University of Groningen Multiple aspects of a plasma cell dyscrasia de Waal, Elisabeth Geertruida Maria

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University of Groningen

Multiple aspects of a plasma cell dyscrasia

de Waal, Elisabeth Geertruida Maria

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Publication date: 2018

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de Waal, E. G. M. (2018). Multiple aspects of a plasma cell dyscrasia. Rijksuniversiteit Groningen.

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CHAPTER 8

Thalidomide and dexamethasone

followed by autologous stem cell

transplantation for scleromyxedema

Reinhard Bos,1

Esther de Waal,2

Hilde Kuiper,3

Bouke P.C. Hazenberg,1

Edo Vellenga2 1_{University Medical Center Groningen, Department of Rheumatology & Clinical Immunology,}

The Netherlands;

2_{University Medical Center Groningen, Department of Hematology, The Netherlands;} 3_{University Medical Center Groningen, Department of Pathology, The Netherlands.}

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R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39 Chapter 8 110

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R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30

8

Sir,

Scleromyxedema is a rare disease which mimics systemic sclerosis. Subtle differences are a waxy non-pruritic eruption over the thickened skin, and the more proximal onset of skin thickening. Systemic manifestations include gastrointestinal, lung or heart involvement. In scleromyxedema the fibroblast is affected by an unrecognized mechanism, resulting in excessive mucin deposition1_{. Most intriguing is the finding of a paraprotein type IgG lambda}

(IgG-λ) in 80% of cases which is the basis that patients are frequently treated with regimens according to myeloma patients.

A 45-year-old woman was referred to our hospital for progressive thickening and tightening of the skin. Her medical history revealed a transient ischemic attack and hypertension three years before presentation. During the last two years she noted a progressive skin thickening. Due to the thickening of the skin she could not make a tight fist. She recently noticed Raynaud’s phenomenon without other complains. A skin biopsy revealed the diagnosis scleromyxedema. In the same period a ductal carcinoma of the right breast was diagnosed (T₁N₀M₀). Treatment consisted of lumpectomy and radiotherapy, but skin abnormalities progressed in the following six months.

At presentation her general physical examination was unremarkable. Her musculoskeletal and skin examination revealed a thickened skin of the fingers, wrists, upper arms, shoulders, around the mouth and forehead, and the upper and lower legs which resulted in a modified Rodnan total skin score (mRTSS) of 34 out of 512_{. A skin-colored papular eruption was present}

at the wrists. She was not able to make a tight fist, and had a reduced oral aperture of 4 cm. Laboratory investigations showed no abnormalities apart from an IgG-λ of 5.7 g/l. Free light chain lambda and kappa concentrations were within the reference ranges. ANA and ENA were negative, complement C3 1.1 g/l, complement C4 0.2 g/l, rheumatoid factor 10 kIU/l. Further investigations of internal organs showed reduced digital perfusion after cooling, a normal pattern at nailfold capillary microscopy, a disturbed esophagus scintigraphy indicating dysmotility and a slightly reduced lung diffusion capacity of 78% of predicted. Bone marrow biopsy and cytogenetic analysis, subcutaneous fat biopsy for amyloidosis, radiology of the skeleton and cardiac ultrasound did not show any abnormalities.

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complications. Current follow-up till 31 months showed a mRTSS of 0 without paraprotein. Her Raynaud’s phenomenon disappeared and the ranges of motion of her oral aperture and the wrists returned to normal. ANA screening remains negative.

For scleomyxedema different treatment regimens have been applied, including corticosteroids, hydroxychloroquine, azathioprine, interferon, cyclophosphamide, oral melfalan, and intravenous immunoglobulin, with disappointing results. However, especially treatment with high-dose chemotherapy directed against the aberrant monoclonal plasma cell population showed positive results in line with results obtained in AL-amyloidosis and POEMS disease4_.

In 2001 Donato et al were the first to describe the positive results of high dose melphalan in the setting of autologous stem cell transplantation (ASCT) in scleromyxedema. In 2006, the same group published a cohort of 7 patients treated with ASCT5_{. In this study no induction}

regimen was applied before ASCT. Also, most of the included patients had extensive disease, some requiring tube feeding due to gastrointestinal dysfunction. From 2001 till now ASCT has been described in 17 scleromyxedema patients including our patient as depicted in Table 1.

Table 1: Results of ASCT in scleromyxedema

Study

(ref) Patients no Pretransplan-tation-treatment Mobilization scheme Conditioning regimen Remission status Survival

I5 _n=7 _No _G-CSF _melphalan (180 mg/m2₎ CR (N=5); _{PR (n=2)} Relapse _{(n=4; 4, 8, 12} months) II6 _n=5 _No _{Cyclo plus G-CSF} (n=4), G-CSF (n=1) HDM or melphalan (140 mg/m2₎ (n=1) CR (n=2); PR (n=2); Stable (n=1) Relapse (n=3; 14, 37 and 45 months) III7 _n=1 _No _{Cyclo plus G-CSF BU plus}

melphalan (140 mg/m2₎

CR CR (>60 months) IV8 _n=1 _No _HDM _{PR, CR after}

sec ASCT relapse (30 months) V9 _n=1 _No _BEAM _PR _{PR (>36}

months) VI10 _n=1 _No _G-CSF _HDM _{NE, †}

VII* n=1 dexamethasone/

thalidomide CAD plus G-CSF HDM CR CR (31 months) G-CSF: Granulocyte colony-stimulating factor; CR: complete remission; PR: partial remission; Cyclo: cyclophosfamide; HDM: High dose melphalan (200 mg/m2_{); BU: busulfan; ASCT: autologous stem}

cell transplantation; BEAM: BCNU, etoposide, ARA-C and melphalan; NE; not evaluable; CAD; cyclophosfamide, adriamycine and dexamethasone. VII*: present case.

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Complete remission (CR) defined as disappearance of all the clinical symptoms, skin abnormality and serum paraprotein was obtained in 58 % and partial remission (PR) defined as significant improvement but without normalization was obtained in 29 % of the patients. At a median follow up of more than 40 months (range 14 - >60 months) persistent CR was only demonstrated in 12% of patients.

These data demonstrate the positive effects of intensive chemotherapy directed against the aberrant plasma cell population in scleromyxedema. However, a high number of patients relapsed which might be due to the fact that the transplantation was performed at a late stage of the disease. Further improvement might be obtained by applying a pre-induction regimen with thalidomide and dexamethasone upfront ASCT thereby reducing the total tumor mass before transplantation which might further improve the long-term outcome. Rheumatology key message

Treatment of scleromyxedema with a pre-induction of thalidomide and dexamethasone upfront ASCT might further improve the long-term outcome.

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References

1. Rongiolette F, Rebora A. Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol 2001;44:273-81.

2. Clements P, Lachenbruch, Siebold J, White B, Weiner S, Martin R, et al. Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol 1995;22:1281-85.

3. Lokhorst HM, Van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood 2010;115:1113-20.

4. Foti R, Leonardi R, Rondinone R, Di Gangi M, Leonettie C, Canova M, et al. Scleroderma-like disorders. Autoimmunity Reviews 2008;331-39.

5. Donato ML, Feasel AM, Weber DM, Prieto VG, Giralt SA, Duvic M. Scleromyxedema: role of high-dose melphalan with autologous stem cell transplantation. Blood 2006;107:463-66.

6. Lacy MQ, Hogan WJ, Gertz MA, Dispenzieri A, Rajkumar SV, Hayman S, et al. Successful treatment of scleromyxedema with autologous peripheral blood stem cell transplantation. Arch Dermatol 2005;141:1277-82.

7. Cheng T, Gnankumar V, Hededus C, Stewart DA. Complete and durable remission in a patient with life threatening scleromyxedema treated with high dose melphalan and BU with auto-SCT. Bone Marrow Transplant 2008;42:215-17.

8. Ataergin S, Arpaci F, Dermiriz M, Ozet A. Transient efficacy of double high dose chemotherapy and autologous peripheral stem cell transplantation, immunoglobulin, thalidomide, and bortezomib in the treatment of scleromyxedema. Am J Clin Dermatol. 2008;9:271-73.

9. Illa I, de la Torre C, Rojas-Garcia R, Altes A, Blesa R, Sierra J, et al. Steady remission of scleromyxedema 3 years after autologous stem cell transplantation: an in vivo and in vitro study. Blood 2006;108:773-74.

10. Iranzo P, Lopez-Lerma I, Blade J, Rovira M, Herrero C. Scleromyxoedema treated with autologous stem cell transplantation. J Eur Acad Dermatol Venereol 2007;21:129-30.

University of Groningen Multiple aspects of a plasma cell dyscrasia de Waal, Elisabeth Geertruida Maria