Sickle Cell Transplantation Evaluation of Long-term and Late Effects Registry (STELLAR) to Compare Long-term Outcomes After Hematopoietic Cell Transplantation to Those in Siblings Without Sickle Cell Disease and in Nontransplanted Individuals With Sickle Cell Disease: Design and Feasibility Study

Background There are sparse data on the long-term and late effects of hematopoietic cell transplantation (HCT) for sickle cell disease (SCD). Objective This study aims to establish an international registry of long-term outcomes post-HCT for SCD and demonstrate the feasibility of recruitment at a single site in the United States. Methods The Sickle Cell Transplantation Evaluation of Long-Term and Late Effects Registry (STELLAR) was designed to enroll patients with SCD ≥1 year post-HCT, their siblings without SCD, and nontransplanted controls with SCD to collect web-based participant self-reports of health status and practices by using the Bone Marrow Transplant Survivor Study (BMTSS) surveys, health-related quality of life (HRQOL) using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Profile-25 or Pediatric Profile-29 survey, chronic graft-versus-host disease (cGVHD) using the symptom scale survey, daily pain using an electronic pain diary, the economic impact of HCT using the financial hardship survey, sexual function using the PROMIS Sexual Function SexFSv2.0 survey, and economic productivity using the American Time Use Survey (ATUS). We also piloted retrieval of clinical data previously submitted to the Center for International Blood and Marrow Transplant Research (CIBMTR); recorded demographics, height, weight, blood pressure, waist and hip circumferences, timed up and go (TUG) test, and handgrip test; and obtained blood for metabolic screening, gonadal function, fertility potential, and biorepository of plasma, serum, RNA, and DNA. Results Of 100 eligible post-HCT patients, we enrolled 72 (72%) participants aged 9-38 (median 17) years. We also enrolled 19 siblings aged 5-32 (median 10) years and 28 nontransplanted controls with SCD aged 4-46 (median 22) years. Of the total 119 participants, 73 (61%) completed 85 sets of surveys and 41 (35%) contributed samples to the biorepository. We completed ATUS interviews of 28 (24%) participants. We successfully piloted retrieval of data submitted to the CIBMTR and expanded recruitment to multiple sites in the United States, Canada, the United Kingdom, and Nigeria. Conclusions It is feasible to recruit subjects and conduct study procedures for STELLAR in order to determine the long-term and late effects of HCT for SCD. International Registered Report Identifier (IRRID) DERR1-10.2196/36780

Overall Impact: This amended application by an outstanding team of investigators proposes to evaluate the late effects and long-term outcomes of hematopoietic cell transplantation (HCT) for sickle cell disease (SCD). The investigators will build on established national collaborations to assemble a cohort of 500 survivors of transplantation for SCD and compare them with 500 age-, sex, and sickle cell type matched untransplanted SCD patients, and 500 sibling bone marrow donors. The study will collect information on health-related quality of life (HRQoL), pain, financial distress, gonadal function, fertility potential, sexual function, and splenic function. The scientific premise is strong, and the study addresses clinically important gaps. SCD is the most common inherited blood disorder in the US (occurs in ~1 in 500 African Americans) and results in substantial morbidity and premature mortality. Currently, HCT is the only curative treatment for SCD. However, the long-term outcomes of HCT are largely unknown. Clinical trials and registries collect outcomes related to HCT including short-term event-free survival but information on long-term outcomes including patient reported outcomes are lacking. The PI is a pediatric hematology oncologist with over 23 years of research experience in SCD. He is PI of a U01 comparing standard of care to HCT for SCD patients. The other investigators bring expertise in cancer survivorship, patient reported health outcomes, biobanking, biostatistics and recruitment into longitudinal studies. Addressing concerns from previous reviews they now include expertise in urology, reproductive endocrinology, and fertility preservation. The study will also establish a biorepository, which is another strength. Pilot work has been conducted to demonstrate the ability to identify HCT survivors and controls. They will use a variety of methods to track HCT survivors. Many of the previous concerns have been addressed. However, feasibility to recruit and enroll at other centers is still not demonstrated. Additionally, lack of clarity in the approach around the aims and data collection still remains.

Strengths
• SCD is the most common inherited blood disorder in the US (occurs in ~1 in 500 African Americans) and results in substantial morbidity, poor health related quality of life (HRQoL), and premature mortality.
• Currently, HCT is the only curative treatment for SCD.
• There are limited data on long-term outcomes of HCT for SCD including limited information on HRQoL as well as gonadal function and fertility potential.
• These gaps limit the applicability and acceptability of HCT for SCD treatment. The findings from this study would help to address these knowledge gaps.

Weaknesses
• Appear to be very small samples sizes for Aim 2 (gonadal and sexual function) and Aim 3 (splenic regeneration, immune reconstitution, response to pneumococcal vaccines) • Strong team experienced in HCT for SCD.

Strengths
• Dr. Krishnamurti (PI) is a pediatric hematologist oncologist with over 23 years of research experience in SCD. He is the Director of the Pediatrics BMT program. Currently, he is PI of an NHLBI U01 grant for a multicenter study of comparing standard of care to HCT for SCD.
• The other Co-Is bring expertise in cancer survivorship, patient reported health outcomes, pediatric endocrinology, fertility preservation, pathogenesis of sickle cell disease, biobanking, graft rejection, biostatistics, recruitment into longitudinal studies.

Weaknesses
• None noted

Innovation: Strengths
• Comparing outcomes in transplanted patients with their sibling HLA identical bone marrow donors (potentially share same genetic and environmental influences).
• Most studies of HCT for SCD have not systematically collected HRQoL and pain data and only at one-year post HCT; the proposed study will capture data over the long-term as well as at 1 year post-HCT which will allow us to understand the impact of complete recovery following HCT as well as the impact of late sequelae on patient reported outcomes PROs.

Approach: Strengths
• Using a variety of methods to track HCT survivors and limiting to large HCT centers initially (can expand if needed).
• Preliminary data indicated that contact was established with 94% of HCT survivors and access to siblings was also achieved.
• Using a variety of methods to collect PROs and biospecimens (online web-based surveys that can be completed via computer, tablet or phone; paper option available as well; home based specimen collection at convenient times) • Created methods and mechanisms to engage investigators, participants and the general public (presentations, annual reunions for survivors and their families, use of Facebook) to facilitate recruitment.
• Ability to identify and match a high number of untranslated SCD controls.
• Employing several analytic approaches (matching, propensity scoring, multivariable regression) to attempt to overcome selection bias and balance known confounders.
• Established an external advisory committee including experts in HCT, SCD and patients.

Weaknesses
• Although the ability to identify and match controls using existing data was shown, the ability to recruit and follow the controls was not demonstrated.
• Although a large number of transplant centers (30 to begin with) will be included, it's not clear how many of the 1217 post-HCT patients are still alive. What are the annual survival rates? • Home based phlebotomy is mentioned but nothing is mentioned about the physical function measures (hand grip, walk test) being conducted in the home and how that would be done systematically and who would perform these measures (trained study staff or mobile phlebotomy techs?).
• It is not clear what is meant by EMA pain data and whether this is completed only by children or everyone recruited for Aim 1.
• Email reminders are sent for surveys, but it is not clear if reminders are sent for completing the pain diary.
• Aims seem to be including different individuals. Age ranges are not specified for each aim. It is not clear who will be asked to complete the PROs, provide the biospecimens to compare gonadal function and fertility potential, questionnaires that measure perceptions of the risk for infertility.
• Aim 3 mentions that 250 patients with a diverse range of age will be included as well as a convenience sample of 30 HCT patients, 30 donors and 30 SCD controls.

Environment: Strengths
• Well established infrastructure at CHOA.

Protections for Human Subjects:
Acceptable Risks and/or Adequate Protections Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):

Not Applicable (No Clinical Trials)
o Included but is relevant to a clinical trial rather than an observational study.

Inclusion of Women, Minorities and Children:
• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: • Inclusion/Exclusion of Children under 18: Including ages <18; justified scientifically • Children ages 3 and older will likely be enrolled; this is justified given the epidemiology of SCD • Largely responsive but a lack of clarity in the approach around the aims and data collection still remains.

Not Applicable (No Foreign Organizations)
Select Agents:

CRITIQUE 2
Significance: 2 Investigator(s): 2 Innovation: 3 Approach: 4 Environment: 2 Overall Impact: This proposal is a resubmission of a prior R01. This study assembles and investigates a large cohort of 1+ year survivors of BMT for Sickle Cell Disease. It proposes to assemble a large retrospective group using information from the IBMTR and 37 primary institutions; it will also create a much smaller prospective cohort. The investigations proposed on QOL, health, fertility and immune function would have tangible impact on transplant decisions and follow up strategies for patients with SCD. These possibilities are tempered by the structure of the grant; in particular the large number of centers and interest in expanding those further, lack of information on the feasibility of the project outside of Children's Hospital of Atlanta, and the unsure future of the cohort. While the resubmission does address some of the concerns of the prior review many remain.

Strengths
• BMT is the only curative therapy for SCD • Utilization of BMT has increased as has survival following BMT • There is limited QOL and overall health data following BMT for SCD • Understanding the late outcomes may clarify decision making for future patients Weaknesses • Cohort is constructed but not clear how successful a prospective cohort it will be 1 R01 HL141882-01A1 7 CHSA KRISHNAMURTI, L

Strengths
• Strong PI in Dr. Krishnamurti • Strong group of collaborators with diverse skills including cohort studies, endocrinology, immunology • Group is focused at Emory

Innovation: Strengths
• Use of multiple sources for patient identification • Innovative strategies for selection of control groups

Weaknesses
• None noted

Approach: Strengths
• Collaboration with the IBMTR • Use of multiple sites to broaden the cohort size

Weaknesses
• The complexity of the study would argue for a more limited number of centers. The criteria of 10 transplants (ever?) is given, but it is not clear how much gain there is at the low end of accrual vs select higher volume centers • No rationale is provided for the expansion to even more centers • The assumption that tracking and participation rates experienced at CHOA would be more convincing if substantiated by data from other major participants • There is little information provided on strategies for retention of individuals who participate • The prospective nature of the study is not well defined

Environment: Strengths
• • The applicants have addressed many of the concerns raised in the initial grant but the proposal is going to be very logistically complicated and it is not clear how they will be able to retain the cohort

Not Applicable (No Foreign Organizations)
Select Agents:

Not Applicable (No Relevant Resources)
Budget and Period of Support:

CRITIQUE 3
Significance: 2 Investigator(s): 2 Innovation: 2 Approach: 5 Environment: 2 1 R01 HL141882-01A1 9 CHSA KRISHNAMURTI, L Overall Impact: This is a resubmission of a grant examining the impact of hematopoietic cell transplantation on patients with sickle cell disease by comparing transplanted patients with sibling donors, matched controls, and baseline values over time. The grant examines outcomes ranging from health-related quality of life, pain scales, financial stress (AIM 1), to gonadal function and fertility potential (AIM 2), and immune reconstitution, splenic regeneration, response to pneumococcal. The applicants leverage a novel network of sites that have transplanted these patients and novel collaborations. The applicants have been responded to the prior application by increasing information on feasibility of enrollment and have bolstered preliminary findings. Feasibility is also aided by simplification of numbers of sites involved. The prior grant had significantly dampened enthusiasms because of the rigor in the approach section which is greatly improved, but still has multiple flaws within each aim, mostly related to the focused on multiple outcomes. The different challenges in the analyses of each are not well addressed (prelim data shows changes in some outcomes but not others, but the rationale for why these should change in the full study is not clear). Financial strain is actually hypothesized to change over time, but this is not specified in the analysis or power calculation (additionally the issue of assessing this outcome across siblings and potential correlation of financial stressors not addressed). Overall, these are multiple minor weakness because within each aim several outcomes are strongly justified and supported by prior data. The importance of the research question and the unique study design and access of patients is a major strength.