Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease

Abstract

Background Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access. Results We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT—multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition. Conclusion We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.

Diagnosis, treatment, and follow-up of a case of Wolman disease with hemophagocytic lymphohistiocytosis

“…This concept is in line with the hypothesis of Taurisano et al that postulated the possible correlation of cholesterol esters with the exaggerated immune response and an interleukine storm of HLH in WD patients [7] . This is also in line with the results of Potter et al who recently described five WD patients, two out of them with HLH phenotype, who showed elevated C-triol levels at diagnosis that reduced within a few months after the start of sebelipase alfa [19] .…”

“…To our knowledge, our patient represents the first case of WD with associated HLH who has not been transplanted with hematopoietic stem cells and survived after the first year of life on sebelipase alfa treatment. However our case showed also that the management of a child with WD is extremely complex and as recently reported by Potter et al [19] the enzymatic replacement therapy (ERT) alone could not be sufficient to allow prolonged survivor for these patients. The combination of ERT with HSCT could represent a more efficacious treatment in WD,however in our opinion this option still raises some concerns, mainly related to the risks related to HSCT procedures in infants with highly deteriorated clinical conditions and adrenal insufficiency.…”

“…)del Deletion of exons 9 and 10, likely pathogenic Anakinra 10 mg/kg twice per day for 7 days Etoposide 150 mg/m2 (3 doses) Died at 5 months Al Essa M et al [4] Saudi Arabia Yes (first cousins) ND – Supportive treatments Died at 4 months Perry R et al [5] Canada ND ND – Chemotherapy NA Perry R et al [5] Canada ND ND – Allogeneic BMT NA Rabah F et al [6] Saudi Arabia Yes (first cousins) No variations detected – Chemotherapy, immunosuppressive Died at 4 months Taurisano R et al [7] Italy No ND – Supportive therapy Died at 5 months Elsayed et al [11] Egypt Yes (double cousins) Homozygous G969A (W130X) Likely pathogenic NA Died Elsayed et al [11] Egypt Yes (double cousins) Homozygous c.438delC (p.S112X) Likely pathogenic NA NA Elsayed et al [11] Egypt Yes (first cousins) Homozygous c.G969A (p.W289X) Likely pathogenic NA NA Potter et al [19] NA NA Missense variant. Homozygous Likely pathogenic Sebelipase alfa, HCT Died at 13 months Potter et al [19] NA NA c.684delT [p.(Phe22Leufs*13)]/ exon 4 deletion (framesh...…”

“…Santos Silva et al [10] reported two cases who died after one and six weeks of treatment, respectively. Potter et al described two patients that received hematopoietic stem cell transplantation (HSCT) after 4 and 3 months from the first infusion of sebelipase alfa respectively: one patient died 5 months after HSCT, the other is still alive and on treatment with sebelipase alfa at the time of the report publication [19] . Our experience showed that sebelipase alfa treatment was very effective in a young WD child with HLH, highlighting promising results on biochemical parameters of inflammation, on liver function, on disease-associated biomarkers as well as on weight gain, and on life expectancy.…”

“Why them, why me, why us?” The Experiences of Parents of Children with Lysomal Acid Lipase Deficiency: An Interpretative Phenomenological Analysis Study

“…Although HSCT carries signi cant risks, multimodal treatment offered to infants has shown an improvement in gastrointestinal symptoms in those who survived the procedure, with some children being able to eat and require less gastrostomy feeding over time. 5 As a result of the relatively new ERT treatment (EMA approved 2015), the natural progression of LALD is unknown. This lack of knowledge increases the uncertainty which parents of children with LALD face.…”