cancer Society) Biotherapeutics - including oncolytic viruses, adoptive cell therapy and therapeutic antibodies - are among the most promising cancer therapies to emerge in the last decade and are often referred to as a fourth pillar for cancer treatment. BioCanRx is building a research portfolio of these immunotherapies but what sets it apart is its commitment to combination therapies. Combining biotherapeutics approaches can amplify effectiveness and result in significantly better outcomes compared to the benefits of an individual biotherapy used on its own. Today's funding announcement will support 16 national research teams comprised of researchers, clinicians and trainees working to find improved treatment options and outcomes for cancer patients. BioCanRx's funded partnerships will strengthen the coordination of research and resources in Canada to further develop a variety of cancer immunotherapy platforms. The research proposed could lead to significantly better outcomes for cancer patients and, potentially, curative approaches to their cancer. "CAR-T technology is a new and exciting development that's really taken the world by storm. We know now that by taking T cells out of patients, and reengineering them as it were in a test tube, we can get them to have dramatic responses in some kinds of cancer patients. Unfortunately, in Canada, we don't have this technology available to us to be used widely across the country. So this funding will allow us to be in a position to manufacture this kind of product ourselves, get our own scientists engaged in being able to actually test their ideas, exploiting this new technology and, we hope, to bring something to the Canadian people much faster than it would be otherwise." "BioCanRx is committed to investing in collaborative research projects aimed at improving the health and lives of thousands of Canadians currently living with cancer. Collaboration is critical to ensuring better use of study results and providing a measurable difference. We are confident that this research will address existing gaps in moving this platform forward." "The impact cancer is having on our population is devastating. While we have made enormous progress in treating cancer, much more needs to be understood about better ways to fight this disease and ultimately cure those afflicted. BioCanRx is committed to supporting research excellence and its translation into health benefits for Canadians. We hope to one day announce that there has been a significant reduction in deaths related to cancer thanks to research support by our network and partners. "My congratulations to the sixteen national teams receiving funding through BioCanRx's research program. By advancing the field of immunotherapies, your work will ultimately be able to support innovative and promising new cancer treatments for Canadians." "Canadian scientists are world-renowned for their research into how the body's immune system can be used to treat cancer. This emerging field of medical research has the potential to save lives as well as improve them. It also creates better jobs and opportunities for Canadians working in the life-sciences sector. The funding being allocated to Canadian research teams through BioCanRx will allow this promising research to move beyond laboratories and into clinics, where it can actually make a difference in people's lives. That's how innovation makes a better Canada." The Honourable Navdeep Bains Canada's Minister of Innovation, Science and Economic Development "The use of CAR-T cells represents a significant and very recent advancement in cancer treatment and has become a powerful tool for converting incurable into curable. Unfortunately, the use of this therapy in Canada has been limited by our access to the product, forcing cancer patients to travel far and wide, usually outside Canada, to access this therapy in US clinical trials. A home grown Canadian solution is long overdue - BioCanRx has taken a bold step in ensuring this innovative new therapy is available for Canadians in Canada." Patrick Sullivan Childhood cancer advocate, President, Team Finn Foundation and founding member of Ac2orn (Advocacy for Canadian Oncology Research Network) The BioCanRx network is accelerating to the clinic Canada's most promising and innovative cancer biotherapeutics designed to save lives and enable a better quality of life. BioCanRx invests in Canadian innovations and the best the field has to offer, always looking for a clear path to the clinic for the benefit of patients. BioCanRx works in partnership with industry, charities and other agencies to translate immune-based technologies from the lab into early phase clinical trials, and addresses socio-economic considerations necessary for their adoption by health-care systems. The network is developing and attracting the talent needed for a thriving health biotechnology sector in Canada. BioCanRx is provided funding from the federal government's Networks of Centres of Excellence, and support from industry, the provinces and many national charities.


Miller J.S.,Blood and Marrow Transplant Program | Rooney C.M.,Baylor College of Medicine | Curtsinger J.,Blood and Marrow Transplant Program | McElmurry R.,University of Minnesota | And 7 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014

Natural killer (NK) cell efficacy correlates with invivo proliferation, and we hypothesize that NK cell product manipulations may optimize this endpoint. Xenotransplantation was used to compare good manufacturing practice (GMP) grade freshly activated NK cells (FA-NK) and exvivo expanded NK cells (Ex-NK). Cells were infused into NOD scid IL2 receptor gamma chain knockout (NSG) mice followed by IL-2, IL-15, or no cytokines. Evaluation of blood, spleen, and marrow showed that persistence and expansion was cytokine dependent, IL-15 being superior to IL-2. Cryopreservation and immediate infusion resulted in less cytotoxicity and fewer NK cells invivo, and this could be rescued in FA-NK by overnight culture and testing the next day. Marked differences in the kinetics and homing of FA-NK versus Ex-NK were apparent: FA-NK cells preferentially homed to spleen and persisted longer after cytokine withdrawal. These data suggest that cryopreservation of FA-NK and Ex-NK is detrimental and that culture conditions profoundly affect homing, persistence, and expansion of NK cells invivo. The NSG mouse model is an adjuvant to invitro assays before clinical testing. © 2014 American Society for Blood and Marrow Transplantation.


Solh M.,Northside Hospital | Morgan S.,University of Minnesota | McCullough J.,University of Minnesota | Shanley R.,Blood and Marrow Transplant Program | Weisdorf D.J.,Oncology and Transplantation
Transfusion | Year: 2016

BACKGROUND Transfusion of blood products is an essential component of the hematopoietic cell transplantation (HCT) process. Blood transfusion carries several risks including, but not limited to, lung injury. The effect of transfusions on lung complications after HCT has not been previously investigated. STUDY DESIGN AND METHODS We retrospectively studied 215 adult allogeneic HCT recipients at the University of Minnesota and examined the association between transfusion of blood components and development of lung complications after HCT. Patients without lung complications were used as the control group. RESULTS A total of 113 (58%) of the patients developed lung injury events before Day 180 after HCT. Six-month survival was significantly lower in the lung event group (52%) versus the controls (78%; p = 0.01). Patients who eventually developed lung events received more transfusion episodes per week in the first month after HCT (median, 4.3 vs. 2.7 for controls), platelet units per week (3.5 vs. 2.0), and RBC units per week (1.8 vs. 1.4; p < 0.01) for all. In a multivariable analysis, each additional transfusion before Day +30 was associated with a 2.7% higher risk of lung complication (95% confidence interval, 0.8-4.8; p = 0.01), adjusting for time to engraftment, conditioning intensity, and donor type. Blood utilization increased after the lung event and remained high for several months relative to controls. CONCLUSION Our data suggest that transfusion of blood products is associated with and may further complicate lung complications after HCT. Cautious use of blood components in the post HCT period is recommended. © 2015 AABB.


PubMed | University of Minnesota, The Blood and Marrow Transplant Group of Georgia, Blood and Marrow Transplant Program. and Oncology and Transplantation.
Type: Journal Article | Journal: Transfusion | Year: 2016

Transfusion of blood products is an essential component of the hematopoietic cell transplantation (HCT) process. Blood transfusion carries several risks including, but not limited to, lung injury. The effect of transfusions on lung complications after HCT has not been previously investigated.We retrospectively studied 215 adult allogeneic HCT recipients at the University of Minnesota and examined the association between transfusion of blood components and development of lung complications after HCT. Patients without lung complications were used as the control group.A total of 113 (58%) of the patients developed lung injury events before Day 180 after HCT. Six-month survival was significantly lower in the lung event group (52%) versus the controls (78%; p = 0.01). Patients who eventually developed lung events received more transfusion episodes per week in the first month after HCT (median, 4.3 vs. 2.7 for controls), platelet units per week (3.5 vs. 2.0), and RBC units per week (1.8 vs. 1.4; p < 0.01) for all. In a multivariable analysis, each additional transfusion before Day +30 was associated with a 2.7% higher risk of lung complication (95% confidence interval, 0.8-4.8; p = 0.01), adjusting for time to engraftment, conditioning intensity, and donor type. Blood utilization increased after the lung event and remained high for several months relative to controls.Our data suggest that transfusion of blood products is associated with and may further complicate lung complications after HCT. Cautious use of blood components in the post HCT period is recommended.


PubMed | Blood and Marrow Transplant Program. and Transfusion Medicine Service.
Type: Journal Article | Journal: Transfusion | Year: 2016

We examined the appropriateness of prophylactic peridischarge platelet (PLT) transfusions and the feasibility of lowering the prophylactic PLT transfusion threshold in transplant recipients within 24 hours of discharge at a National Cancer Institute-designated comprehensive cancer center.From April 2011 to June 2014, each prophylactic PLT transfusion that was administered to transplant recipients within 24 hours of discharge was identified. Each transfusion was reviewed to identify the indication and to determine if the transfusion adhered to institutional guidelines.Of the 187 transplant patients identified, 44 patients received a prophylactic PLT transfusion within 24 hours of discharge. Of these 44 patients, transfusions were administered to fulfill a PLT count of 20 10(9) /L required for discharge (n=25 patients), for the removal of a tunneled central venous catheter (n=16 patients), for active bleeding (n=1 patient), or due to active anticoagulation (n=2 patients).The majority of PLT transfusions (95%) were appropriate, and only 5% were avoidable. If the prophylactic PLT transfusion threshold was decreased to 15 10(9) /L from 20 10(9) /L for central line removal and to fulfill discharge PLT count criteria, 41% of the currently appropriate PLT transfusions could have been avoided. These results suggest that a risk-adapted method to select autologous transplant recipients for prophylactic PLT transfusions may be beneficial. A future study is needed to address this issue.

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