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stem cell transplantation

Shelly Carter

Joanne Kurtzberg

To evaluate if HLA-mismatched, unrelated-donor umbilical cord blood stem and progenitor cell units (UCBU) offered a clinically acceptable alternative to matched unrelated-donor allogeneic bone marrow for transplantation with 180-day disease free survival as the endpoint. HLA typing was performed using DNA-base high resolution methods to determine HLA alleles. Patients with "true" HLA 3/6 and 4/6 matches were evaluated. In addition, a separate study in adults addressed the problem of limited cell dose and engraftment failure. The study was not planned as a randomized comparative clinical trial. Instead, it is a phase II/III efficacy study.

BACKGROUND:

Bone marrow transplantation is an effective therapy for a variety of genetic and hematologic disorders. Donated bone marrow, which provides a source of stem and progenitor cells for bone marrow reconstitution, is obtained either from related donors, usually HLA-matched siblings, or from HLA-matched unrelated donors. Because of the limited availability of HLA-matched related donors, HLA-matched unrelated donors are frequently the only alternative source of bone marrow for transplantation. To provide matched volunteer bone marrow donors for unrelated recipients, the National Marrow Donor Program (NMDP) was established in 1986 to develop a national Registry of HLA-typed individuals who agree to donate bone marrow if needed. More than 3 million potential marrow donors are now enrolled. A limitation of the registry approach is the time needed to identify a donor and complete the necessary clinical evaluation and laboratory testing for histocompatibility, infectious diseases, and general good health. Moreover, a certain proportion of potential donors change their minds or otherwise become unavailable between the time they enter the Registry and the time they are called as a preliminary match for a patient. Another disadvantage is the marrow harvesting procedure which requires the normal donor to be hospitalized and given general anesthesia in an operating room. Finally, the NMDP Registry consists of potential donors that are primarily of European Caucasian ancestry. Although great strides have been made in increasing the numbers of African-Americans, Hispanics, Asian-Americans, and Native Americans, it is still more difficult to find matches for these ethnic minorities than for Caucasian patients.

Human umbilical cord blood is an alternative source of hematopoietic stem and progenitor cells capable of reconstituting the bone marrow of recipients with a variety of diseases. Cord blood stem and progenitor cells from related donors have been successfully transplanted world-wide in children with genetic or hematologic diseases. These results suggested that cord blood from unrelated, HLA-matched donors also can be used for patients who need a transplant but don't have a related donor. The existing problems in unrelated-donor bone marrow transplantation with donor recruitment, bone marrow harvesting, and matching for antigens peculiar to a particular ethnic group would be reduced if typed, tested, and frozen umbilical cord blood could be made easily and rapidly available. Such a system, which could complement or partially replace the present process, has been shown to be feasible. In an NHLBI-sponsored program, investigators have collected and cryopreserved a bank of about 9,000 human UCBUs. In addition, successful searches and matches (including many 4/6 antigen matches) have resulted in more than 900 unrelated-donor, UCBU transplants to date. Preliminary data from both these unrelated-donor and other related-donor cord blood transplants suggest that there is less GvHD than if the source of the graft were adult bone marrow. The severity of GvHD also seems less even in highly mismatched recipients. One important question is whether or not 3/6 HLA matched transplants in children will have acceptable 180-day disease free survival. It also remains to be determined if the graft-vs-leukemia effect is also less or if unrelated-donor cord blood grafts are as durable as those from matched, related-donors. Most transplants conducted thus far have been in children. Hence another important question is whether or not there are sufficient numbers of stem cells in cord blood to support transplantation to an unrelated adult.

The initiative was proposed by the Division of Blood Diseases and Resources staff and approved by the February 1995 National Heart, Lung, and Blood Advisory Council. The Requests for Proposals were released in June 1995. Contracts were awarded September 30, 1997.

DESIGN NARRATIVE:

The study is multicenter, with six Cord Blood Transplant Centers (CBTCs), two collecting and storage centers (Cord Blood Banks -- CBBs) and one Coordinating Center. Each CBB used the same protocol for recruiting donors, collecting, processing, testing, storage, retrieval from storage, reprocessing from the frozen state, and shipping. Each participating CBTC used the same patient selection criteria, preparative regimen for patients in the same class, initial graft-versus-host disease (GvHD) prophylaxis, indications for the use of cytokines, definitions for events and complications, and methods for evaluating immune reconstitution. The main study evaluated the impact of HLA 3/6 and 4/6 matching on outcome. The primary endpoint was 180-day disease free survival after UCBU transplantation. Secondary endpoints included engraftment, the frequency and severity of acute and chronic GvHD with stratification by degree of HLA match, overall survival, and immunologic reconstitution. Data were collected on banked UCBUs to define unit quality by nucleated cell count and flow cytometry of surface markers to identify effects on patient outcome. Recruitment ended December 31, 2003 with the accrual of 326 subjects. .

Cord Blood Stem Cell Transplantation Study (COBLT)

National Heart, Lung, and Blood Institute (NHLBI)

Skin and Connective Tissue Diseases

Hematologic Neoplasms

Mucopolysaccharidoses

Mucopolysaccharidosis I

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

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Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

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Metabolism, Inborn Errors

Carbohydrate Metabolism, Inborn Errors

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Mucinoses

Connective Tissue Diseases

Mucopolysaccharidosis

Mucopolysaccharidosis Type I

Neuroepithelioma

All Drugs and Chemicals

Vaccines

Immunologic Factors

Venipuncture

Stephen Gottschalk, MD

This protocol (GENEFU) provides a mechanism for the 15-year followup period that the FDA requires for all participants in gene transfer protocols and assures that adequate followup can be maintained for a wide variety of participants on different individual gene therapy protocols at St. Jude Children's Research Hospital.

GENEFU serves as an umbrella protocol for long-term follow-up (LTFU) for recipients of gene therapy/gene marked (GT/GM) products at St. Jude Children's Research Hospital. The FDA has recommended methods to assess the risk of delayed adverse events after GT/GM and has provided specific requirements regarding the duration and design of LTFU observations. This protocol is intended to provide LTFU in accordance with the FDA guidelines for those who received a GT/GM product as part of a St. Jude-sponsored clinical trial or compassionate use treatment plan. The protocol calls for a physical examination or general health evaluation and collection of required blood samples annually for up to 15 years after the last receipt of a GT/GM product.

Goals will be to obtain clinical histories in order to detect late clinical outcomes suggestive of retroviral or lentiviral disease, including but not limited to cancer/second malignancies, neurologic disorders, autoimmune disorders, and hematologic disorders. Blood samples will be archived and tested when clinically or scientifically indicated, as in the event of development of a second malignancy. This prospective cohort study will utilize descriptive statistics in the analysis of long-term late effects outcomes. It offers a uniform approach to long-term safety monitoring in research participants who have received a gene-transduced product as part of St. Jude-sponsored GT or GM protocols and compassionate use treatment plans.

Secondary objectives include the following: to obtain and archive blood samples to 1) detect frequency of vector marking in peripheral blood mononuclear cells when clinically or scientifically indicated, such as in the event of participant development of second malignancy, autoimmune disease, hematologic abnormality, or neurologic event, and; 2) To obtain and archive blood samples to detect and characterize clonal proliferation events occurring in gene transfer trials when clinically or scientifically indicated.

Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products

Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products at St. Jude Children's Research Hospital

Obtain histories for detection of significant delayed medical events including hematologic, malignant, autoimmune, and neurologic events in research participants who have received an integrating vector-based gene therapy/gene marked product at St. Jude Children's Research Hospital (SJCRH).

St. Jude Children's Research Hospital

Hemoglobinopathies

Aplastic Anemia

Acute Graft Versus Host Disease

The intervention consists of an adapted physical activity (APA) program defined at baseline, incorporating supervised sessions with an APA teacher, as well as autonomous sessions. The program is individualized according to age, aerobic capacity, and PA preferences.

The total duration of the intervention is a maximum of 3 months (during the period of hospitalization in a sterile room).

Supervised sessions of at least 15 minutes 4 times a Week combined with unsupervised sessions.

The supervised activities include moderate-intensity aerobic activities (exercise bike), muscle strengthening (dumbbells, elastic bands, medicine balls) and playful situations (ball games, cooperative games, body expression games).

Each patient can also do unsupervised sessions, autonomously, on the bike thanks to a smartphone application developed by the Kiplin company, with challenges to be carried out by teams of 2 to 5 people (team including several patients, possibility to include relatives) over periods of 1 to 3 weeks per challenge.

Physical activity program

Carine HALFON-DOMENECH, MD

To date, allogeneic haematopoietic stem cell transplantation (aHSCT) is the only curative treatment for many paediatric and young adult haematological pathologies (acute leukaemia, myelodysplastic syndromes, haemoglobinopathies, bone marrow aplasia, severe combined immunodeficiency). Despite the major therapeutic progress made over the last 50 years, particularly in terms of supportive care, post-transplant morbidity and mortality remains high. Infectious complications, whose incidence varies between 30 and 60%, are the first cause of mortality in the immediate post-transplant period.

In order to protect the patient from the occurrence of severe infectious episodes, aHSCTmust be performed in a highly protected environment (positive pressure chambers).

This has implications for the experience and impact of hospitalization on the patient and family. This is particularly true in paediatrics, whether in children, adolescents or young adults, where it is not only the patient's quality of life that is at stake, but also their emotional and psychomotor development. In these patients, prolonged hospitalization (at least 6 weeks) in a sterile room will be responsible for physical deconditioning accompanied by a decrease in muscle mass, itself concomitant with undernutrition, and an increase in sedentary lifestyle. This prolonged hospitalisation in a sterile room, associated with myeloablative treatments, is therefore the cause of social isolation of patients, but it is also often synonymous with physical inactivity leading to a rapid decrease in physical condition, quality of life and an increase in fatigue.

Today, the benefits of physical activity (PA) during and after cancer treatment have been widely demonstrated.

The objective is to evaluate the feasibility of an adapted physical activity program during the isolation phase for achieving aHSCT in children, adolescents and young adults. This is a prospective, interventional, monocentric cohort study conducted at the Institute of Paediatric Haematology and Oncology in Lyon. The intervention will take place during the isolation phase and consists of an adapted physical activity (APA) program defined at inclusion, integrating supervised sessions with an APA teacher, as well as autonomous sessions. The program is individualized according to age, aerobic capacity, and PA preferences. Sessions are also tailored to the biological, psychological, and social parameters of patients.

The total duration of the intervention is 3 months. To date, no PA studies have been performed in patients under 21 years of age requiring aGCSH during the sterile isolation phase. EVAADE will therefore be the first study in this population to offer an innovative procedure with a connected device.

A Study to Assess a Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Allografts

A Feasibility Study to Assess Connected Bikes as a Means of Adapted Physical Activity in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Allografts

achieved/non-achieved (achived meaning the patient attended at least one session of 15 minutes weekly during the whole program

Centre Leon Berard

The intervention will take place during the whole isolation phase and will consist of an APA program defined at inclusion, integrating supervised sessions with an APA teacher, as well as unsupervised sessions. The program will be individualized according to the patient's age, physical condition and PA preferences. The sessions will also be adapted to the biological, psychological and social parameters of the patients.

The intervention will be carried out during the entire hospitalization period and for a maximum of 3 months. An connected bike will be installed in the patient's room for the duration of the hospitalization.

The supervised sessions will be offered 4 times a week in the participants' rooms by the APA teachers and will include moderate intensity aerobic activities (exercise bike), muscle strengthening (dumbbells, elastic bands, medicine balls) and playful situations (ball games, cooperative games, body expression games).

Each patient will also be able to perform unsupervised sessions (on their own), following the advice given by the APA teacher. These unsupervised sessions can be done independently on the bike.

In order to encourage patients to perform these unsupervised sessions, patients and their relatives will be given a connected device and will have access to a mobile application developed by the Kiplin company, which offers connected physical activity games to be performed in teams (from 2 to 4 participants). These games, lasting from 1 to 3 weeks, use the participants' daily PA level as a unit of animation and are punctuated by challenges.

Rodolf MONGONDRY, MSc

Olivia PEROL, MSc

Cécile RENARD, MD

Allogeneic haematopoietic stem cell transplantation (aHSCT) is the only curative treatment for many paediatric and young adult haematological pathologies (acute leukaemia, myelodysplastic syndromes haemoglobinopathies, bone narrow aplasia, severe combined immunodeficiency). Despite the major therapeutic progress made over the last 50 years, particularly in terms of supportive care, post-transplant morbidity and mortality remain high. Infectious complications, whose incidence varies between 30 and 60%, are the first cause of mortality in the immediate post-transplant period.

In order to protect the patient from the occurence of severe infectious episodes, aHSCT must be performed in a highly protected environment (positive pressure chambers).

This has consequences for the experience and impact of hospitalization on the patient and family. This is particularly true in pediatrics, with children, adolescents or young adults, where it is not only the patient's quality of life that is at stake, but also his emotional and psychomotor development. In this specific population, prolonged hospitalization (at least 6 weeks) in a sterile room will be responsible for physical deconditioning accompanied by a decrease in muscle mass. Patients often experience an deteriorated quality of life.

Today, the benefits of physical activity (PA) during and after cancer treatment have been widely demonstrated.

The objective of the study is to assess the feasibility of an adapted physical activity program during the isolation phase for achieving aHSCT in children, adolescents and young adults. This is a prospective, interventional, monocentric cohort study conducted at the institute of Paediatric Haematology and Oncology in Lyon. The intervention will take place during the isolation phase and will be based on an adapted physical activity (APA) program defined at inclusion, integrating supervised sessions with an APA teacher, as well as autonomous sessions performed by means of a connected bike in the sterile room. The program will be individualized according to age, aerobic capacities, and PA preferences. Sessions will also be tailored to the biological, psychological, and social parameters of patients.

The total duration of the intervention is 3 months. To date, no PA studies have been performed in patients under 21 years old requiring aHSCT during the sterile isolation phase. EVAADE will therefore be the first study in this population to offer an innovative procedure with a connected device.

Feasibility Study to Assess an Adapted Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Transplantation

A Feasibility Study Evaluating Connected Bikes as a Means of Adapted Physical Activity in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Transplantation

achieved/non achieved (achieved meaning the patient attended at least one session of 15 minutes weekly during the whole program, considering both supervised and unsupervised sessions)

Rate of unsupervised sessions/total of performed sessions

PA practice of patient / PA practice of relatives

Number of enrolled patients/number of eligible patients

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cord Blood Stem Cell Transplantation Study (COBLT)	NCT00000603	Anemia, Aplasti... Fanconi Anemia Hematologic Dis... Leukemia Neoplasms Severe Combined... Hematopoietic S... Myelodysplastic...	stem cell trans...	- 55 Years	National Heart, Lung, and Blood Institute (NHLBI)
Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products	NCT00695279	Severe Combined... Malignancy, Hem... Neuroblastoma Neoplasm Mucopolysacchar...	Venipuncture	-	St. Jude Children's Research Hospital
A Study to Assess a Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Allografts	NCT04331483	Haematological ... Acute Leukemia Myelodysplastic... Hemoglobinopath... Bone Marrow Apl... Severe Combined...	Physical activi...	8 Years - 21 Years	Centre Leon Berard
A Study to Assess a Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Allografts	NCT04331483	Haematological ... Acute Leukemia Myelodysplastic... Hemoglobinopath... Bone Marrow Apl... Severe Combined...	Physical activi...	8 Years - 21 Years	Centre Leon Berard
Feasibility Study to Assess an Adapted Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Transplantation	NCT05298930	Haematological ... Acute Leukemia Myelodysplastic... Hemoglobinopath... Bone Marrow Apl... Severe Combined...	Physical activi...	8 Years - 21 Years	Centre Leon Berard
Cord Blood Stem Cell Transplantation Study (COBLT)	NCT00000603	Anemia, Aplasti... Fanconi Anemia Hematologic Dis... Leukemia Neoplasms Severe Combined... Hematopoietic S... Myelodysplastic...	stem cell trans...	- 55 Years	National Heart, Lung, and Blood Institute (NHLBI)

Spots Global Cancer Trial Database for severe combined immunodeficiency