1. Haematopoietic stem cell transplantation alongside enzyme replacement therapy in infantile onset lysosomal acid lipase deficiency
Ghosh A1, Lum SH2, Jones SA1, Wynn RF2
1. Manchester Centre For Genomic Medicine, Central Manchester University Hospitals, UK 2. Bone Marrow Transplantation Unit, Royal Manchester Children’s Hospital, UK
INTRODUCTION
The infantile onset form of lysosomal acid lipase deficiency (LALD), also known as Wolman disease, is a rare lysosomal disorder characterized by growth failure, gastrointestinal manifestations and liver involvement. Without treatment the disease is rapidly progressive and fatal, with death typically before 6 months of age.
Prior to the availability of enzyme replacement therapy (ERT), a number of infants were treated with haematopoietic stem cell transplantation (HSCT), but outcomes were generally unfavourable [1-3]. The main cause of mortality appears to be liver damage, either due to progression of underlying disease or veno-occlusive disease (VOD) [3].
We report the outcomes of three individuals with LALD who underwent HSCT in Manchester, two of whom also received ERT with sebelipase alfa (KanumaTM, Alexion).
CASE (3)
CASE (1)
CASE (2)
This female infant was diagnosed at 8 months of age following presentation with vomiting, diarrhoea and massive hepatosplenomegaly. Liver transaminases were only moderately elevated. This infant presented prior to the development of ERT for LALD.
She underwent HSCT within a month of diagnosis. She developed significant weight gain during conditioning followed by jaundice, consistent with a diagnosis of VOD. She continued to deteriorate, developing fulminant VOD and massive fluid retention, and died on day +4 post-HSCT.
This female infant presented at 4 months with typical features of LALD as well as respiratory failure, persistent fever, cytopenia, and elevated CRP, ferritin and sCD25, consistent with haemophagocytic lymphohistiocytosis (HLH). HLH was subsequently confirmed on bone marrow examination.
At 6 months she commenced etoposide, cyclosporine A and dexamethasone (HLH 2004 protocol), followed by HSCT at 8 months. Transplant course was complicated by mild VOD and microangiopathy. She continued to receive ERT 5mg/kg weekly post-HSCT. She did not develop anti-sebelipase antibodies.
Despite full engraftment, fever and splenomegaly persisted and there was continuing inflammation with elevated IL-1β, indicating persistent macrophage activation. She subsequently died due to catheter associated sepsis.
This female infant presented with typical features of LALD at 2 months and commenced ERT. She responded to ERT but had multiple central venous catheter occlusions. In addition she developed high titre anti-sebelipase antibodies, with inhibitory antibodies.
Due to poor venous access and repeated ERT dose escalations, HSCT was performed at 25 months. ERT was continued post-transplant.
Despite secondary reconstitution, liver transamin-ases, albumin, organomegaly and gastrointestinal symptoms have improved, allowing for reduction in ERT dose from a maximum of 7.5mg/kg weekly to a current dose of 1mg/kg weekly. Trough (pre-infusion) LALD enzyme activity was monitored, using a dried blood spot assay (whole blood LAL activity). This is stable at approximately 50% of lower limit of normal. She no longer has high titre anti-drug antibodies.
RESULTS (1)
Table 1: Donor / transplant characteristics and outcomes
Case
Age at starting ERT
Age at HSCT
Donor / stem cell source
Conditioning
Engraftment metrics (most recent values)
Transplant related
complications
Survival
Day of transplant
Donor chimerism (%)
Whole blood
CD15+ (myeloid)
CD3+ (T cell) 1
No ERT
8 months
Matched unrelated donor,
cord blood
Treo/Cy/ATG
VOD
Died on day +4 post-HSCT (VOD / progressive disease) 2
4 months
7 months
Matched family donor, PBSCs
Treo/Flu/Alem
+152 83
Mild VOD, transplant related microangiopathy
Died at 13 months (sepsis, HLH) 3
3 months
25 months
Carrier matched sibling donor, bone marrow
Treo/Flu/Thio/ Alem
+272
34.5
20.5
47.2
None
Alive at 36 months
Treo, treosulfan; Cy, cyclophosphamide; ATG, anti-thymocyte globulin; Flu, fludarabine; Alem, alemtuzumab; Thio, thiotepa; PBSCs, peripheral blood stem cells
RESULTS (2)
CONCLUSIONS
This is the first report of HSCT in LALD infants in whom ERT improved clinical status prior to HSCT. The poor outcome of Case 1 without ERT is similar to previous reports [1-3].
In the other two individuals, HSCT was feasible but outcomes differed. In Case 2, hepatomegaly reduced post-transplant and liver transaminases normalised, suggesting a degree of metabolic correction, though she continued to receive ERT post-HSCT. However, features of HLH persisted (fevers, splenomegaly). The pre-HSCT status of Case 3 was favourable in comparison. Though ERT was continued post-HSCT, repeated dose reductions have been well tolerated, and liver transaminases and albumin stabilised within the normal range. However, at 11 months post-HSCT there is secondary reconstitution and donor chimerism is being regularly monitored. In both individuals, HSCT was followed by a sustained reduction of plasma oxysterols (a putative biomarker; see poster #104.)
The difference in outcomes in these two individuals likely reflects their pre-morbid status. Understanding the role of HSCT in the management of LALD and the extent to which it modifies underlying disease will require longer term follow up and further experience.
Figure 1: Timeline of HSCT and ERT for cases 1-3 q
REFERENCES
1. Krivit, W et al. (2000). Bone Marrow Transplant 26(5): Tolar, J. et al. (2009). Bone Marrow Transplant 43(1): Yanir, A. et al. (2013). Mol Genet Metab 109(2):