Acute lymphoblastic leukemia in a patient with type 1 Gaucher disease developing 1 year after discontinuation of enzyme replacement therapy
Authors: Aditi Ranade, Sorin Selegean, Gagangeet Sandhu, Violette Ghali, Vijay P. Shah
Journal: American Journal of Hematology (2010)

To the editor: Gaucher disease (GD) is the commonest lysosomal storage disorder resulting because of the deficiency of an enzyme beta glucocerebrosidase. The progressive glucocerebroside accumulation in the macrophages provides a chronic antigenic stimulus to the immune system resulting in lymphoproliferation and impaired cellular immunity. This could lead to the pathogenesis of hematological malignancy; the mean age of presentation for which is reported to be 57 years [1]. Enzyme replacement therapy (ERT) is the standard of treatment in GD, but it is unknown if it has a role in mitigating cancer development. Our patient was a 31-year-old male with a family history of GD and was diagnosed to have type 1 GD at age 14. The patient had been relatively free from any significant complications associated with the disease. He presented to his primary care physician with a 1 month history of progressive generalized weakness, fatigue, and a 5 to 6 pounds weight loss over a period of 2 months. Physical examination revealed mild hepatomegaly and marked splenomegaly. Of note, he had self discontinued the ERT for the past 1 year. The pertinent laboratory findings on admission were hemoglobin of 3.7 g/dL, hematocrit 10.2%, white blood cell count 1.3 K/uL, and platelets 117 K/uL. In addition, the peripheral blood smear revealed occasional immature looking cells. A buffy coat preparation, however, revealed many blasts (Fig. 1a). Based on this, a bone marrow biopsy was advised, which showed a hypercellular (>90%) marrow with almost complete replacement of normal marrow elements by monotonous intermediate size immature cells having high nuclear: cytoplasmic ratio and clefted nuclei (Fig. 1b,c). Also noted were sheets of foamy macrophages with crumpled tissue paper like cytoplasm having eccentric nuclei corresponding to the patient's history of GD (Fig. 1c). These macrophages were further highlighted by a PAS stain (Fig. 1d). Immunohistochemistry showed the immature cells to be positive for CD10, CD19, and TdT, and negative for CD20 and CD22 (Fig. 1e,f). Flow cytometry was consistent with a pre-B acute lymphoblastic leukemia. The patient was eventually started on chemotherapy. (a) Buffy coat preparation showing blasts with clefted nuclei and having nucleoli, (b) hypercellular bone marrow composed predominantly of blasts and foamy macrophages having crumpled tissue paper like cytoplasm, (c) high power of image of b, (d) PAS stain highlighting macrophages of Gaucher's disease, (e) CD19 staining the lymphoid blasts, and (f) TdT staining nuclei of lymphoid blasts. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] It has been reported that patients with GD are not at an increased risk of cancer in their early and middle age [2]. The mean age of hematological malignancy is reported to be 57 years [1]. However, some others have reported that cancer risk occurs at all age groups in patients with type 1 GD [3]. Our patient presented at an age of 31 years. There is also much debate as to which hematological malignancy is more common in patients with GD. A two- to threefold increased risk of non-Hodgkin's lymphoma, malignant melanoma, and pancreatic cancer has been reported. Others have reported the association to be significant for multiple myeloma only [2]. Our patient had ALL; one of the least reported malignancies in patients with GD. Both the clinical presentation and response to therapy in GD are variable, and it has been postulated by some that both high dose and frequent low dose ERT are effective in patients with GD [4]. Although the pathogenesis of cancer development is thought to be related to glucocerebroside deposits, it is unknown whether ERT has a role in mitigating cancer development [2]. Our patient had an uncomplicated course until 1 year after the discontinuation of ERT, when he developed ALL. It is possible that the discontinuation of ERT could have led to an increase in glucocerebroside deposits, leading to lymphoproliferation and also a defect in the cellular immunity. Both these factors are known to increase the risk of malignancy [1]. In conclusion, though it is known that there is an increased risk of cancer in patients with GD, whether discontinuation of ERT potentiates this risk needs to be further evaluated.