The Contribution of Cardiac Hypertrophy on Transplant Outcome in Patients with HLH Undergoing BMT

Hemophagocytic Lymphohistiocytosis (HLH) is a rare immunodeficiency disease of early childhood characterized by immune dysregulation due to impaired cytoxic killing and uncontrolled activation of T cells and macrophages. HLH can be congenital or acquired; approximately 40 % of children have an identified genetic defect. The standard approach to HLH is several months of therapy with dexamethasone, cyclosporin and etoposide to achieve disease control, followed by allogeneic hematopoietic stem cell transplant (HSCT). Outcomes with myelaoblative conditioning have been surprisingly poor with almost 1/3 of patients succumbing to early transplant related mortality (TRM). Most of the fatalities occur due to cardiopulmonary failure. Mortality is higher than that in other immunodeficiency syndromes, however the reasons for this increased toxicity are unclear.

We hypothesized that prolonged steroid exposure during HLH therapy may cause the development of cardiac hypertrophy.  Compromised cardiac reserve could contribute to poor outcome because of the multiple physiological stressors associated with transplant.

We reviewed the records of 11 consecutive children undergoing HSCT at our institution from January 2004- December 2012. The age at diagnosis ranged from birth to 60 (median 2.5) months and the age at HSCT from 6-70 (median 9) months.  8/11 had identified genetic defects (5 perforin, 2 MUNC, 1 Griscelli). All 11 received pre-HSCT therapy with etoposide, cyclosporin and dexamethasone.  10/11 were in complete disease remission at the time of HSCT.  Conditioning was fully ablative in 9/11(Bu, Cy, VP, ATG) and reduced intensity in 2 (Flu/campath). 6 received marrow as stem cell source. Donors were matched sibling in 1, and unrelated donor in 5. 5 received unrelated umbilical cord. All patients except the sibling donor received methylprednisonole at 1-2 mg/kg/day as GVHD prophylaxis. 3 had acute GVHD and received additional therapy with high dose (>2 mg/kg/day) steroids.

Pre transplantation echocardiograms were accessible for 6 patients; none had evidence of LVH. Post transplantation echocardiograms were reviewed for all patients.  7/11 (64%) never evidenced LVH at any point post-HSCT. TRM in this group was 3/7 (42%) due to multi-organ system failure (MOSF) (2) and adenovirus infection (1).  4/11 patients (36%) developed LVH 1 - 18 weeks post-HSCT. TRM was 100% in this group, higher than those without LVH (p=0.58) and all due to MOSF. Infectious agents were only identified in ¼ (adeno / EBV) and recurrent HLH in one.

In light of these findings, particular attention to cardiac status in patients with HLH is highly recommended. Further investigation is needed to identify pre and post SCT factors contributing to cardiac hypertrophy. This will allow both preventative measures to be developed and optimal management to be provided when these patients become critically ill.