Shwachman-Diamond Syndrome

The study uses reduced intensity conditioning that is immune suppressive to achieve donor cell engraftment without exposure to radiation or high dose chemotherapy in children with non-malignant disorders. The intent is to minimize early and late regimen related toxicities in the context of a reduced intensity regimen. In addition to maximizing opportunity for donor cell engraftment, the trial seeks to minimize toxicities associated with transplant such as graft versus host disease and employs GVHD prophylaxis that seeks to decrease rates of acute and chronic GVHD in the setting of matched and mismatched donor stem cell transplants from marrow and cord blood sources.

Study Description: This is a natural history study involving questionnaires, clinical and research evaluations, clinical and research laboratory tests, review of medical records, cancer surveillance. A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders. Pathogenic variant(s) in IBMFS genes are relevant to carcinogenesis in sporadic cancers. This study will determine whether patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer. These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer. Carriers of IBMFS gene pathogenic variant(s) are at increased risk of cancer. The prototype disorder is Fanconi Anemia (FA); other IBMFS will also be studied. Objectives: To determine the types and incidence of specific cancers in patients with an IBMFS. To investigate the relevance of IBMFS gene pathogenic variants in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers. To identify risk factors for IBMFS-related cancers in addition to the primary germline pathogenic variant(s). To determine the risk of cancer in IBMFS carriers. Endpoints: Primary Endpoint: -All cancers, solid tumors, and cancers specific to each type of IBMFS. Secondary Endpints: -Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones.

Hematopoietic stem cell transplantation (HSCT) from a healthy donor can cure or alleviate a broad spectrum of non-malignant disorders (NMD). Although reduced-intensity conditioning (RIC) regimens promise decreased treatment-related morbidity and mortality, graft failure and infections are limiting the use of RIC in chemotherapy-naive patients. Dr. Szabolcs have completed several trials to evaluate a novel RIC regimen of alemtuzumab, hydroxyurea, fludarabine, melphalan, and thiotepa. The last trial at UPMC Children's Hospital of Pittsburgh of a highly effective and biologically rational chemotherapy-based RIC regimen paired with simple alemtuzumab dosing strata was tested and resulted in outstanding survival and remarkably low rates of graft failure. The favorable outcome described may serve as a toxicity and efficacy reference for emerging gene therapy strategies as well. This prospective collection of clinical data will allow the investigators to further assess engraftment, GVHD, immunosuppressant use and overall survival in this patient population.

IBMFS-RD are a heterogeneous group of rare diseases resulting in significant morbidity and early mortality. These syndromes are individually and collectively rare (affecting \<1 per 10,000 people) and a significant proportion are unexplained by mutations in known genes. Whilst rare, these familial conditions are also likely underdiagnosed due to their relatively recent description and also due to lack of accessible genomic testing. For patients with clinically suspected IBMFS-RD, receiving a genomic diagnosis is critical to: * Establish a precise and reliable diagnosis (including distinguishing a monogenic aetiology from more common acquired or autoimmune causes of bone marrow failure which have dramatically different treatments (e.g. immunosuppression) * Inform prognosis, clinical course, optimal treatment choice and screening for non-haematological organ dysfunction * Optimise allogeneic haematopoietic stem cell transplant (HSCT) chemotherapy conditioning and minimise regimen-related toxicity * Inform risk-benefit analysis of performing allogeneic HSCT to potentially prioritise other therapies (including novel gene therapy strategies) * Avoiding the catastrophe of HSCT donation from occult genetically affected relatives * Provide counselling (including stem cell donor counselling) and offer genetic testing for potentially affected family members * Provide accurate reproductive counselling and reproductive options to affected individuals This study aims to provide WGS and WTS to a national cohort of patients with IBMFS-RD to determine diagnostic rate, health economic impact, health implementation challenges and other exploratory endpoints.

Studying the genetic etiology underlying unclassifiable IBMFSs with bone fragility fractures should be useful for clarifying the undiagnosed pathophysiological mechanisms and other accessory factors to improve the diagnosis, follow-up, prognosis, and management of these patients as well as prevent future complications. Moreover, early diagnosis of risk factors of unusual presentations of IBMFSs will be a useful tool for better treatment strategy. In addition, along with typical IBMFSs, novel clinical entities must be included in an overall molecular portrait of IBMF disorders. As a result, comprehensive genetic analysis will be effective in establishing an accurate genetic diagnosis at medical evaluation.

The risk of severe graft versus host disease (GVHD) is increased with the use of unrelated and partially matched related donors. T cell depletion reduces the risk of severe GVHD, but immune reconstitution is delayed. Important memory T cells that may protect patients from fungal and viral infections are also removed in the T depletion process. CD45RA depletion has been studied both as a single step to reduce the risk of GVHD, and also, in conjunction with αβTCR depleted hematopoietic stem cell grafts to accelerate immune reconstitution. This single institutional trial builds on data from our protocol #18-015286, NCT03810196, "CD45RA Depleted Peripheral Stem Cell Addback for Patients at Risk for Viral or Fungal Infections Post-TCRαβ/CD19 Depleted Hematopoietic Stem Cell Transplant". This prior protocol was limited to patients with hematologic malignancies using only unrelated donors as the stem cell source. This new study will broaden the eligible diagnoses to include non-malignant transplant indications and participants with greater than or equal to 5/10 HLA matched related donors (also known as haploidentical). This will be a phase 1 and phase 2 study depending on the donor type. Phase 1 will include patients receiving cells from mismatched/haploidentical related donors. This will be a dose escalation study to determine the maximum tolerated cell dose of the CD45RA depleted addback. Once that dose is determined, patients with this donor type will be treated as part of phase 2. Patients receiving their cells from unrelated donors ( 9/10 or 10/10 HLA matched) will be treated as part of phase 2 with the CD45RA depleted addback cell dose that was used on our prior study. Phase 1 and phase 2 will run concurrently.

For some non-malignant diseases (NMD; i.e., thalassemia, sickle cell disease, most immune deficiencies) a hematopoietic stem cell transplant may be curative by healthy donor stem cell engraftment alone. HSCT in patients with NMD differs from that in malignant disorders for two important reasons: 1) these patients are typically naïve to chemotherapy and immunosuppression. This may potentially lead to difficulties with engraftment. And 2) RIC with subsequent bone marrow chimerism may be beneficial even in mixed chimerism and result in decreased transplant-related mortality (TRM). Nevertheless, any previous organ damage, as a result of the underlying disease, may remain present after the HSCT. For other diseases (metabolic disorders, some immunodeficiencies, etc.), a transplant is not curative. For these diseases, the main intent of the transplant is to slow down, or stop, the progress of the disease. In select few cases/diseases, the presence of healthy bone marrow derived cells may even prevent progression and prevent neurological decline. Research funds are not available to assist with enrollment on this trial. In this research study, instead of using the standard myeloablative conditioning, the study doctor is using RIC, in which significantly lower doses of chemotherapy will be used. The lower doses may not eradicate every stem cell in the patient's bone marrow, however, in the presented combination, the intention is to eliminate already formed immune cells and provide maximum growth advantage to healthy donor stem cells. This paves the way to successful engraftment of donor stem cells. Engrafting donor stem cells can outcompete, and donor lymphocytes could suppress, the patients' surviving stem cells. With RIC, the side effects on the brain, heart, lung, liver, and other organ functions are less severe and late toxic effects should also be reduced. The purpose of this study is to collect data from the patients undergoing reduced-intensity conditioning before HSCT, and compare it to the standard myeloablative conditioning. It is expected there will be therapeutic benefits, paired with better survival rate, less organ toxicity and improved quality of life, following the RIC compared to the myeloablative regimen.

The Shwachman-Diamond Syndrome Registry (SDSR) is dedicated to accelerating research and treatment for SDS to improve survival and quality of life for all patients with the disease. The SDSR is run jointly by Boston Children's Hospital and Cincinnati Children's Hospital Medical Center. Objective and Aims: The long term goals of the Registry are to improve diagnosis, inform medical management, and to develop better treatments for SDS and SDS-Like disorders. To achieve these objectives, the Registry has the following specific aims: * Characterize the natural history, medical complications, and treatment outcomes for patients with SDS and SDS-Like disorders. * Investigate the molecular and genetic pathogenesis of SDS/SDS-Like conditions and their complications such as marrow failure and clonal evolution. * Identify new genes causing SDS/SDS-Like conditions. * Provide education on the diagnosis, medical management and treatment of SDS for patients, families and the medical/scientific community. Methods: The SDSR collects information from medical records and biological samples. Samples for the SDSR are collected when they are obtained for clinical care so that no extra visits or procedures are needed. These samples may include blood, bone marrow, skin cells, saliva, or discards from other clinical procedures. Family members may also contribute blood samples. All information obtained by the SDSR is housed on a secure, HIPAA-compliant database. No personal information is shared outside of the study team.

What is SDS-GPS? The Shwachman-Diamond Syndrome Global Patient Survey and Collaboration Program (SDS-GPS) is an opportunity for patients and their families - from anywhere in the world - to share their experience living with SDS via a safe, secure, and convenient online platform, with the goal of * expanding the understanding of SDS and related conditions * improving the lives of people with SDS and related conditions, and * accelerating the development of new therapies and cures for SDS. SDS-GPS was created for the patients, by the patients, with thoughtful input from patients, families, advocates, caregivers, researchers, clinicians, and regulators. Participants will be part of a global community that cares, turns hope into action, and drives research. Participants' experience - whether it falls in the mild or severe end of the spectrum - matters. Their voice counts. How can patients' stories help drive therapies and cures? Participants' stories help paint a more complete picture of what SDS is and how it impacts the people living with it. Their participation helps build a strong, engaged community, which is critical to drive progress. Without patients and their families, research cannot advance. The investigators (the SDS-GPS team at the SDS Alliance) use participants' de-identified aggregate survey responses and other data they share to develop a deeper understanding of the unmet needs of the community. The investigators use the insights to * Prioritize research, educational resources, and community programming * Promote data and knowledge sharing via collaborations, publications, conference presentations, and other communication channels * Provide participants with information about relevant research opportunities (such as the SDS Registry and other natural history studies), clinical trials, educational resources, and community support connections. What aspects of their story can participants share through SDS-GPS? Surveys on the SDS-GPS Program Platform are designed to be quick and easy, without the need to have to look up any details from medical records. They can save their progress and come back anytime. Survey topics include: * Socio-demographics * Medical history and diagnostics * Treatment and disease progression * Management of and access to care * Quality of life How does SDS-GPS work? * Sign up for a free SDS-GPS account and enter a little bit about the participant. Enrolling and participating takes little time, and they can come back later to update any information. * Answer surveys from the comfort of their home at any time that works for them. * Privacy and security are protected to the highest standard. * Move research forward without any clinic visits or virtual appointments. With participants' consent, the investigators publish and share de-identified data (your survey responses) with approved researchers to support research to benefit the SDS community. The information participants provide through easy surveys is structured and coded behind the scenes, to be usable for high-quality, impactful research. * Keep track of the participants' medical appointments, medications, and symptoms via their SDS-GPS account, and have all the information at their fingertips whenever and wherever they need it. * Share any information participants like with their care team. Participants retain full control over access. The platform, consent forms, and surveys are available in five languages: English, Spanish, French, German, and Italian. More languages to come.