Slow increase of bilirubin concentration during administration of lenalidomide, bortezomib and dexamethasone for multiple myeloma (unmasking previously undiagnosed Gilbert syndrome) and disappearance of necrobiotic xanthogranuloma after complete remission of multiple myeloma

Česká verzia

Authors: Z. Adam ¹; Z. Řehák ²; Z. Adamová ³; L. Pour ¹; K. Dvořáková ⁴; B. Packová ⁵; R. Koukalová ²; Martin Krejčí ^1*; Marta Krejčí ^1**; M. Štork ¹; V. Sandecká ¹; I. Boichuk ¹; Z. Král ¹
Authors place of work: Interní hematologická a onkologická klinika LF MU a FN Brno ¹; Oddělení nukleární medicíny, MOU Brno ²; Chirurgické oddělení, Nemocnice ve Frýdku-Místku ³; Patologicko-anatomické oddělení, Nemocnice Jihlava ⁴; Interní gastroenterologická klinika LF MU a FN Brno ⁵
Published in the journal: Klin Onkol 2022; 35(4): 315-322
Category: Case Report
doi: https://doi.org/10.48095/ccko2022315

Summary

Background: Lenalidomid ranks among immunomodulatory drugs. There are a few of the more common side effects, like a higher risk of venous trombembolism or diarrhea. Other side effects are rare. The hyperbilirubinemia described in this article can be assigned to them. In our case, the increase of bilirubin was associated with unrecognized Gilbert syndrome. Case description: We report a patient with multiple myeloma and necrobiotic xanthogranuloma (NXG) of the skin and liver. After the treatment with bortezomib, lenalidomid and dexamethasone, complete remission was attained after 4 cycles with decrease of monoclonal immunoglobulin to an unmeasurable concentration. At the same time, the disappearance of cutaneous and hepatic lesions of NXG on FDG-PET/CT was evident. The administration of bortezomib was stopped after 8 cycles and only continued with lenalidomide as a maintenance therapy. However, after four cycles of this therapy, bilirubin increased above the upper limit and the increase continued till the 11^th month of lenadomide administration, when bilirubin reached the highest concentration of 75 μmol/l (more than the three-fold of the upper limit, grade III toxicity). The patient had asymptomatic hyperbilirubinemia with no underlying liver disease or renal impairment while being on lenalidomide therapy. Genetic studies proved mutation; insertion in the promotor gene UGT1A1 typical for Gilbert syndrome. Hyperbilirubinemia may be attributed to the unmasking of previously undiagnosed Gilbert syndrome. Therefore, the therapy with lenalidomide was interrupted after 11 months. The bilirubin level decreased after the discontinuation of the drug. Conclusion: NXG disappeared after fulfilling complete remission of multiple myeloma with disappearance of monoclonal immunoglobulin. This observation supports the hypothesis that monoclonal immunoglobulin has a crucial role in the ethiopathogenesis of NXG and suggests the treatment of monoclonal gammopathy if present in a patient with NXG, hoping that this will result in xantogranuloma disappearance.

Keywords:

Multiple myeloma – necrobiotic xanthogranuloma – monoclonal Gilbert syndrome – hyperbilirubinemia

Zdroje

1. Nelson CA, Zhong CS, Hashemi DA et al. A multicenter cross-sectional study and systematic review of necrobiotic xanthogranuloma with proposed diagnostic criteria. JAMA Dermatol 2020; 156 (3): 270–279. doi: 10.1001/jamadermatol.2019.4221.

2. Král Z, Krejčí M, Kynclová J et al. Nekrobiotický xantogranulom asociovaný s monoklonální gamapatií: popis případu a přehled léčebných možností. Transfuze Hematol dnes 2020; 26 (4): 310–319.

3. Zahradová L, Adam Z, Fait J et al. Nekrobiotický xantogranulom – vzácná kožní komplikace u nemocného s mnohočetným myelomem. Vnitr Lek 2010; 56 (Suppl 2): 179–182.

4. Sýkorová T. Histiocytózy z non-Langerhansových buněk. Klinická dermatovenerologie. Praha: Mladá fronta 2019: 1027–1036.

5. Adam Z, Zahradová L, Krejčí M. Difuzní plošná normolipemická xantomatóza a nekrobiotický xantogranulom, asociované s monoklonální gamapatií – přínos PET-CT pro stanovení rozsahu nemoci a zkušenosti s léčbou. Popis dvou případů a přehled literatury. Vnitr Lek 2010; 56 (11): 1158–1159.

6. Adam Z, Veselý K, Motyčková I et al. Eyelids with yellow granulomas and cough – periocular xanthogranuloma associated with adult-onset asthma. A case study and an overview of clinical forms of juvenile xanthogranuloma and its therapy. Vnitr Lek 2012; 58 (5): 365–377.

7. Szalat R, Pirault J, Fermand JP et al. Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy. J Intern Med 2014; 276 (3): 269–284. doi: 10.1111/joim.12195.

8. Szalat R, Arnulf B, Karlin L et al. Pathogenesis and treatment of xanthomatosis associated with monoclonal gammopathy. Blood 2011; 118 (14): 3777–3784. doi: 10.1182/blood-2011-05-356907.

9. Miguel D, Lukacs J, Illing T et al. Treatment of necrobiotic xanthogranuloma – a systematic review. J Eur Acad Dermatol Venereol 2017; 31 (2): 221–235. doi: 10.1111/jdv.13786.

10. Wick MR, Patterson JW. Cutaneous paraneoplastic syndromes. Semin Diagn Pathol 2019; 36 (4): 211–228. doi: 10.1053/j.semdp.2019.01.001.

11. Hilal T, DiCaudo DJ, Connolly SM et al. Necrobiotic xanthogranuloma: a 30-year single-center experience. Ann Hematol 2018; 97 (8): 1471–1479. doi: 10.1007/s00277-018-3301-1.

12. Khoschbin T, Löser C, Dippel E. Paraneoplastic skin diseases. Internist 2019; 60 (8): 775–782. doi: 10.1007/s00 108-019-0636-1.

13. Weidenthaler-Barth B. Clinical and histological spectrum of palisaded granulomatous dermatitides: granuloma annulare, necrobiosis lipoidica, rheumatoid nodules, and necrobiotic xanthogranuloma. Hautarzt 2017; 68 (7): 536–541. doi: 10.1007/s00105-017-39 95-3.

14. Nguyen BD. Hepatobiliary and pancreatic: hepatic necrobiotic xanthogranuloma. J Gastroenterol Hepatol 2017; 32 (10): 1667. doi: 10.1111/jgh.13858.

15. Santosaputri E, Ellis EJ, Nagiah S et al. A multisystem granulomatous disease: necrobiotic xanthogranuloma with hepatic involvement. Med J Aust 2014; 200 (8): 490–493. doi: 10.5694/mja13.11303.

16. Mello RB, Vale ECSD. Necrobiotic xanthogranuloma associated with smoldering multiple myeloma: satisfactory response to cyclophosphamide, dexamethasone, and thalidomide. An Bras Dermatol 2019; 94 (3): 337–340. doi: 10.1590/abd1806-4841.20198500.

17. Efebera Y, Blanchard E, Allam C et al. Complete response to thalidomide and dexamethasone in a patient with necrobiotic xanthogranuloma associated with monoclonal gammopathy: a case report and review of the literature. Clin Lymphoma Myeloma Leuk 2011; 11 (3): 298–302. doi: 10.1016/j.clml.2011.03.020.

18. Mahendran P, Wee J, Chong H et al. Necrobiotic xanthogranuloma treated with lenalidomide. Clin Exp Dermatol 2018; 43 (3): 345–347. doi: 10.1111/ced.13293.

19. Dholaria BR, Cappel M, Roy V. Necrobiotic xanthogranuloma associated with monoclonal gammopathy: successful treatment with lenalidomide and dexamethasone. Ann Hematol 2016; 95 (4): 671–672. doi: 10.1007/s00277-016-2604-3.

20. Ghani S, Al Ustwani O, Khalid B et al. Periorbital necrobiotic xanthogranuloma treated successfully with novel multiple myeloma therapy. Clin Adv Hematol Oncol 2013; 11 (10): 678–680.

21. Olson RM, Harrison AR, Maltry A et al. Periorbital necrobiotic xanthogranuloma successfully treated with intravenous immunoglobulin. Case Rep Ophthalmol 2018; 9 (1): 70–75. doi: 10.1159/000485 913.

22. Goyal A, O‘Leary D, Vercellotti G et al. Intravenous immunoglobulin for treatment of necrobiotic xanthogranuloma. Dermatol Ther 2019; 32 (1): e12744. doi: 10.1111/dth.12744.

23. Lukács J, Goetze S, Elsner P. Periocular necrobiotic xanthogranuloma successfully treated with intravenous immunoglobulin. Acta Derm Venereol 2017; 97 (6): 754–755. doi: 10.2340/00015555-2626.

24. Rubinstein A, Wolf DJ, Granstein RD. Successful treatment of necrobiotic xanthogranuloma with intravenous immunoglobulin. J Cutan Med Surg 2013; 17 (5): 347–350. doi: 10.2310/7750.2013.13012.

25. Liszewski W, Wisniewski JD, Safah H et al. Treatment of refraktory necrobiotic xanthogranulomas with extracorporeal photopheresis and intravenous immunoglobulin. Dermatol Ther 2014; 27 (5): 268–271. doi: 10.1111/dth.12135.

26. Nambudiri VE, McLaughlin C, Lo TC et al. Successful multimodality treatment of recalcitrant necrobiotic xanthogranuloma using electron beam radiation and intravenous immunoglobulin. Clin Exp Dermatol 2016; 41 (2): 179–182. doi: 10.1111/ced.12719.

27. Pedrosa AF, Ferreira O, Calistru A et al. Necrobiotic xanthogranuloma with giant cell hepatitis, successfully treated with intravenous immunoglobulins. Dermatol Ther 2015; 28 (2): 68–70. doi: 10.1111/dth.12211.

28. Haber R, Bachour J, Gemayel ME. Scleromyxedema treatment: systemic reviewand update. Intern J Dermatol 2020; 59 (10): 1191–1201. doi: 10.1111/ijd.14888.

29. Eltilib M, Fenner J, Saramago I et al. Necrobiotic xanthogranuloma on 18F-FDG PET/CT. Clin Nucl Med 2020; 45 (12): 967–969. doi: 10.1097/RLU.0000000000003 300.

30. Hou J, Long T, Hu S. Application of F-FDG-PET/CT in necrobiotic xanthogranuloma involving multiple organs. Eur J Nucl Med Mol Imaging 2021; 48 (1): 321–322. doi: 10.1007/s00259-020-04841-8.

31. Koukalová R, Selingerová I, Řehák Z a kol. FDG-PET/CT v diagnostice a hodnocení léčebné odpovědi Castlemanovy choroby – retrospektivní studie 29 případů z jednoho centra. Klin Onkol 2021; 34 (2): 120–127. doi: 10.48095/ccko2021120.

32. Azmy V, Neparidze N. Hyperbilirubinemia following lenalidomide administration. Clin Case Rep 2018; 6 (5): 875–877. doi: 10.1002/ccr3.1471.

33. Thoguluva Chandrasekar V, Faust TW, John S. Gilbert syndrome. Treasure Island: StatPearls Publishing 2022.

34. Jirsa M, Sticová E. Neonatal hyperbilirubinemia and molecular mechanisms of jaundice. Vnitr Lek 2013; 59 (7): 566–571.

35. Zmetáková I, Čierna I, Székyová D et al. Molekulová diagnostika dedičných nekonjugovaných hyperbilirubinémií na Slovensku. Čes-slov Pediat 2009; 64 (5): 223–229.

36. Vítek L. The role of bilirubin and UGT1A1 mutations in health and disease Prague medical report. Prague: Karolinum 2004–2008: 122–124.

37. Fremuth J, Sýkora J, Boday A et al. Analýza UGT 1A1*28 polymorfismu v oblasti TATA-box promotoru genu pro UDP-glukuronyltransferázu u Gilbertova syndromu v dětském věku. Čes-slov Pediat 2005; 60 (1): 7–13.

38. King D, Armstrong MJ. Overview of Gilbert‘s syndrome. Drug Ther Bull 2019; 57 (2): 27–31. doi: 10.1136/dtb. 2018.000028.

39. Slachtova L, Seda O, Behunová J et al. Genetic and biochemical study of dual hereditary jaundice: Dubin-Johnson and Gilbert‘s syndromes. Haplotyping and founder effect of deletion in ABCC2. Eur J Hum Genet 2016; 24 (5): 704–709. doi: 10.1038/ejhg.2015.181.

40. Memon N, Weinberger BI, Hegyi T et al. Inherited disorders of bilirubin clearance. Pediatr Res 2016; 79 (3): 378–386. doi: 10.1038/pr.2015.247.

41. Zanella M, Rubia-Brandt L, Giostra E et al. A case of drug--induced hepatitis due to lenalidomide. Case Rep Gastroenterol 2011; 5 (1): 217–222. doi: 10.1159/000326935.

42. Nojkov B, Signori C, Konda A et al. Lenalidomide-associated hepatotoxicity – a case report and literature review. Anticancer Res 2012; 32 (9): 4117–4119.

43. Hussain S, Browne R, Chen J et al. Lenalidomide-induced severe hepatotoxicity. Blood 2007; 110 (10): 3814. doi: 10.1182/blood-2007-06-097758.

44. Zanella MC, Rubbia-Brandt L, Giostra E et al. A case of drug-induced hepatitis due to lenalidomide. Case Rep Gastroenterol 2011; 5 (1): 217–222. doi: 10.1159/ 000326935.

45. Jena RK, Swain TR, Kansurkar SS et al. Lenalidomide induced intrahepatic cholestasis in newly diagnosed patients of multiple myeloma. Eur J Clin Pharmacol 2012; 68 (5): 881–884. doi: 10.1007/s00228-011-1152-y.