Successful autologous stem cell transplantation in Gaucher disease patient with multiple myeloma
Authors: Alexandre Aubourg, Lotfi Benboubker, Laurence Picon, Philippe Goupille, Francois Maillot
Journal: American Journal of Hematology (2011)

To the editor: An increased incidence of malignant disorders, particularly multiple myeloma (MM), has been reported in patients with type 1 Gaucher disease (GD), possibly due to chronic stimulation of the immune system [1]. We report here the case of MM occurring during Gaucher enzyme replacement therapy (ERT). Distinguishing features of this case are the evolution of monoclonal gammopathy to a malignant hematological disease, successfully treated by hematopoietic stem cell transplantation (HSCT). A male patient born in 1948 was referred to our centre in 1993 for liver and spleen enlargement investigation. He had neither personal nor familial past medical history. He had no symptoms, and hepatosplenomegaly was known for 10 years. Liver and spleen were measured 20 cm on right midclavicular line and 30 cm on left midclavicular line, respectively. Blood count showed hemoglobin 117 g/L, neutrophils 1.4 g/L, and platelets 50 g/L. Quantitative immunoglobulin analysis showed immunoglobulin (Ig) G 33.6 g/L (8–18), IgA 2.65 g/L (0.9–4.5), IgM 3.55 g/L (0.6–2.8). Serum protein electrophoresis and immunofixation revealed two IgG kappa and lambda monoclonal bands. No light chain proteinuria was identified. Bone marrow aspiration and bone biopsy showed 4% of large storage cells, characterized by abundant cytoplasm with wrinkled tissue-paper appearance, evocative of Gaucher cells. There was no evidence of increased plasmacytosis on bone marrow examinations. Serum acid phosphatases were 50 U/L (2.3–4.9) and tartrate resistant type phosphatases were 38 U/L (1.2–2.8). There were neither clinical nor radiological signs of bone involvement. As glucerebrosidase activity was not measured initially, diagnosis of GD was based on the association of both clinical and biological presentations as well as the presence of Gaucher cells in bone marrow. Diagnosis was further confirmed through genotyping, which showed an homozygoty for the N370S mutation in the GBA1 gene. ERT with alglucerase (Ceredase®) was started in March 1994, initially at the dose of 60 U/kg every 2 weeks for 1 year, then 45 U/kg every 2 weeks. No ERT side effects were reported, and a favourable clinical response was assessed at 1 year by both spleen and liver size reduction (from 30 to 20 cm and from 20 to 15, respectively). Tartrate resistant acid phosphatases decreased from 38 to 8 U/L following 2 years of treatment. In January 1997, human β glucocerebrosidase was replaced by imiglucerase (Cerezyme®) at a dose of 60 U/kg every 2 weeks. From 1994 to 1996, serum protein electrophoresis was not modified, with two monoclonal bands. In December 1997, while the patient stayed asymptomatic, a bone scintigraphy performed for GD annual work-up revealed a mild, isolated hyperfixation located on the fourth and fifth thoracic vertebra (T4–T5). In August 1998, symptoms of thoracic medullar compression (T4–T5 level) occurred within few weeks, combined with dorsal pain. Computed tomography and magnetic resonance imaging showed a lytic bone tumor involving the fourth and fifth thoracic vertebrae. In October 1998, surgical resection, only partial because of hemorrhagic complications, led to neurological recovery. Histological examination showed that the tumor contained a high amount of immature plasmocytes as well as Gaucher cells in some extracts. An adjuvant local radiotherapy (30 Grays) was performed. In the absence of arguments for MM, diagnosis of spine solitary plasmocytoma was proposed and a close monitoring was planned afterward. At this time, IgG was 18.4 g/L, with a major lambda monoclonal band estimated at 15 G/L, associated with two minor bands Ig G kappa and IgA lambda. In June 1999, the patient reported a pain of left ischium area. X-rays showed several lytic bone lesions of pelvis, lumbar spine, and skull. Neurological examination was normal. Serum protein was 81 g/L (58–75). Monoclonal IgG lambda was estimated at 14 g/L similar to previous measurement, IgA at 1.8 g/L, and IgM at 1.7 g/L. Bone marrow aspiration showed 4% of immature plasmocytes and 3% of Gaucher cells. Pelvis bone biopsy confirmed the diagnostic of MM. Serum beta-microglobulin at 1.32 mg/L (1–2.4) and serum albumin at 43 g/L (36–46) defined a stage 3 MM (International Staging System). Chemotherapy with Vincristine, Doxorubicin and Dexamethasone were prescribed and subsequently an autologous HSCT was performed in 2000, leading to remission. No major side effect was reported after HSCT. ERT was maintained following HSCT, without any loss of efficacy. In 2005, ERT was stopped and replaced by miglustat because of poor venous access and also patient's request to move from ERT to oral treatment. To date, the patient was considered as being in remission for MM according to the last evaluation in July 2010. We report here the first case of MM in non-neuropathic type I GD treated with autologous HSCT, with a very good long-term outcome. Treatment of MM was well tolerated without any increased hematologic toxicity or impact on the course of GD. Moreover, the original fact reported in this case is the presence of monoclonal gammopathy at the time of diagnosis of GD, its persistence during ERT, and its disappearance after treatment of MM. In our case, monoclonal gammopathy had presented a progressive change from two monoclonal bands at the time of diagnosis of GD to one monoclonal band when malignant hematologic disease (plasmocytoma then myeloma) was diagnosed. A close attention to serum electrophoresis, proteinuria, and uncommon bone lesions is indicated in GD, even before the age of 50 years (age of plasmacytoma diagnosis in our case). Recent guidelines have been established about the management of haematological aspects of GD: at diagnosis patients should be examined for abnormal immunoglobulin profiles using a serum protein electrophoresis and an immunofixation test, then monitored every 2 years before the age of 50 years and every year afterward. In case of monoclonal gammopathies, any patient should have a bone marrow biopsy in search for abnormalities consistent with MM [2]. Incidence of malignant diseases was thought to be increased in patients with GD. Rosenbloom et al. [3] showed a sixfold increased risk of MM in 3,000 patients from the Gaucher registry compared to the estimated risk in US population, although incidence of other hematologic diseases or solid tumors did not differ. In Western Europe, de Fost et al. estimated, in 131 patients with GD with a follow-up for 20 years, an increased risk for cancer and hematologic malignancies of 2.5 and 12.7, respectively. In this study, incidence of MM in GD was increased with a standardized rate ratio of 51 [4]. Recently Taddei et al. [5] determined an increased lifetime risk of hematologic malignancies (relative risk 3.45) and particularly of MM (relative risk 25) from a cohort of 403 Gaucher patients with the N370S mutation which corresponds to our patient's genotype and has been established as the most common GD mutation among Ashkenazi Jewish and non-Jewish Caucasian patients. Monoclonal and polyclonal gammopathies have been reported frequently in type I GD, and it has been thought that there was a link between the increased risk for myeloma in this population and the incidence of gammopathies [6, 7]. Chronic antigenic stimulation by the abnormal lipid storage is supposed to be one of the mechanisms of immune dysfunction in patients with GD. In vitro studies revealed that exposure of cultured human monocytes to glucocerebroside led to release of cytokines able to stimulate lymphocytes [8]. It has also been suggested that accumulation of glycosphingolipid in Gaucher's cells was able to induce an immune response. Allen et al. [9] showed that IL 6 and IL 10 concentrations were significantly increased in patients with GD compared to controls. Thus, increased levels of IL6 may lead to plasmacytoma cells proliferation, as IL6 is known to stimulate plasma cells. Brautbar et al. [10] studied the effects of ERT on gammopathies in GD: polyclonal gammopathies (20% of study cohort) decreased significantly following ERT, especially IgG type. However, monoclonal gammopathies (1% of patients) were not modified. These results suggest that initially, stimulated plasmocytes are accountable of polyclonal gammopathies, responding to ERT. The question remains whether monoclonal gammopathy represents an evolution from a stimulated proliferation of plasma cells to an uncontrolled proliferation, or if monoclonal gammopathy is an independent process. In our case, monoclonal gammopathy was not modified by ERT but disappeared after autologous bone marrow transplantation. Grosbois et al. have reported the evolution of monoclonal gammopathy in a series of 17 Gaucher patients. Among the 13 patients treated with ERT, monoclonal gammopathy disappeared in three cases, decreased significantly in two, and remained unchanged in the last seven cases [11]. In conclusion, the case reported here emphasizes the need for monitoring serum electrophoresis closely in every GD patients to detect the onset of MM and haematologic malignancies and to treat them promptly. This case also suggests that prognosis of MM may not be worse for patients with GD, as regards to the evolution of MM or GD following usual treatments, including HSCT. However, it seems to remain a risk of recurrent malignancies justifying a close monitoring of these patients [12]. Alexandre Aubourg*, Lotfi Benboubker , Laurence Picon*, Philippe Goupille , Francois Maillot§, * Department of Hepatogastroenterology, CHRU Tours, Department of Hematology, CHRU Tours, Department of Rheumatology, CHRU Tours, § Department of Internal Medecine and Nutrition, CHRU Tours.