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Advances in pediatric blood and marrow transplantation (BMT) are slowed by the small number of patients with a given disease transplanted, a lack of sufficient infrastructure to run early phase oncology protocols and studies of rare non-malignant disorders, and challenges associated with funding multi-institutional trials. Leadership of the Pediatric Blood and Marrow Transplant Consortium (PBMTC), a large pediatric BMT clinical trials network representing 77 active and 45 affiliated centers worldwide, met in April 2009 to develop strategic plans to address these issues. Key barriers including infrastructure development and funding, along with scientific initiatives in malignant and non-malignant disorders, cellular therapeutics, graft versus host disease, and supportive care were discussed. The PBMTC agenda for approaching these issues will result in infrastructure and trials specific to pediatrics that will run through the PBMTC or its partners, the Blood and Marrow Transplant Clinical Trials Network and the Children’s Oncology Group.
The field of pediatric blood and marrow transplantation (BMT) has long been challenged by the fact that pediatric transplants are undertaken for a diverse group of relatively rare disorders. Accepted BMT indications in the pediatric population include 8 different hematopoietic malignancies, themselves uncommon, and at least another 20 even less common non-malignant diseases. Because the largest pediatric blood and marrow transplant centers only perform between 50–100 transplants yearly, even high-volume centers do only a handful of transplants per year for any specific indication. There has been increasing recognition that meaningful clinical research requires collaborative, multi-institutional studies with a large number of relatively small centers.
Over the past few years, efforts between three large, cooperative groups in North America and Australia, the Children’s Oncology Group (COG), the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) and the Pediatric Blood and Marrow Transplant Consortium (PBMTC), have resulted in the planning and implementation of a series of multi-center pediatric transplant trials (see table 1). The COG conducts cancer-related BMT trials in children and the BMT CTN conducts adult and pediatric multi-center trials addressing all aspects of the transplant experience. Both focus on large phase II and III trials. The BMT CTN is committed to the development of selected larger trials in malignant and non-malignant pediatric conditions and currently has a phase II trial evaluating transplantation in children with sickle cell disease, but its commitment to larger trials means that ideas requiring small pilot studies are generally not considered in its scientific agenda. Pilot data are necessary to consider planning larger trials and these data are lacking for many issues related to pediatric BMT, including transplant strategies for both malignant and non-malignant disorders.
The PBMTC is comprised of 77 full-member pediatric centers in North America, Australia, and New Zealand, and is the largest clinical trials group focused exclusively on blood and marrow transplantation in children and adolescents. The PBMTC works closely with both COG and the BMT CTN. Most PBMTC centers participate in COG trials and many PBMTC investigators are involved in COG HSCT Committee leadership and COG study development. This facilitates transition of successful PBMTC pilot trials focused on cancer into larger COG trials. The BMT CTN consists of 16 core centers, 13 of which are large transplant centers with both adult and pediatric programs, two of which are small consortia, and the remaining core center is the PBMTC. As mentioned, pediatric transplant indications are rare, and the inclusion of the PBMTC as a core center of the BMT CTN gives the opportunity of participation in BMT CTN studies to more than 60 additional pediatric centers, who are not part of other core centers. This is important, as successful pediatric HSCT trials often require at least 30–40 centers due to the rarity of the diseases transplanted. As a core center, the PBMTC chair is on the BMT CTN steering committee, and PBMTC leadership participate in BMT CTN committees and leadership. In addition, PBMTC members can propose trials for consideration by the BMT CTN steering committee.
As alluded to above, the PBMTC has assumed a role in developing novel, early-phase trials that can provide necessary preliminary data for larger COG and BMT CTN trials. The PBMTC is the only large cooperative group committed to studying many rare conditions in which phase III trials are not possible. BMT for these orphan diseases can only be advanced by smaller studies performed by a large group, such as the PBMTC. As an approach to develop both pilot studies and to develop broadly-based trials addressing rare orphan diseases treated by BMT, the PBMTC has developed the needed infrastructure with a grant from the St. Baldrick’s Foundation, a charitable organization dedicated to fighting childhood cancer. A formal collaboration agreement was established in 2009 between the PBMTC and the clinical trial arm of the CIBMTR, the Resource for Clinical Investigations in Blood and Marrow Transplantation (RCI-BMT). This collaboration included development of a high-quality, GCP-compliant clinical trials infrastructure that utilizes the data and trials management resources and expertise of the CIBMTR.
Both the PBMTC and the CIBMTR perform studies involving centers in countries throughout the world. The PBMTC operations center is part of the National Children’s Cancer Foundation (NCCF, the charitable arm and financial operations center of COG). This organization performs contracts with COG affiliated centers throughout the world, and this expertise is utilized by the PBMTC. The long-standing membership in PBMTC of transplant groups from Canada, Australia, and New Zealand has resulted in established methods for institutional ethics board review, and data quality assurance. The NMDP/CIBMTR has established contractual relationships with PBMTC centers inside and outside the United States, simplifying data transfer arrangements. Trials proposed by members are developed and prioritized through a subcommittee structure (see below). Developed protocols undergo review through the PBMTC Scientific Review Committee, with a non-binding review of the Scientific Advisory Committee of the RCI-BMT. Final study approval occurs through vote of the PBMTC Executive Committee, a body elected by PBMTC members. Studies are funded by the St. Baldrick’s foundation, individual governmental and non-governmental research grants, and industry sponsorship.
In April 2009, A PBMTC strategic planning meeting was held in Vancouver, Canada, that included senior PBMTC and COG transplant leadership and chairs and vice-chairs of PBMTC subcommittees in 1) non-malignant disorders, 2) oncologic disorders, 3) stem cell sources/cellular therapeutics, 4) graft versus host disease (GVHD), and 5) supportive care. In addition, representatives from the RCI BMT, the National Heart, Lung, and Blood Institute (NHLBI), the National Cancer Institute (NCI), the National Institute of Allergy and Infectious Diseases (NIAID), and the St. Baldrick’s Foundation participated in the discussions, each group sharing its research agenda. The meeting focused on defining knowledge gaps and study opportunities in the five broad strategy group areas mentioned above. The meeting concluded by developing research priorities along with strategies for infrastructure development and funding for pediatric BMT. Priorities in the five areas addressed by PBMTC subcommittees are outlined below.
Nonmalignant diseases treated by blood and marrow transplantation represent a wide array of diverse disorders comprising approximately 35% of pediatric patients undergoing BMT among PBMTC member institutions. Recognizing that each of these disorders is rare, PBMTC investigators seek to develop feasible national protocols, using the accrual power of the consortium, to address the most pressing clinical questions that may enhance our current treatment of children with these disorders. While some disorders engender unique issues most effectively addressed by disease-specific protocols, others share common challenges allowing for multi-disease protocols. The PBMTC has developed collaborations with established diseases-specific networks when possible and initiated trials to fill unmet needs. There are five major categories of non-malignant disorders treatable by BMT: 1) hemoglobinopathies, 2) immune deficiency and dysregulation disorders, 3) metabolic storage diseases, 4) bone marrow failure syndromes, and 5) a group of individually unique disorders such as the leukodystrophies and osteopetrosis. Novel indications for blood and marrow transplantation such as autoimmune illness and the use of other cellular therapeutic approaches to treat these and other diseases are also part of the non-malignant disorders group.
What are the pressing clinical challenges in BMT of non-malignant disorders? First, while matched sibling transplantation using myeloablative approaches is well established for many non-malignant disorders, transplant related mortality (TRM) and morbidity associated with GVHD remains high with unrelated donor (URD) BMT.1,2 Reduced intensity regimens hold promise of decreasing TRM in these disorders, but graft rejection has limited wide-spread application of this approach.3 PBMTC investigators have developed a novel reduced intensity approach which has been adopted by the BMT CTN as an unrelated donor transplantation protocol for sickle cell anemia (BMT CTN 0601, Tables 1,,22).4 In addition, the PBMTC has launched a similar trial for thalassemia in cooperation with the Thalassemia Clinical Trials Network (TCRN-PBMTC NMD091). PBMTC investigators are collaborating with the BMT CTN to develop a trial of a novel reduced intensity transplant regimen to treat the immune regulation disorder hemophagocytic lymphohistiocytosis (HLH). Continued efforts to develop regimens that ensure engraftment in non-malignant disorders while limiting TRM and GVHD will remain top priority over the next several years.
A second major clinical challenge in non-malignant BMT is found in the lack of understanding of outcomes and consensus of approach to BMT for immunodeficiency disorders, especially severe combined immune deficiency (SCID).5 In the past, most of the transplants for these disorders occurred at a limited number of large centers. Now, however, a large number of smaller centers are performing BMT for these children. Because of the ability to engraft T-cells with minimal preparation in many of these children, approaches vary dramatically, from simple infusions of T-cell depleted maternal haplo-identical grafts without a preparatory regimen, to myeloablative approaches for all patients.6 The PBMTC is working cooperatively as a participant in the Primary Immune Deficiency Treatment Consortium (PIDTC), which has been recently awarded an NIAID/Office of Rare Diseases (ORD) U54 grant to study survival and immunological outcomes, both retrospectively and prospectively, in these patients. PBMTC investigators feel that a key initiative in the coming years will be to design therapeutic trials based upon data gathered by the PIDTC with a primary aim to establish both T- and B-cell immune competence using both related and URD stem cell sources.
A PBMTC protocol team is working with the Hunter’s Hope Foundation and a U54 funded team from the Lysosomal Disease Network (LDN) to develop 1) an initiative aimed at standardizing evaluation of the neurocognitive outcomes of children who have previously undergone BMT and 2) a prospective therapeutic transplant study for selected metabolic disorders. A key opportunity with BMT for metabolic storage diseases is that several states will be performing newborn screening for these diseases.7 Identification of younger, high risk children with some of these diseases may allow BMT at an earlier time point, limiting neurological damage and possibly improving outcomes. Questions regarding the impact of genotype/phenotype analysis of specific mutations will assist in identifying individuals with severe or milder phenotypes, guiding the use of BMT vs. enzyme replacement strategies.
Finally, while umbilical cord blood (UCB) transplantation is done routinely for many malignant and non-malignant disorders, high rates of rejection and TRM have limited the use of this stem cell source for BMT of children with severe aplastic anemia who have failed immune suppressive therapies.8 Recent data generated by PBMTC investigators has formed the basis for an initiative currently underway to develop an innovative reduced intensity approach to allow use of UCB in this population.9 BMT has been most effective in this group to date only when fully HLA-matched URD are available (approximately 30–40% of the time). Because UCB BMT can succeed with less stringent HLA-matching, improving UCB outcomes in SAA could allow more than 90% of children with this disorder who fail immune suppression a chance at curative therapy.
In summary, PBMTC initiatives to improve outcomes after BMT for nonmalignant disorders include targeted efforts to 1) establish long-term engraftment of unrelated donor sources using safer reduced intensity approaches, 2) ensure T- and B-cell engraftment and functional immunity after BMT in SCID patients, 3) standardize assessment of and learn more about neurological outcomes after transplant of selected metabolic storage diseases to establish the timing and appropriateness of BMT, and 4) establish approaches that result in high rates of engraftment and survival using umbilical cord blood for patients with SAA who have failed immune suppressive therapy (Table 2).
Approximately 65–70% of blood and marrow transplants in children are performed for high-risk malignancies. Myeloablative approaches to BMT deliver maximal treatment intensity and allogeneic BMT approaches deliver immunotherapy through a graft vs. malignancy effect. In spite of this intense approach, relapse remains the major cause of death in children undergoing BMT for malignancy. With that in mind, the major focus of PBMTC Oncology Strategy Group is prevention of relapse. Understanding the mechanisms of relapse after BMT is critical for designing more effective and selective BMT therapy. Relapse after BMT implies the existence of mechanisms of chemoresistance, radioresistance and immunoresistance. The presence of detectable minimal residual disease (MRD) at the time of the pre-transplant workup is associated with an increased risk of relapse.10,11 Possible mechanisms to explain this observation include a threshold effect, with an unfavorable effector: target ratio; a dose phenomenon that alters the immunologic response; active induction of tolerance by malignant cells; suppression of immune responses by malignant cells; lack of immunogenicity in malignant cells; loss of target antigens by malignant cells; exhaustion of effector clones; or inadequate T cell function against malignant clones.
Two strategies to reduce the risk of relapse after allogeneic BMT are 1) give agents that increase cancer cell susceptibility to immune approaches (i.e. induction of apoptosis) or 2) increase the effectiveness of the BMT in treating the malignant clone. One way of affecting cancer cell susceptibility is to give mTOR inhibitors such as sirolimus, which induce apoptosis. Sirolimus has both anti-tumor and immunosuppressive properties, and is currently being studied in a phase III COG/PBMTC study ASCT0431/PBMTC ONC051, with a hypothesis that its anti-leukemic and pro-apoptotic effect will decrease relapse post transplant for children with ALL.12 Targeted therapies with side effect profiles compatible with post-transplant administration such as tyrosine kinase inhibitors (TKIs, i.e. imatinib mesylate) may take MRD below an immunologic threshold post transplant, reducing relapse. In addition, TKIs have been shown to have a number of immunologic effects, working synergistically with donor lymphocyte infusions.13 Top priority of the oncology strategy group will be further testing of targeted agents and immunotherapeutic strategies (see Cellular Therapeutics) that will prevent relapse in the very high risk patients who undergo allogeneic and autologous BMT. In addition, while the role of BMT as active immunotherapy is well established in hematologic malignancies, the role of alloimmunity to treat chemorefractory pediatric solid tumors is being explored. Efforts to improve efficacy of BMT or immunotherapeutic approaches to refractory solid tumors deserve continued attention.
Finally, an important issue after BMT of growing, developing children is the challenge of late-effects, including infertility, endocrine issues, and second malignancies. The PBMTC has made significant contributions to defining the role of reduced intensity transplantation in pediatric hematologic malignancies.12 Continued efforts to define novel approaches to reduce toxicity and decrease late effects, while preserving anti-cancer efficacy, will continue to be a priority.
In summary, future efforts to improve outcomes after BMT for malignant disorders should focus on prevention of relapse through 1) manipulation or enhancement of alloimmunity after transplant, 2) use of peri-transplant cellular or immunotherapy, and 3) use relevant molecularly targeted therapies that can be given peri-transplant. In addition, further exploration of the appropriate role of reduced intensity approaches for pediatric malignancies is warranted.
An ideal stem cell source provides early myeloid and lymphoid engraftment without excessive graft-versus-host disease (GVHD). To achieve this goal, the PBMTC conducted a pilot trial using granulocyte colony stimulating factor (GCSF) primed bone marrow for children undergoing transplant from related donors.14 Graft content of G-CSF primed marrow included high doses of CD34+ cells with low CD3+ doses compared to PBSC, resulting in rapid engraftment and low rates of chronic GVHD. The study provided preliminary data for an ongoing, jointly developed (PBMTC/COG) phase 3 trial running through the Children’s Oncology Group (ASCT0631, Table 1). An important question in alternative donor sources is the effect of the use of one or two cord blood units on transplant outcomes. PBMTC is participating BMT CTN 0501, a study of single versus double cord blood transplant in pediatric malignancies, testing whether or not a second cord leads to less relapse due to added immunogenicity. These studies will add to a large body of work over the past decade that has defined high-quality stem cell sources for the large majority of patients requiring BMT.
To improve outcomes using these stem cell sources further, the next generation of studies in this area will involve manipulation cells within a graft to improve engraftment, decrease GVHD, or enhance anti-malignancy effect. Though all forms of BMT are cellular therapy, our use of the term includes manipulations and enhancement of grafts or generation of cellular products from non-graft sources. There are two broad approaches to performing cellular therapy in the context of BMT.15 One method involves using autologous cells that have been manipulated to better target the patient’s cancer and strengthen the patient’s immune response. Patient’s tumor has escaped their body’s immune surveillance, and overcoming this immunologic resistance can be challenging, however, autologous cells can live longer, continuing immune surveillance if appropriately stimulated, and thus they have a smaller chance of untoward reactions such as GVHD. A second approach involves using allogeneic cells, which have the capacity for more potent anti-tumor activity. Modified allogeneic cells can be used prior to a transplant to increase the depth of a remission or as part of the BMT or post transplant to decrease the risk of relapse or GVHD. While immunoresitance is the primary challenge in the application of autologous cells, alloimmune-mediated morbidity (i.e. GVHD, organ damage) will remain a challenge with the use of allogeneic approaches.
PBMTC centers are pursuing a variety of immunologic and cellular therapeutic approaches to decrease relapse. The infusion of antigen-specific T cells for children with cancer is appealing as cellular immunotherapy offers an approach to treating malignancies that may avoid the long-term toxicities associated with conventional cytotoxic chemotherapy and radiation therapy. Current studies of reconstituting or augmenting cellular immunity through the infusion of T cells are limited to single center or small group studies because of a number of barriers.16
The major challenges in pursuing adoptive cellular therapies in children are the current lack of significant funding for such trials and the daunting regulatory burden associated with conceiving and executing such therapies in a multi-center setting. The PBMTC cellular therapy strategy group is committed to evaluating cellular therapies in a multi-center setting. The most pressing initial challenge is establishing regulatory infrastructure within the PBMTC necessary to conduct and monitor such multi-center trials. The feasibility and safety of shipping cells between centers and incorporating such therapies with current therapies must be studied and issues regarding limiting indemnification of the sponsoring institution must be resolved. We believe that important advances in curing high-risk malignant diseases will involve directed adoptive cellular therapies.
In summary, PBMTC efforts in cellular therapy will start with testing promising approaches in a limited center setting, and once feasibility is established, we will expand promising cellular approaches into larger multi-center studies.
Young children differ in their rates of development of and ability to recover from GVHD, likely because of thymic activity in the first decades of life. Drug metabolism differences and challenges of administering some GVHD therapies to younger children add to the complexity. Only studies that take these distinct differences in young children into account will define optimal GVHD therapy for this group.17
GVHD still represents the major complication of allogeneic BMT. Approaches to improve treatment have focused on biomarkers that can predict development of GVHD or a better understanding of which therapies work best. The PBMTC has assessed both mechanisms and biomarkers associated with the development of GVHD and tested novel therapies for acute and chronic GVHD. Approaches that have augmented treatment to all patients diagnosed with acute GVHD can lead to over-treatment of some patients and worse outcomes due to increase in relapse and infectious mortality.18 Therefore, identification of patients at high risk of developing acute GVHD could lead to individualized treatment approaches based on risk for GVHD. The PBMTC conducted a study of cytokine gene polymorphisms in 185 children undergoing 6/6 matched unrelated donor transplants at 28 institutions. A significant relationship was observed between TNF-alpha genotypes and haplotype and risk of acute GVHD.19 We are currently evaluating the relationship between other gene polymorphisms and post-transplant outcomes. A major goal of the PBMTC in the next few years will be to prospectively validate multiple biomarkers (e.g proteomic, RNA-based studies of genetic alterations prior to GVHD) in the pediatric SCT setting. These results, combined with our cytokine polymorphism study outcomes, will result in identification of patients who are at high risk for GVHD and therefore may benefit from augmented immunosuppression.
The PBMTC recently completed accrual of 51 children from 24 institutions onto a phase II study in which safety and efficacy of pentostatin in refractory chronic GVHD were evaluated. The drug was well-tolerated and overall response was 53%.20 A small group of PBMTC centers will conduct a limited-institution phase I study to determine toxicity of the CellEx photopheresis machine in children with refractory chronic GVHD. This study will explore the feasibility of apheresis for ECP in very young children using newer generation machines better able to serve “small volume” young children.
In summary, future GVHD studies should focus on validating biomarkers and performing trials of specific agents and approaches that allow us to understand and respond to the unique therapeutic needs and immunological and physiological differences of young children.
Supportive care practices comprise a panoply of medical interventions that improve the outcome of BMT. Over the past two decades, improvements in supportive care have been a key component of the significant decrease in TRM that has occurred in both autologous and allogeneic BMT. Of note, although outcomes have improved, centers vary widely in supportive care practices such as anti-bacterial prophylaxis or treatment, anti-fungal prophylaxis and treatment, viral monitoring, nutritional support, menstrual suppression, and others. Well-designed trials may help to standardize and improve supportive care practices. Two examples from the PBMTC supportive care group include a phase III study demonstrating the utility of oral glutamine for prevention of mucositis21 and a recently completed phase I trial of palifermin in children.
There are two areas in supportive care we consider to be high priority in children. First, the use of total body irradiation (TBI) in very young children has generated considerable debate. There is concern about long-term neurocognitive and neuroendocrine sequelae of TBI when irradiating children less than two or three years of age. PBMTC data since 2000 reflects marked variation in practice by center: 46% of reported patients with ALL under the age of 2 years received TBI, with remaining institutions using a variety of other approaches. There is a paucity of information on this subject as few studies have targeted this population. Sanders et al showed that in 15 infants who received 13.2–15.75 cGy TBI the mean Full Scale Intelligent Quotient was 104 ± 14 at a median time of 4.4 years of age.22 Phipps et al (3), however, described declining IQ scores at 1 and 3 years post-transplant in children transplanted at less than three years of age,23 though there were not enough patients in this age group to discern whether TBI had a greater impact than non-TBI regimens. In addition, these findings were questioned in a subsequent report by the same group.24 Because TBI-based regimens offer a survival benefit for older recipients with high-risk ALL,25 it is important know the developmental implications of this therapy on infants. PBMTC will seek funding to address this issue by studying very young patients in the PBMTC database who were transplanted with and without TBI, comparing their neurocognitive and functional outcomes. This study will be also able to address the neurocognitive implications of other transplant preparative agents, such as busulfan, very commonly used in this population and also noted to have long-term implications in pediatric transplant survivors.26
Another area of interest especially concerning in pediatrics is the treatment of opportunistic viral pathogens. The frequent use of cord blood (relatively T-cell depleted product with slower immune recovery), transplantation of children with inherited immune deficiencies (often starting BMT with active viral infections), and transplantation of infants (immature immune systems) lead to unique infectious complications that warrant specific study. While cytomegalovirus (CMV) has been widely investigated, approaches to very young children with infections due to other pathogens such as adenovirus, BK virus, and HHV-6, require further study. Reports have demonstrated a mortality of 50% (27%–65%) from invasive adenovirus post- allogeneic BMT.27,28 More recently, reports have shown improved outcomes using strategies that combine close monitoring for adenovirus with either pre-emptive or therapeutic cidofovir.29,30 The use of cidofovir, however, is limited by nephrotocixity, leaving patients with no other proven therapeutic options. New compounds, such as CMX001, a lipid-ester derivative of cidofovir, may be able to be studied in the near future.31 Understanding the significance of BK and HHV-6 detection and infection, as well as the risks and benefits of therapy of these infections also require further study. The PBMTC, in partnership with industry and viral study groups, is committed to developing approaches to better understand and treat these infections in the pediatric BMT setting.
In summary, PBMTC efforts in supportive care studies will focus on 1) understanding the developmental impact of total body irradiation and other types of intense preparative regimens in infants and younger children, and 2) understanding and treating unusual viral infections relatively common in pediatric BMT, including adenovirus, BK virus, and HHV-6.
Advancement in several key areas of pediatric BMT will be strengthened by the newly-formed partnership between the PBMTC and the CIBMTR/NMDP (RCI-BMT). This partnership will facilitate accomplishment of important pediatric BMT priorities (summarized in table 3). Close working relationships between the BMT CTN, COG and the PBMTC have been established, and are vital in developing early phase trials and then transitioning them to large phase II and III trials. Cooperation with disease specific groups such as the Thalassemia Clinical Trials Network, the Primary Immune Deficiency Treatment Consortium, and the Lysosomal Disease Network further facilitate trial development. Finally, however, only through recognition of the unique aspects of pediatric BMT and commitment by both governmental and non-governmental agencies to fund trials, will the field move forward.
This work is supported by a generous grant from the St. Baldrick’s Foundation. Further support is provided by award number U01HL069254 from the National Heart, Lung, and Blood Institute and the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the St. Baldrick’s Foundation, the National Heart, Lung, and Blood Institute, the National Cancer Institute, or the National Institutes of Health.
Alberta Children’s Hospital (Calgary AB, Canada)
All Children’s Hospital (St. Petersburg, FL)
The Floating Hospital for Children at Tufts Medical Center
British Columbia Children’s Hospital (Vancouver, British Columbia, Canada)
CancerCare Manitoba (Winnipeg, Manitoba, Canada)
Children’s Healthcare of Atlanta at Egleston (Atlanta, GA)
Seattle Children’s/Fred Hutchinson Cancer Center (Seattle Washington)
Children’s Hospital Oakland (Oakland, CA)
Children’s Hospital of Los Angeles (Los Angeles, CA)
Children’s Hospital of Michigan (Detroit, MI)
Children’s Hospital of Orange County (Orange, CA)
Children’s Hospital of Philadelphia (Philadelphia, PA)
Children’s Hospital of Pittsburgh (Pittsburgh, PA)
Children’s Memorial Medical Center at Chicago (Chicago, IL)
Children’s National Medical Center (Washington, DC)
Children’s of New Orleans/LSUMC (New Orleans, LA)
Cincinnati Children’s Hospital Medical Center (Cincinnati, OH)
Cook Children’s Hematology & Oncology Center (Fort Worth, TX)
Dana-Farber Cancer Institute (Boston, MA)
Doernbecher Children’s Hospital/Oregon Health & Sciences University (Portland, OR)
Duke University Medical Center (Durham, NC)
Hackensack University Medical Center (Hackensack, NJ)
CHU Sainte-Justine (Montreal, Quebec, Canada)
Johns Hopkins Hospital (Baltimore, MD)
Kosair Children’s Hospital (Louisville, KY)
Levine Children’s Hospital (Charlotte, NC)
Loma Linda University Medical Center (Redlands, CA)
Mayo Clinic (Rochester, MN)
MD Anderson Cancer Center (Houston, TX)
Medical University of South Carolina (Charleston, SC)
Methodist Children’s Hospital of South Texas (San Antonio, TX)
Miami Children’s Hospital (Miami, FL)
Midwest Children’s Cancer Center/Medical College of Wisconsin (Milwaukee, WI)
Mount Sinai School of Medicine (New York, NY)
Nationwide Children’s Hospital (Columbus, OH)
Nemours Children’s Clinic-Jacksonville (Jacksonville, FL)
New York Medical College (Valhalla, NY)
New York University Medical Center (New York, NY)
Penn State University - Milton S. Hershey Medical Center (Hershey, PA)
Phoenix Children’s Hospital (Phoenix, AZ)
Rady Children’s Hospital San Diego (San Diego, CA)
Rainbow Babies & Children’s Hospital/Case Western Reserve Univ (Cleveland, OH)
Riley Hospital for Children-Indiana University (Indianapolis, IN)
Roswell Park Cancer Institute (Buffalo, NY)
Schneider Children’s Hospital (New Hyde Park, NY)
St. Jude Children’s Research Hospital (Memphis, TN)
Stanford University School of Medicine (Stanford, CA)
Texas Children’s Cancer Center at Baylor College of Medicine (Houston, TX)
The Children’s Hospital of Denver (Denver, CO)
The Children’s Mercy Hospital (Kansas City, MO)
The Hospital for Sick Children (Toronto, Ontario, Canada)
The Morgan Stanley Children’s Hospital of New York - Presbyterian (New York, NY)
The University of Chicago Comer Children’s Hospital (Chicago, IL)
UCLA Medical Center/Mattel Children’s Hospital (Los Angeles, CA)
UCSF School of Medicine (San Francisco, CA)
University of Alabama at Birmingham (Birmingham, AL)
University of Arizona Health Sciences Center (Tucson, AZ)
University of California-Davis School of Medicine (Sacramento, CA)
University of Florida (Gainesville, FL)
University of Iowa Hospitals & Clinics (Iowa City, IA)
University of Miami Jackson Memorial Hospital (Miami, FL)
University of Michigan Health System/C.S. Mott Children’s Hospital (Ann Arbor, MI)
University of Minnesota Cancer Center (Minneapolis, MN)
University of Mississippi Medical Center (Jackson, MS)
University of Nebraska Medical Center (Omaha, NE)
University of North Carolina at Chapel Hill (Chapel Hill, NC)
University of Oklahoma Health Sciences Center (Oklahoma City, OK)
University of Rochester Medical Center (Rochester, NY)
University of Utah Med Ctr/Primary Children’s Medical Center (Salt Lake City, UT)
University of Wisconsin Children’s Hospital (Madison, WI)
UT Southwestern Medical Center/Children’s Medical Center (Dallas, TX)
Vanderbilt University Medical Center (Nashville, TN)
Virginia Common Wealth University Health System (Richmond, VA)
Washington University-St. Louis Children’s Hospital (St. Louis, MO)
Princess Margaret Hospital for Children (Perth, Western Australia)
Royal Children’s Hospital, Brisbane (Brisbane, Queensland, Australia)
Starship Children’s Hospital (Auckland, New Zealand)
The Children’s Hospital at Westmead (Westmead, New South Wales, Australia)
Cancer Institute of New Jersey (New Brunswick, NJ)
Cardinal Glennon Children’s Medical Center-Saint Louis University (St. Louis, MO)
Children’s Hospital of Central California (Madera, CA)
Children’s Hospital Medical Center of Akron (Akron, OH)
Children’s Hospital of Montefiore (Bronx, NY)
Children’s Hospitals and Clinics of Minnesota (Minneapolis, MN)
DeVos Children’s Hospital (Grand Rapids, MI)
Florida Hospital Cancer Institute (Orlando, FL)
Maine Children’s Cancer Program (Scarborough, ME)
McGill Univ Health Ctr - Montreal Children’s Hospital (Montreal, Quebec, Canada)
Medical College of Georgia (Augusta, GA)
National Cancer Institute (Bethesda, MD)
St. Christopher’s Hospital for Children (Philadelphia, PA)
Stollery Children’s Hospital (Edmonton, Alberta, Canada)
Tulane University/Tulane University Hospital & Clinic (New Orleans, LA)
U of Hawaii/Kapiolani Med Ctr for Women & Children (Honolulu, HI)
University of Arkansas for Medical Sciences (Little Rock, AR)
University of Kentucky Markey Cancer Ctr/A.B Chandler Med Ctr (Lexington, KY)
Yale University School of Medicine (New Haven, CT)
Colombian Childhood Cancer Parents Organization (Bogota, DC, Colombia)
Hospital de Clinicas de Porto Alegre (Porto Alegre, RS, Brazil)
Instituto de Oncologia Pediatrica (Sao Paulo, Brazil)
Ramathibodi Hospital (Bangkok, Thailand)
Royal Children’s Hospital, Univ of Melbourne (Parkville, Victoria, Australia)
Sydney Children’s Hospital (Sydney, New South Wales, Australia)
University Hospital Brno (Brno, Czech Republic)
Women & Children’s Hospital, Adelaide (North Adelaide, South Australia)
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