There are several barriers to advancing care of patients with SAA. First, the disease is rare. Only about 600 new cases/year are expected in the United States. This makes all types of studies difficult because any given center will only have a handful of patients. Second, the natural history of the disease plays out over more than a decade, with some patients failing multiple courses of therapy, but still surviving for 5-10 years, and others developing late-onset secondary MDS/AML. Third, referral to centers with specific expertise in SAA is sporadic and varies by patient location. Referral is important in order to have the latest testing performed to rule out inherited bone marrow failure syndromes, hypoplastic MDS, and other conditions that mimic SAA, and to enroll patients in studies. Fourth, timing and indications for referral for transplant vary considerably among centers, with many patients delayed excessively and referred to BMT only after they have developed active infections, significant transfusion burden, alloimmunization, and/or platelet refractoriness. Finally, because patients with SAA may be seen by local physicians or hematologists, referred to a regional academic center, and then referred a second time for BMT evaluation, it is difficult to follow patients from diagnosis through all of their therapeutic courses with an observation period sufficient to understand their long-term outcomes. In the US, particularly, a mechanism to track patients through multiple care-providers is lacking.
The SAA working group agreed that advances in biology and BMT survival warrant a series of initiatives to better understand the appropriate roles and timing of IST and BMT in treating SAA. One important effort that would greatly assist in moving the field forward would be to create a mechanism for identifying a high percentage of SAA patients at diagnosis, obtaining blood specimens to evaluate prognostic biomarkers, and following these patients through their treatment courses. Biologic samples for later studies could be obtained, with appropriate consent, and an SAA repository established. Patients could be offered participation in studies of related donor BMT, IST, URD BMT and alternative donor BMT as they became eligible for such studies. BMT timing would be determined by patient age, the availability of well-matched related or unrelated donors, response to IST and risk as determined by biologic markers. All patients would be followed long-term, and quality of life studies could carefully compare outcomes of surviving patients receiving URD BMT vs. IST.
The working group felt that the most appropriate way to improve care and enroll patients onto a large registry study would be to designate regional centers of excellence, where comprehensive evaluations, including key biologic assessments (telomere studies, etc.) could be performed at diagnosis and other key time points. Vital to this process is early assurance that the diagnosis of SAA is correct. A subcommittee headed by Dr. Richard Harris was appointed to assemble comprehensive diagnostic guidelines including tests to rule out inherited BM failure syndromes and other non-SAA diseases. Because the therapy of SAA patients sometimes involves transplantation and the CIBMTR currently has a large database of information on patients receiving BMT, the CIBMTR is a possible choice to manage an SAA registry or longitudinal observational study. Trials of biology, IST and BMT could be facilitated by a population-based SAA outcomes registry by identifying potential study subjects; patients would benefit by having wider access to studies of relevance to them. Patients in the registry could also be targeted for distribution of educational and support materials. The working group plans to seek funding from patient advocacy groups, private corporations and governmental funding sources in order to established a population-based outcomes registry and accompanying biologic sample repository to facilitate studies to address many of the issues discussed in this document.
The important questions in the therapy of acquired SAA can be addressed most effectively with collaboration among transplantation physicians, hematologists interested in IST, and scientists studying the biology of marrow failure. The relevant issues are interdependent. For instance, can telomere length and telomerase complex mutations help predict whether patients will fail IST and should, therefore, seek early transplantation therapy? Can selected biological factors (cytokine profiles, etc.) better define clinical risk groups? If we can define patients at high risk of IST failure, do the same or different factors predict outcomes after BMT? If a patient either fails to respond to IST or relapses afterwards, can new agents induce or prolong responses (alemtuzumab, etc.)? Can cyclophosphamide, given at a modified dose, improve the durability of initial responses without excessive early morbidity? Finally, we need to know whether novel strategies for URD BMT that decrease GVHD and maintain engraftment can be developed and performed safely with reasonable survival in older patients. Can alternative donor grafts be used successfully so that more patients are able to go to transplantation if immunosuppression is unsuccessful?
These questions can be directly addressed through the proposed SAA registry/biology study, since at given time points (first or subsequent failure of IST, etc.) patients who have appropriate donors and go to BMT can be compared with similar patients who undergo IST. Questions regarding access to BMT (inability to get BMT due to insurance, etc) can be addressed by the registry study as well. Transplantation studies could be performed through the BMT CTN in cooperation with international study groups as needed to allow for sufficient accrual or to rapidly test highly promising ideas.