Gaucher Disease and LGL Proliferations: Provocative Commonality?

Abstract

Abstract 1100Large granular lymphocytes(LGL)which may be of T or NK phenotype, normally account for 10–15% of peripheral blood(PB)lymphocytes. T-LGL leukemia is a clonal expansion of antigen-primed competent cytotoxic-T-lymphocytes(CTL)which is unique in that these cells retain many phenotypic and functional properties of normal cytotoxic effector T cells. Sphingolipid-mediated signaling has been shown to have a role in long-term survival of CTLs.The diagnosis of T-LGL leukemia requires proof of clonality, yet clonal T-LGL proliferations may occur in normal individuals with autoimmune diseases, viral infections, B cell lymphoproliferations and post bone marrow transplantation rendering the differentiation of malignant (leukemic) from benign LGL expansions at times difficult. It has been suggested that T-LGL proliferations with polyclonal or oligoclonal TCR gene rearrangement may be a response to a stimulus before the emergence of a dominant clone.Gaucher disease (GD)is a lysosomal storage disease caused by mutations in the gene encoding acid β-glucocerebrosidase, leading to the accumulation of glucocerebroside in tissue macrophages (Gaucher cells) and resulting in hepatosplenomegaly, cytopenias and skeletal involvement. GD and T-LGL leukemia share strikingly similar clinical features, including cytopenias, splenomegaly, B cell dyscrasias, arthralgias, pulmonary hypertension (PHT), and increased association with neoplasms and autoimmune disorders. The etiology of PHT, B cell dyscrasias, and the increased frequency of neoplasms in GD remains unclear.Table 1 describes the characteristics of 4 GD patients suffering from severe cytopenias relative to the overall phenotype of their GD in whom LGL were found to comprise the majority of the PB lymphocytes. Patient #1: 31year-old female suffering from severe GD with massive splenomegaly and severe cytopenias but refuses Gaucher-specific therapy; Patient #2: 31year-old female has suffered from severe Gaucher disease since childhood, was splenectomized, has unexplained anemia and known LGL expansion for 7 years but clonality studies continue to be negative; Patient #3: 45 year-old female with severe GD, splenectomized, suffered from AVN, bone crisis autoimmune hemolytic anemia, PHT, and B cell dyscrasia; and Patient #4: 72 year-old male has asymptomatic GD with progressive pancytopenia who was diagnosed with myelodysplastic syndrome(MDS),T-LGL proliferation and monclonal gammopathy of unknown origin(MGUS). LGL cells comprised 70% of PB lymphocytes in addition there was severe trilineage dysplastic changes, TCR rearrangement was positive. Interestingly, 8 months after the start of enzyme replacement therapy(ERT),counts improved and the number of PB LGL was reduced to <10% of lymphocytes. In a cohort of 55 consecutive GD patients, 38% had LGL expansions in the PB smears. Since both conditions may be asymptomatic for many years, their co-existence can easily be missed.Table 1:Patient characteristics1234Age at diagnosis31314572GenderFemaleFemaleFemaleMaleSplenectomyNoYesYesNoBony diseaseAVNBone crisis, AVN, osteomyelitisNo?Pulmonary HypertensionNoNoYesNoAutoimmune phenomenonNoNoAIHANoB cell dyscrasiasYesNoPolyclonal hypergammagloblulinemiaMGUSOther neoplasmsNoNoNoMDSLeucocyte count (×10/ul)2.213.36.62.9LGL percent of lymphocytes52%62%30%70%LGL absolute count (×10/ul)0.55.111.10.532LGL phenotypeCD3+,CD8+, CD56+, CD16−, CD57−, TCR αβ+CD3+, CD8+, CD16−, CD56−, TCR αβ+?CD3+, CD8+, CD16−, CD56−, TCR αβ+2 populationsa) CD3+, CD8+, CD56+, TCR αβ+9.3g/dlb) CD3−,CD56+,CD4−, CD8−Hemoglobin (g/dl)4.911.311.4Platelet count (x10/ul)111779630TCR rearrangementNegativeNegativePositivePositiveBone marrow pattern of involvementMild interstitial infiltrate of small lymphocytes CD8+TMild interstitial infiltrate of small lymphocytes CD8+TERTNoYesYesYesERT: improvement of cytopeniasUntreatedNoNoYesThe co-existence of two hematological pathologies in more than one patient and the possibility that therapy for one may impact the other, is provocative. We suggest that LGL expansions in GD may be reactive to glucocereborside accumulation in Gaucher cells, and may play a pathogenic role in the development of some of the features of GD as well as induce/exacerbate some associated disorders. Disclosures:Zimran:Actelion: Honoraria.