Gaucher Disease and Multiple Myeloma: A Diagnostic and Treatment Challenge

Abstract Abstract 2166 Background: Type I Gaucher disease (GD) is characterized by hepatosplenomegaly, pancytopenia and skeletal complications. Pancytopenia is attributed to the infiltration of bone marrow with the lipid laden Gaucher cells, fibrosis and hypersplenism. Bone involvement includes osteopenia, osteolytic lesions, pathological fractures, infarcts and avascular necrosis. Association between Type I Gaucher disease (GD) and hematological malignancies was suggested in several reports. Coexistence of GD and multiple myeloma (MM) was the most common neoplasm. Diagnosis of MM in GD patients is challenging due to the difficulty in identifying myeloma cells in the bone marrow heavily infiltrated with Gaucher cells, requiring immunohistochemistry, immunophenotyping, as well as molecular and cytogenetic evaluations. Bone complications in GD and MM may be similar, hindering the differential diagnosis of the two states. Treatment is also challenging because of the possible prolonged pancytopenia following intensive chemotherapy. The current study has summarized diagnostic and treatment approaches in patients with concomitant GD and MM. Methods and patients: Clinical and laboratory data of the cohort of 160 Type I GD patients followed at the Department of Hematology of the Rambam Medical Center (Haifa, Israel) were analyzed aiming to evaluate the incidence of MM and management of the disease in this specific population. Results: Among the 160 GD patients, 6 (3.7%) were diagnosed with MM. Five were males and one female, with a median age of 65 years (range 38–87) at diagnosis of both GD and MM. All these patients were of Ashkenazi descent, homozygous for N370S mutation and presented with moderate to severe pancytopenia at diagnosis. In 5/6 individuals, MM and GD were diagnosed concomitantly at presentation and only 1/6 developed MM during the follow up of known GD. The MM subtype included: IgGk (n=3) IgAl(n=1) and IgAk (n=2). Bone complications were found in all the 6 patients, including severe osteoporosis, lytic lesions and pathological fractures, which may be related to both GD and MM, while bone infarcts and avascular necrosis were typical of GD only. In one patient with resistant course of MM successful autologous peripheral stem cell transplantation (APBCT) was performed following intensive chemotherapy. Enzyme replacement therapy (ERT) which was initiated shortly after APBCT resulted in significant improvement in the response to MM treatment. Two other elderly patients were treated with melphalan and prednisone (in the pre-ERT era), resulting in a stable MM course. Three patients received ERT only for symptomatic GD and remained stable regarding MM, with an improvement in their GD status. Conclusion: GD appears to be associated with a higher incidence of MM compared to that reported for general population. Both diagnosis and treatment are challenging, given the presence of Gaucher cells in the bone marrow, interfering with identification of MM cells and resulting in pancytopenia, which makes treatment for MM more complicated and less effective. Therefore, therapy should include a combination of chemotherapy and ERT to prevent prolonged severe pancytopenia in GD and MM patients who are resistant to treatment. Disclosures: No relevant conflicts of interest to declare.

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Novel Management of Immune Thrombocytopenia in Gaucher Disease Patients

Blood ◽

10.1182/blood.v124.21.5006.5006 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5006-5006

Author(s):

Hanna Rosenbaum

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Avascular Necrosis ◽

Gaucher Disease ◽

Immune Thrombocytopenia ◽

High Dose ◽

Type I ◽

Platelet Counts ◽

Skeletal Complications

Abstract Type I Gaucher disease (GD) the is characterized by hepatosplenomegaly, pancytopenia and skeletal complications due to the accumulation of glucocerebroside in macrophages. Thrombocytopenia is usually related to hypersplenism and infiltration of bone marrow by lipid-laden macrophages namely Gaucher cells. Enzyme replacement therapy (ERT) restores the hemoglobin and platelet count in GD patients. In GD ERT treated patients, manifesting persistent low platelet counts, immune thrombocytopenia (ITP) should be considered.Treatment of GD with concomitant ITP is a challenge. Splenectomy may worsen bone manifestations in GD patients and is controversial. Steroids should be used with caution because of possible induction of osteopenia and joints avascular necrosis. Thrombopoietin receptor analogues (TPO-RA) are therapeutic option in GD patients with ITP. Beneficial use of TPO-RA is reported in 2 cases. Patient 1: 39 YO male with new onset of purpura and low platelet count failed treatment with 1 mg/kg of Prednisone. Bone marrow biopsy (BM) showed Gaucher cells infiltration, numerous atypical megakaryocytes, normal erythropoiesis and myelopoiesis with no fibrosis. Low level of ß-glucocerebrosidase activity with compound heterozygosity for 84GG /R495H mutations, established the diagnosis of Type I GD. Low C4 and detection of IgG platelet antibodies added to the diagnosis of concomitant immune thrombocytopenia. ERT with taliglucerase alfa (ElelysoTM) 60 Units/kg/month was given with Prednisone for six weeks. Occurrence of retinal bleeding and purpura, with decrease of platelet count necessitated addition of high-dose IVIG with no response regarding platelet counts. Splenectomy was not considered due to known bony complication risk in splenectomised GD patients. Rituximab was given to prevent wet purpura recurrence with short response regarding platelet count. Romiplostim was initiated raising platelet count from 29,000/µL to 60,000/µL after 3 wks. and to 90,000/µL after 8 wks. enabling corticosteroids withdrawal. Same dose Romiplostim is maintained for the last 30 months with platelet counts of 90,000 - 110,000/µL with no bleeding events. Repeated BMB showed no increase in collagen fibrosis. Patient 2: 63 YO female patient diagnosed with Gaucher at age 33 with a history of purpura, ecchymosis, and occasional vaginal bleeding episodes. At age 53 the platelet count dropped to < 20,000/µL with presence of Anti Platelets Ab (IgG). BMB revealed megakaryocytic hyperplasia with atypical forms, focal infiltration by Gaucher cells and no fibrosis. Combined therapy by ERT (Imiglucerase® followed by Velaglucerase Alfa®), Prednisone (1mg/kg/d for 2 months) and one course of IVIG yielded no increase in platelet count. The patient refused Rituximab®. Romiplostim was initiated increasing platelet count to100,000/µL maintained throughout a year of follow up. Repeated BMB showed slight increase of fibrosis and marked hyperplasia of atypical megakaryocytes. Discussion: Thrombocytopenia is often present in GD and may be severe in approximately 15% of the patients. Persistent cytopenias may be caused by other underlying pathologies such as autoimmune disorders and are important to be recognized and addressed. Before ERT era GD patients with hypersplenism and severe cytopenia were splenectomised. Risks of splenectomy include serious bacterial infection and vascular complications limiting its use in chronic refractory ITP. Splenectomy is avoided in Gaucher patients, due to risk of exacerbating skeletal complications (bone infarcts, avascular necrosis). Stable bone marrow results regarding fibrosis in our patients are consistent with data from a recent 2-year follow-up of 100 ITP patients receiving Romiplostim treatment with no evidence of BM fibrosis. Conclusion: In patients with type I Gaucher disease and concomitant ITP, adjunctive treatment with Romiplostim was successful in maintaining haemostatic platelet counts with no adverse effects. Traditional treatment regimens of corticosteroids and splenectomy should be used with caution or avoided in GD patients due to possible aggravation of Gaucher skeletal disease and the risk of osteopenia and avascular necrosis resulting in increased morbidity in this cohort of patients. Use of TPO-RA should be considered in GD patients with ITP. Disclosures Off Label Use: Romiplostim in gaucher patients.

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Immune Thrombocytopenia in Type I Gaucher Disease.

Blood ◽

10.1182/blood.v110.11.3200.3200 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3200-3200 ◽

Cited By ~ 2

Author(s):

Hanna Rosenbaum ◽

Tina Napso ◽

Lilach Bonstein

Keyword(s):

Bone Marrow ◽

Gaucher Disease ◽

Immune Modulation ◽

Hematological Parameters ◽

Autoimmune Disorder ◽

Type I ◽

Bleeding Tendency ◽

Platelet Surface ◽

Platelet Counts ◽

Enzyme Replacement

Abstract Backgound: Type I Gaucher disease (GD) the non-neuronopathic form is characterized by hepatosplenomegaly, pancytopenia and skeletal complications due to the accumulation of glucocerebroside in macrophages. Thrombocytopenia is usually related to hypersplenism and/or infiltration of bone marrow by the lipid-laden macrophages namely Gaucher cells. Enzyme replacement therapy (ERT) restores the hemoglobin and platelet count in treated GD patients within 12–24 months of treatment. In GD patients, including ERT treated, with persistent low platelet counts other ethiological factors should be considered. Goals: To determine the etiology of persistent thrombocytopenia in Type I GD patients and to evaluate their clinical course and hematological parameters. Methods: Flow cytometric technique was used to detect platelet-surface associated IgG/M (PSIgG/M) in a cohort of 24 Type I GD patients followed at the Gaucher clinic in Haifa, Israel. The evaluated hematological parameters of the thrombocytopenic GD patients include: bleeding phenomena, concurrence of autoimmune phenomena, hematological malignancies and bone marrow findings. Results: Twenty four Type I GD patients, 15 females and 9 males with an age range of 35 to 80 years (median 53 years) were included in the study. Seventeen of the evaluated 24 patients were thrombocytopenic with platelet counts less than <100×109/l and 7/24 were in the normal range. Bone marrow aspirate was performed in 16 of the 17 thrombocytopenic patients and showed normal or hyperplasic megakariopoiesis together with Gaucher cells infiltrates. Six of the 17 thrombocytopenic patients received ERT for at least 24 months with no effect on the low platelet counts. Elevated platelet surface IgG was detected in 16/17(94%) of GD patients with thrombocytopenia and in only 1/7 (14%) of non thrombocytopenic patients (p<0.0001). In 6/17 of the thrombocytopenic patients, surface IgM (PSIgM) was found, in addition to the PSIgG. Those six patients are known with monoclonal IgM (concomitant Waldenstrom macroglobulinemia), markedly elevated polyclonal IgM levels, or lupus like autoimmune disorder which may have been responsible for the positive PSIgM. Only three thrombocytopenic patients with platelet counts less than 40×109/l had bleeding tendency (mainly purpura) with no response to steroid treatment (two of them were also resistant to ERT concerning their thrombocytopenia). Conclusions: Thrombocytopenia in Type I GD is related to either infiltration of bone marrow compromising megakariopoiesis or hypersplenism, but immune factors should also be considered. Despite the lack of response to steroids, the observed megakaryocytic hyperplasia in Gaucher infiltrated marrows, the failure to respond to ERT, and the presence of platelet surface antibodies in the thrombocytopenic patients, strongly implicate autoimmune etiology. The present study demonstrates that surface platelet antibodies may play a role in refractory thrombocytopenic GD patients. Since the role of splenectomy is controversial in GD, immune modulation approach should be considered.

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Prognostic Significance of Morphological Evaluation of Tumor Cells in Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.4889.4889 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4889-4889

Author(s):

Mohammed Al-sahmani ◽

Irena Trnavska ◽

Monika Antosova ◽

Libuse Antosova ◽

Jarmila Kissova ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Treatment Response ◽

Plasma Cell ◽

Diagnostic Procedures ◽

Lower Number ◽

Lower Percentage ◽

Type I ◽

Prognostic Impact ◽

Type Ii

Abstract Abstract 4889 Multiple myeloma (MM) is the second most common hematological malignancy. It is caused by clonal proliferation of terminally differentiated cells of B-lineage. Morphology assessment including the determination of plasma cell percentage in the bone marrow remains one of the basic diagnostic procedures even in the era of genomics. The objective of this study was to evaluate the prognostic impact of the presence of different plasma cell morphological subtypes on overall treatment response and long-term survival. We also analyzed whether this parameter can be correlated to other conventional prognostic/predictive markers. Our cohort consisted of 139 newly diagnosed MM patients who subsequently underwent autologous transplantation (AT) within the 4W and CMG 2002 clinical trials in a single center. Percentage of plasma cell subtypes in the bone marrow was evaluated based on the progressive nucleolus analysis, assessment of nuclear chromatin, and the nucleus/cytoplasm (N/C) ratio. A combination of these elements permits differentiation of eight subtypes P000-P111 and four subclassifications. Mature plasma cells (P000, P001) were found in 42.4% of patients; type I proplasmocytes (P010, P011, P100) in 38.1% of patients; and type II proplasmocytes (P101, P110) in 19.4% of patients. For patients undergoing AT, there was a statistically significant association between the presence of P000 subtype and overall treatment response whereas group of patients with overall therapeutic response ORR has lower number of mature plasma cell (P000 subtype) than patients without treatment response (median 24.0% vs. 36.0%, p = 0.032). Patients with <10% bone marrow infiltration by mature plasmocytes (P000 subtype) had shorter overall survival compared with patients with P000 percentage of ≥37% (46.8 months vs. 77.8 months; p = 0.020). The presence of <3% proplasmocytes (P110 subtype) was associated with longer time to progression compared with P110 ≥31% infiltration (median: 54.6 months vs. 22.4 months; p=0.045). Patients in ISS stage 1 or 2 had lower percentage of P010 (type I) proplasmocytes than patients in stage 3 (11.5% vs. 23.0%; p=0.030). In contrast, higher infiltration of P100 (type I) proplasmocytes and P101 (type II) proplasmocytes was observed in patients in 1-2 ISS stage compared with stage 3 patients (12.0% vs. 6.5%; p=0.015 for P100 and 1.0% vs. 0.0%; p=0.046 for P101). Patients without deletion of 13q14 chromosome had higher bone marrow percentage of mature P000 plasmocytes than patients with deletion of 13q14 (35% vs. 13%; p=0.014). Deletion of 13q14 was also associated with lower number of type II P110 proplasmocytes (36.5% vs. 6.0%; p=0.012). Despite advances in high-tech genomic technologies, evaluation of plasmocyte infiltration of the bone marrow still belongs to basic diagnostic procedures in MM and further morphological subtyping of plasmocytes should provide important prognostic information for MM patients treated by autologous stem cell transplantation. Supported by grants MSM 0021622434, MŠMT LC06027, MZCR NR9225-3 and IGA NR9225-3. Disclosures No relevant conflicts of interest to declare.

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149. Avascular Necrosis in type I Gaucher disease: Analysis of risk factors

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2008.11.150 ◽

2009 ◽

Vol 96 (2) ◽

pp. S45

Author(s):

Neal Weinreb ◽

Patrick Deegan ◽

Ashok Vellodi ◽

J. Alexander Cole ◽

Michael Yeh ◽

...

Keyword(s):

Risk Factors ◽

Avascular Necrosis ◽

Gaucher Disease ◽

Type I ◽

Disease Analysis

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Successful and uncomplicated transfer of MRI Quantitative Chemical Shift Imaging (QCSI) technology for the detection of bone marrow fat signal fraction in type I Gaucher disease

Medical Research Archives ◽

10.18103/mra.v0i3.158 ◽

2015 ◽

Author(s):

Annick Vanclooster ◽

Wouter Meersseman ◽

Mario Maas ◽

Stefan Ghysels ◽

Ronald Peeters ◽

...

Keyword(s):

Bone Marrow ◽

Chemical Shift ◽

Gaucher Disease ◽

Chemical Shift Imaging ◽

Type I ◽

Marrow Fat ◽

Bone Marrow Fat ◽

Quantitative Chemical

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Host Immune Responses Against CT Antigens in Multiple Myeloma Patients.

Blood ◽

10.1182/blood.v108.11.3492.3492 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3492-3492 ◽

Cited By ~ 1

Author(s):

Nikoletta Lendvai ◽

Sacha Gnjatic ◽

Erika Ritter ◽

Yao-Tseng Chen ◽

Christina Coughlin ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Immune Responses ◽

Humoral Immunity ◽

Cellular Immunity ◽

Therapeutic Vaccine ◽

Type I ◽

Humoral And Cellular Immunity ◽

Ct Antigen ◽

Ct Antigens

Abstract The type I Melanoma Antigen GEne (MAGE) proteins belong to the Cancer-Testis (CT) family of tumor-associated antigens and are widely expressed in solid and hematologic malignancies. They are immunogenic and frequently elicit spontaneous immune responses in patients with CT antigen-expressing tumors, particularly in malignant melanoma. In melanoma patients, there is high concordance between humoral and cellular immunity. Based on these findings, CT antigens are widely investigated as potential antigenic targets for tumor-specific therapeutic vaccines. We previously showed that the type I MAGE proteins CT7 (MAGE-C1), CT10 (MAGE-C2) and MAGE-A3 were commonly detected in primary myeloma specimens, and expression of CT7 and MAGE-A3 was correlated with abnormally elevated plasma cell proliferation. These findings suggest that type I MAGE may be rational targets for vaccine therapy in multiple myeloma. Therefore, it is important to determine if type I MAGE elicit cellular or humoral immune responses in myeloma patients. To investigate this hypothesis, we assessed cellular immunity against CT7 and humoral immunity against a broad panel of CT antigens. To quantify CT7-specific cellular immunity, expanded, polyclonal pools of T cells from the bone marrow, the tumor microenvironment, were co-cultured in interferon gamma (IFNγ) ELISpot assays with autologous antigen-presenting cells (APC) transduced with in vitro transcribed mRNA coding for CT7 or control antigens. CT antigen-specific humoral immunity was examined by ELISA assay using patient serum or plasma and recombinant CT antigens. This analysis demonstrated that 2/9 patients exhibited specific T cell immunity against CT7 in their bone marrow lymphocytes as measured by IFNγ secretion. These same two patients had positive titers for other CT antigens; one for MAGE-A1 (another type I MAGE), the other for SSX-1 (a structurally distinct CT antigen). Interestingly, neither patient had positive serology for CT7. Serum from 16 other myeloma patients did not have detectible antibody titers for a broad panel of CT antigens. These results show that CT antigens are immunogenic in myeloma patients, with cellular responses against CT7 and humoral responses against MAGE-A1 and SSX-1. However, unlike other types of cancer, there appears to be discordance between humoral and cellular immunity against CT7 in multiple myeloma. This may be due in part to the significant derangements of humoral immunity in this disease. These results support further investigation of immunologic therapies targeting type I MAGE in myeloma, especially therapeutic vaccine strategies.

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Increased Incidence of Autoimmune and Lymphoproliferative Disorders in Gaucher Patients Accompanied with Significantly Impaired Dendritic Cell Function,

Blood ◽

10.1182/blood.v118.21.3211.3211 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3211-3211

Author(s):

Hanna Rosenbaum ◽

Noam Bettman ◽

Tamar Katz ◽

Irit Avivi

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Gaucher Disease ◽

Hematological Malignancies ◽

Cell Polarization ◽

Lymphoproliferative Disorders ◽

T Cell Response ◽

Type I ◽

T Cell Polarization ◽

Autoimmune Phenomena

Abstract Abstract 3211 Background: Type I Gaucher disease (GD) is characterized by hepatosplenomegaly, pancytopenia and skeletal complications. Recent studies report an increased incidence of autoimmune complications and lymphoproliferative malignancies in patients with Gaucher disease (GD), suggesting the existence of an impaired immune function. The current study has investigated whether the inherent accumulation of glucocerebrosidase in monocytes and macrophages results in abnormal function of monocyte-derived dendritic cells (DCs). According to our hypothesis, this could lead to abnormal T cell polarization (regulatory versus effector cells) and function, partly explaining the markedly increased incidence of both autoimmune and hematological malignancies observed in this patient population. Patients and Method: Thirty three GD patients, followed at the Gaucher clinic of the Rambam Health Care Campus (Haifa, Israel), were enrolled. The study was approved by the local IRB. Monocyte-derived DCs were assessed to determine their functional properties.CD14+ monocytes were isolated from peripheral blood mononuclear cells (PBMCs) of untreated GD patients and healthy volunteers, using immunomagnetic bead separation (Miltenyi Biotec). Monocytes were developed into immature DCs (iDCs) with granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 4 to 6 days. The iDC ability to process antigens was evaluated by an antigen uptake assay using 1mg/ml FITC-dextran. Mannose receptor-mediated endocytosis was measured by determining the cellular uptake of FITC-dextran, using FACS. iDCs were maturated with tumor necrosis factor α (TNF-α) for 48 hours. Stimulatory capacity of mature DCs (mDCs) was estimated by measuring the allogeneic T cell response, induced by stimulation with mDCs. T cell response was examined using proliferation and INF-g expression assays. Clinical data focusing on autoimmune phenomena and coexistence of hematological malignancies, mainly lymphoproliferative disorders (lymphoma, multiple myeloma and monoclonal gammopathy), were retrospectively collected from patient charts. Results: Thirty three type I GD patients, 19 males and 14 female, with a median age at analysis of 50.5 years (range 20–74), were included in the analysis. Eight (24%) patients presented with clonal lymphoproliferative disorders, including malignant lymphoma (2), multiple myeloma (3) and monoclonal gammopathies (3). In 15/33 (45%) patients, autoimmune phenomena were revealed. In 12/15 thrombocytopenic GD patients, platelet antibodies were detected, suggesting immune etiology of their thrombocytopenia. Antiphospholipid and antiDNA antibodies were found in 3 other patients with no clinical evidence for autoimmune complications. All these complications appeared prior to the administration of enzyme replacement therapy (ERT). Immunological assessment, performed in 10 untreated patients from this cohort and compared with 10 healthy volunteers, revealed a decrease in the patient DC uptake capacity compared to that observed in DCs obtained from healthy subjects (Table 1). Additionally, GD-derived DCs exhibited impaired maturation, reflected by their limited ability to induce T cell activation, as demonstrated by decreased INF-γ secretion levels and proliferation capacity (Table 1). Conclusions: Forty five percent of the evaluated type I Gaucher patients exhibited autoimmune phenomena. Additionally, 24% presented with lymphoproliferative disorders. DC function analysis showed a significant impairment of both iDCs and mDCs, reflected by their decreased uptake and antigen presenting capacities. These abnormalities may adversely affect T cell polarization and functional abilities, resulting in autoimmune complications as well as hematological clonal disorders. Further studies, exploring the precise association between the existence of autoimmune/lymphoproliferative disorders, and the observed in vitro immunological impairment are required. Disclosures: No relevant conflicts of interest to declare.

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