Research Needs

A total of seven research gaps were identified through a combination of the BCBSA TEC draft HSCT CER and conversations with the key informants (including patient advocates). These gaps are crosscutting in that they apply to more than one indication for HSCT. The gaps are:

• Long-term consequences of HSCT, measured by overall survival, functional measures, quality of life, and adverse effects
• Mitigation of long-term adverse effects by changes in regimen, including reduced intensity approaches, and changes in subsequent medical or psychosocial intervention
• Role of novel therapies for HSCT in altering short-term adverse effects and the long-term effects of these therapies. Such approaches include:
  • novel cellular therapies (such as natural-killer-cell therapy), and
  • immunomodulatory therapies (including vaccine therapy).
• Multicenter collaboration to increase accrual of patients and systematize outcome reporting
• Effectiveness of survivorship planning on long term, comprehensive followup and outcomes
• Impact on outcomes of a “family-centered” approach to transplantation. Advocates of children who have undergone HSCT transplantation defined such an approach as including:
  • emotional and psychosocial counseling for the family with a special attention on donor and nondonor siblings,
  • information to share with caregivers and peers, and
  • tools rather than only a large amount of information for navigating the complexities of the medical system and medication management.
• Uniform reporting of outcome data to allow patient comparison of HSCT outcomes by transplant center

As stated in the Methods section, we attempted to have the Key Informants rank the research gaps and generate Key Questions online prior to a teleconference. Only half of the group responded to the online request. Therefore, on the teleconference, the Key Informants discussed the evidence gaps and appropriate Key Questions. Both the preliminary results based on the five responses and the more complete results based on eight responses elicited after the conference call are found in Appendix H. During the teleconference (#2), the Key Informants discussed the relative importance of each of the seven identified gaps, and then addressed the important Key Questions within each gap. After the teleconference (#2), followup phone calls were completed with two members not on the call, and one additional Key Informant submitted rankings, bringing the total to eight. The rankings from one original Key Informant were never received. The EPC generated the final ranking of research gaps taking all Key Informant comments into account. In the final ranking of the research gaps based on feedback from the key informants on gaps where research was known to be underway were removed from the listing.

The final four research gaps, in priority order are:

1. Mitigation of long-term adverse effects by changes in regimen, including reduced intensity approaches, and changes in subsequent medical or psychosocial intervention.
2. Role of novel therapies for HSCT in altering short-term adverse effects and the long-term effects of these therapies. Such approaches include:
   1. novel cellular therapies (such as natural-killer-cell therapy), and
   2. immunomodulatory therapies (including vaccine therapy).
3. Impact on outcomes of a “family-centered” approach to transplantation. Advocates of children who have undergone HSCT transplantation defined such an approach as including:
   1. emotional and psychosocial counseling for the family with a special attention on donor and nondonor siblings,
   2. information to share with caregivers and peers, and
   3. tools rather than only a large amount of information for navigating the complexities of the medical system and medication management.
4. Effectiveness of survivorship planning on long-term, comprehensive followup and outcomes.

Within Gap 1, mitigation of long-term effects by changes in regimen and changes in subsequent medical or psychosocial intervention, the Key Informants were particularly interested in addressing the impact of post-transplant psychological disorders in pediatric HSCT recipients and families. Patient advocates initiated the emphasis on psychosocial support and their view was embraced by all the key informants. Moreover, the matter of changes in regimen was of less interest, as there is ongoing research in the area. It is estimated that as many as 41 percent^{6, 7} of survivors of HSCT have persistent PTSD symptoms for up to 10 years post-transplant.^{8, 9} Further, parents of pediatric transplant recipients also have high levels of PTSD.¹⁰ In 2010, DuHamel and colleagues reported that a brief telephone-administered cognitive behavioral therapy intervention for HSCT survivors was effective in reducing illness-related PTSD and general distress.¹¹ Addressing this gap would add to the minimal literature specifically addressing the psychosocial needs of pediatric patients and families post-HSCT.

Gap 2 addresses ways to reduce the adverse effects of HSCT. Our Key Informant panel believed this to be the future of transplantation as novel approaches are discovered. They kept the Key Questions broad for the purposes of this report, as they felt that data are too sparse to point to one focus area.

Gap 3, impact on outcomes of a “family-centered” approach to transplantation, was proposed by the patient advocates and endorsed by the combined panel. Families of pediatric HSCT recipients are asked to endure a great deal over time and to acquire extraordinary new skills to care for their child. As the medical home model takes shape, families of pediatric HSCT recipients are asking whether the model might work for them. According to the Joint Principles of the Patient-Centered Medical Home,¹² a patient-centered medical home should have a personal physician, physician-directed medical practice, whole person orientation, coordinated care, quality and safety, enhanced access, and adequate payment. The number of autologous transplants in the U.S. has steadily increased since 2000, and allogeneic transplants from unrelated donors surpassed the number of allogeneic transplants from related donors after 2007.¹³ With the rising number of affected families, addressing this gap could have a large and beneficial impact on how these children and their families receive care.

Finally, Gap 4 focuses on the specifics of survivorship planning or long-term care planning. Cancer advocacy groups and many cancer centers have taken on the task of aiding patients develop these plans. At issue is whether the creation of such a formal document affects outcomes. The National Academies Press published a book called Implementing Cancer Survivorship Care Planning.¹⁴ They advocate the implementation of survivorship planning, but acknowledged that while it could reasonably be expected that survivorship planning would improve outcomes, prospective research is needed to confirm or refute this assumption. Addressing Gap 4 would begin to answer this question specifically for pediatric patients undergoing HSCT.

Gaps not included in the prioritized list include (1) long-term effects of HSCT measured by overall survival, functional measures, quality of life, and adverse effects; (2) multicenter collaboration to increase accrual of patients and systematize outcome reporting; and (3) uniform reporting of outcome data to allow patient/caregiver comparison of HSCT outcomes by transplant center. These gaps were assigned lower priority than the others not due to their relative importance, but because other groups are working on these issues. First, the Pediatric Blood and Marrow Transplant Consortium (PBMTC) is currently working on and has generated multiple Key Questions to specifically target and investigate long-term effects.¹⁵ The Key Informants stated that while multicenter collaboration is encouraged and mechanisms are in place, low levels of funding for pediatric research and pressure to close studies with slow accrual limit a center's ability to engage in such research. Addressing funding streams was outside the scope of this project. Finally, the issue of uniform reporting of outcome data to allow patient comparison of HSCT outcomes by transplant center is being handled by the Center for International Blood and Marrow Transplant Research (CIBMTR).¹⁶ CIBMTR was awarded a contract to administer the Stem Cell Therapeutic Outcomes Database (SCTOD) of the C.W. Bill Young Cell Transplantation Program. The Key Informants discussed that while this database is not perfect, it provides statistics on outcomes from autologous, related and unrelated allogeneic transplants performed by U.S. transplant centers.

As described above, during teleconference #2 the combined Key Informant panel discussed relevant Key Questions for each gap, and followup calls were conducted with members unable to attend the main call. Consensus on the important Key Questions for each gap was achieved. Therefore, no additional ranking of Key Questions was performed.

The final prioritized list of research gaps and Key Questions, in order of priority are:

Research Question Number 1.1

Can intense psychological support of patients, parents and siblings prevent development of post-transplant psychological disorders (including PTSD, depression, anxiety, other adverse psychological outcomes) in surviving and nonsurviving family members? (Table 3)

Table 3

Study design evaluations for research question 1.1.

The study design evaluations for research questions 2.1 and 2.2 were combined as they would require the same design and face similar challenges (Table 4).

Table 4

Study design evaluations for research questions 2.1 and 2.2.

Research Question 3.1

What approaches to integrated care, from diagnosis forward, have the greatest impact in family functioning and overall health and well-being for families faced with pediatric transplant? (Table 5)

Table 5

Study design evaluations for research question 3.1.

Research Question 4.1

Does survivorship planning enhance compliance with long-term followup? (Table 6)

Table 6

Study design evaluations for research question 4.1.

Research Question 4.2

What are the comparative outcomes for those that participate in long-term survivorship followup versus those who do not? (Table 7)

Table 7

Study design evaluations for research question 4.2.