Work thus far reveals that RIC HCT using alemtuzumab, fludarabine, and melphalan has dramatically improved patient survival at 2 centres in London and Cincinnati. However, clinical experience following RIC HCT remains relatively short, and further time is needed to confirm that patients will maintain sufficient donor contribution to haematopoiesis to sustain disease remission. Additionally, multi-centre trials are needed to confirm that the improved results observed with RIC HCT can be reproduced at other centres.
RIC HCT can be associated with a high incidence of mixed donor and recipient chimerism. This often complicates and lengthens the treatment of patients following HCT due to the need for aggressive monitoring of donor/recipient chimerism and interventions such as DLI or stem cell boost. RIC regimens could possibly be improved by optimizing the timing and dosing of alemtuzumab, such that an adequate amount is given to limit the incidence of acute GVHD, but not offer such profound graft T lymphocyte depletion as to contribute unnecessarily to the development of mixed chimerism. However, until RIC regimens are improved, DLI and stem cell boost may continue to be necessary for many patients.
Unfortunately, there is currently limited data upon which to base decisions regarding instigation of DLI or stem cell boost. Formal studies are needed to accurately define the risk of HLH with low-level donor chimerism and to determine which specific donor lymphocyte populations are required for permanent remission. HLH has been observed at whole blood donor chimerism levels of less than 20%,(Marsh, et al 2010b
, Ouachee-Chardin, et al 2006
) but it is notable that long-term remission has been observed in a patient with donor cells found only in the T cell compartment.(Cooper, et al 2006
Decisions regarding DLI should currently be made on a case-by-case basis, based on patient chimerism trends, availability of DLI product, active infections, history of GVHD, and other factors. At our centre, DLIs are often pursued when donor contribution to overall haematopoiesis and/or T- and/or NK-cell chimerism is rapidly or persistently declining during the early post-transplant period towards thresholds that cause concern for eventual HLH relapse. In practical terms, patients with trends of donor contribution to haematopoiesis that are decreasing to levels lower than 40-60% within the first 6 months post-HCT are often considered for DLI. Consideration is at this point so as to avoid further decreases to levels below 20%. The onset and rate of decline of donor chimerism are also useful indices. Patients with earlier onset or more rapid decline of donor chimerism appear to be at higher risk of graft loss or HLH recurrence.
Despite the association of RIC HCT with mixed chimerism, it is the authors’ opinion that RIC HCT using alemtuzumab, fludarabine, and melphalan should be considered for all patients with HLH when an appropriate related or unrelated donor bone marrow or peripheral blood stem cell graft is available. Caution should be used when considering RIC for cord blood transplantation. Cord blood offers no source of additional donor stem cells or T cells after transplant, which prevents the possibility of stem cell boost or DLI should they be needed. The risks and benefits of RIC HCT versus traditional myeloablative HCT should be contemplated on a case-by-case basis for patients with cord blood as their only option for HCT.
In addition to the future improvements in the transplantation process for patients with HLH, ongoing efforts to improve the pre-transplant treatment of HLH will improve the outcomes of HCT. Patients with active HLH at the time of transplantation generally have worse outcomes compared to patients with inactive disease, (Baker, et al 2008
, Horne, et al 2005
, Ouachee-Chardin, et al 2006
) and complete responses to conventional HLH therapies are only observed in 50%-75% of patients.(Henter, et al 2002
, Mahlaoui, et al 2007
) Formal trials of salvage therapies and standardization of second-line treatment schemas are needed, and will improve HCT outcomes. Additionally, further experience with post-HCT CNS HLH will improve transplant outcomes. In our experience, early post-transplant CNS disease is not uncommon. Children with low donor chimerism also appear to be at increased risk for the development of CNS disease. We have found that cerebrospinal fluid analysis and brain magnetic resonance imaging (MRI) can be helpful in the early post-transplant period, and that systemic dexamethasone and intrathecal treatment can be beneficial in affected patients. However, there is very little data regarding the incidence, course, treatment, or outcome of CNS HLH that occurs in the post-transplant period. Formal studies are needed.
In summary, we have reviewed the current experience with allogeneic HCT for patients with HLH. Although important steps forward have been made with regard to patient survival using RIC-HCT, many steps remain to optimize this approach and further improve patient outcomes.