Baker, R

Ganeshaguru, K

Krishnan, B

Mehta, AB

Richfield, L

English

UCL Discovery

Multidrug resiatance and myelomonocyticleukemia in Gaucher's diseaseGaucher's Disease (GD) is associated with anincreased risk of haematological malignancies. Wepresent a patient with GD who had a preleukaemicphase prior to developing acute leukaemia. Hepresented with a negative multidrug resistance(MDR) profile that became positive at relapse.Haematologica 2007; 88:(1)e3-e4Gaucher's Disease (GD) is the most common lysoso-mal storage disease. It results from a genetic deficiencyof the lysosomal enzyme ?- glucocerebrosidase causingan abnormal accumulation of glucocerebrosides inmacrophages. Type ? GD is the commonest, defined bythe absence of neurologic involvement. Characteristicfeatures include hepatosplenomegaly, skeletal involve-ment, elevated levels of serum ferritin, acid phosphatase,angiotensin converting enzyme and chitotriosidaseenzyme. Treatment consists of enzyme replacementtherapy (ERT).1 Haematological conditions reported inGD include benign monoclonal gammopathy, multiplemyeloma, Hodgkin's and non Hodgkin's lymphoma andall forms of leukaemia.2A male born in 1938 of Ashkenazi Jewish extractionwas diagnosed with type ? (genotype N370S/N370S) GDin 1974 when he presented with splenomegaly and mildthrombocytopenia. Bone marrow (BM) examinationrevealed classical Gaucher cells and leucocyte assay con-firmed a marked reduction in β-glucosidase enzymeactivity. In 1997 he presented with fatigue and bruising.Haematological and biochemical data are presented inTable 1. He was commenced on enzyme replacementtherapy (ERT) with cerezyme. This promptly improvedmarkers of GD activity with a reduction in spleen size,decrease in plasma chitotriosidase enzyme activity to251 nmol/h, but there was no significant improvementin the pancytopenia. By January 1999 (Table 1) dysplas-tic changes affecting all three cell lineages in addition toinfiltration by Gaucher cells was observed. A course ofintravenous immunoglobulin did not improve theplatelet count. He subsequently developed a blood pic-ture compatible with chronic myelomonocyticleukaemia (CMML). In September 2000 (Table 1) the BMcontained blasts cells (Figure 1) positive for CD117,CD34, CD13, and CD14 confirming a diagnosis ofAML/M4. The plasma chitotriosidase activity rose fromlate 1999 reaching 877 nmol/h in May 2000. He wasenrolled in the UKMRC AML14 trial and randomised toreceive DAT (daunorubicin, cytosine arabinoside,thioguanine) plus PSC 833, an inhibitor of P-glycoprotein(P-gp). He achieved a partial remission and proceeded toa second course of combination chemotherapy. His mar-row however failed to regenerate adequately. BM analy-sis revealed a hypoplastic marrow with no residualleukaemic cells. Subsequent cytogenetic analysisrevealed trisomy 8 confirming aggressive myelodyspla-sia. The BM in November 2001 showed 10% blasts; hisdisease progressed, he was treated palliatively and diedin March 2002.Multidrug resistance (MDR) may arise when cytotoxicagents are effluxed by malignant cells over-expressing P-glycoprotein (P-gp). The MDR profile and drug sensitiv-ity (IC50) on the patient's blast cells were investigatedby FACscan analysis and the cell viability assay (MTT)respectively.3 At presentation with AML, the blast cellswere rhodamine 123 (R123) efflux negative with normalexpression of P-gp, multidrug resistance protein (MRP1)and lung resistance protein (LRP). IC50 studies showedsensitivity to daunorubicin. Blast cells at relapse howev-er, showed significant efflux of R123 with overexpres-sion of P-gp (mean cell fluorescence, MCF 2.17 vs 0.94 atpresentation, overexpression MCF >1.1) reversible withverapamil, a known inhibitor of P-gp. Expression ofMRP, LRP and the IC50 for daunorubicin did not signifi-cantly change. The presentation cells were efflux-ve, P-gp-ve and acquired a effux+ve, P-gp+ve phenotype on relapseafter treatment with daunorubicin, a well characterisedinducer of MDR. The plasma chitotriosidase enzymeactivity that was near normalised with ERT increasedcoinciding with the onset of AML reflecting increasedturnover of cells imposing a burden on the reticulo-endothelial system .4All four reported cases of acute leukaemia in GD havedeveloped a myelomonocytic type of leukaemia follow-ing myelodysplasia.2,5 Our patient is the first to have hadhis MDR status studied and is the longest survivor. InGD the abnormal accumulation of glucocerebroside inBM, liver and spleen provides constant antigenic stimulihaematologica online 2003haematologica/the hematology journal | 2003; 88(online) | 3 |Figure 1 Bone marrow aspirate showing AML blasts cells.Table 1 Biochemical and haematological characteristics.to the immune system which may predispose to lym-phoid malignancy.6 Similarly, monocytes that are defec-tive due to excess glucocerebroside load could interferewith normal immune regulation. Consequently all casesof AML reported so far in GD are in the myelomonocyt-ic form.Although GD is rare its association with haematologi-cal malignancy is reasonably strong. A retrospectivestudy found a 3.6 and 14.7 fold risk of cancer andhaematological malignancy respectively in Jewishpatients.7 Alterations in ceramide metabolism may affectP-gp mediated drug resistance and that inhibitors of glu-cosylceramide synthesis may have a role in modulatingdrug resistance phenotype.8 We hope this report and dis-cussion will increase awareness of the risk of haemato-logical malignancy in GD, leading to earlier diagnosisand management.B. Krishnan, K. Ganeshaguru, R. Baker, L. Richfield, A.B. Mehta Department of Haematology, Royal Free Hospital and Royal Free& University College Medical School, Pond Street, London NW32QG, UKCorrespondence: Dr K. Ganeshaguru,Department of Haematology, Royal Free & University CollegeMedical School, Rowland Hill Street, London NW3 2PF, UK.Key words: Gaucher's Disease, AML, MDRReferences1.  Zimran A, Elstein D, Levy-Lahad E. Replacement therapy withiminiglucerase for type 1 Gaucher's Disease. Lancet 1995; 345,1479-1480.2. Bohm P, Kunz W, Horny H-P, Einsele H. Adult Gaucher'sDisease in association with primary malignant bone tumours.Cancer 2001; 91; 457-462.3.  Ganeshaguru K, Wickremasinghe RG, Jones DT, Gordon M,Hart SM, Virchis AE, Prentice HG, Hoffbrand AV, Man A,Champain K, Csermak K, Mehta AB. Actions of the selectiveprotein kinase C inhibitor PKC412 on B- chronic lymphocyticleukaemia cells in vitro. Haematologica 2002; 87; 167-176.4.  Aerts JMFG & Hollak CEM. Plasma and metabolic abnormal-ities in Gaucher's disease. Balliere's Clin Haematol 1997;10;691-709. Ed: Zimran A5. Gelfand MI, Gribogg SI. Gaucher's disease and acuteleukaemia. J Mt Sinai Hosp NY 1961; 28; 278-82. 6.  Shoenfeld Y, Gallant LA, Shaklai M, Livni E, Djaldetti M,Pinhas. Gaucher's disease: a disease with chronic stimulationof the immune system. Arch Pathol Lab Med 1982; 106; 388-91.7.  Shiran A, Brenner B, Laor A, Tatarsky I. Increased risk of can-cer in patients with Gaucher disease. Cancer 1993; 72; 219-224.8.  Lavie Y, Cao H, Volner A, Lucci A, Han T-Y, Geffen V, GiulianoAE, Cabot MC. Agents that reverse multidrug resistance,tamoxifen, verapamil, cyclosporin A, block glycospingolipidmetabolism by inhibiting ceramide glycosylation in humancancer cells, Journal of Biological Chem 1997; 272; 1682-7.B Krishnan et al.| 4 | haematologica/the hematology journal | 2003; 88(online)

Actions of the selective protein kinase C inhibitor PKC412 on B- chronic lymphocytic leukaemia cells in vitro. Haematologica

Adult Gaucher's Disease in association with primary malignant bone tumours. Cancer

Agents that reverse multidrug resistance, tamoxifen, verapamil, cyclosporin A, block glycospingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells,

Gaucher's disease and acute leukaemia.

Gaucher's disease: a disease with chronic stimulation of the immune system. Arch Pathol Lab Med

Increased risk of cancer in patients with Gaucher disease. Cancer

Plasma and metabolic abnormalities in Gaucher's disease. Balliere's Clin Haematol 1997;10; 691-709. Ed: Zimran A

Replacement therapy with iminiglucerase for type 1 Gaucher's Disease. Lancet

Multidrug resistance and myelomonocytic leukaemia in gaucher's disease

Multidrug resistance and myelomonocytic leukaemia in gaucher's disease

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