Hepatology Research 2015; 45: E150–E155
doi: 10.1111/hepr.12462
Case Report
Treatment of hepatic amyloid light-chain amyloidosis with bortezomib and dexamethasone in a liver transplant patient Ryosuke Nakano,1 Masahiro Ohira,1 Kentaro Ide,1 Kohei Ishiyama,1 Tsuyoshi Kobayashi,1 Hiroyuki Tahara,1 Hirotaka Tashiro,1 Yoshiaki Kuroda,2 Tatsuo Ichinohe,2 Koji Arihiro,3 Kazuaki Chayama4 and Hideki Ohdan1 1 Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, 2Department of Hematology and Oncology, Research Center for Radiation Casualty Medicine, Research Institute for Radiation Biology and Medicine, 3Department of Pathology, Graduate School of Biomedical Sciences, and 4Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
Hepatic amyloid light-chain (AL) amyloidosis is characterized by abnormal deposition of amyloid fibrils in the liver. As this precursor protein is produced by a proliferative plasma cell clone in the bone marrow, liver transplantation (LT) does not affect the disease’s progression. Here, we describe the successful treatment using bortezomib- and dexamethasonebased chemotherapy, following LT, of hepatic AL amyloidosis in a 65-year-old woman with progressive liver failure. The patient presented with progressive hepatic dysfunction accompanied by hepatorenal syndrome requiring hemodialysis, and living donor LT was successfully performed. Histology revealed amyloid deposits in the liver and stomach, and
serum immunofixation revealed AL amyloidosis (κ-type). The patient began chemotherapy on day 45 after the LT, and remission was achieved after one course. She was subsequently discharged 83 days after the LT, with normal liver and renal function, and no clinical evidence of recurrent disease was observed at the latest follow up (22 months post-LT).
INTRODUCTION
the extracellular matrix and vessel walls of various organs.1 Liver transplantation (LT) is a therapeutic option for patients with familial amyloid polyneuropathy; as the liver produces most of the amyloid precursors, LT resolves the condition by eliminating production of the precursor protein.2 However, in amyloid light-chain (AL) amyloidosis, the precursor protein is produced by a proliferative plasma cell clone in the bone marrow. Thus, LT alone has no effect on the production of the precursor protein, as the plasma cell clone persists in the bone marrow. Accordingly, the prognosis of hepatic AL amyloidosis is poor, with a median survival from diagnosis of only 10–14 months.3 Systemic AL amyloidosis patients should be considered for stem cell transplantation, although only a minority are eligible, or for trials of systemic chemotherapy.4 Moreover, although no standard treatment for hepatic AL amyloidosis exists,5 several cases of successful LT for hepatic AL amyloidosis followed by curative stem
S
YSTEMIC AMYLOIDOSIS IS a group of diseases that are characterized by deposition of amyloid fibrils in
Correspondence: Dr Masahiro Ohira, Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. Email: [email protected] Author contribution: R. N. and M. O. performed the research/ study, analyzed the data and wrote the manuscript. K. I., K. I., T. K., H. T. and H. T. performed the research/study and analyzed the data. Y. K., T. I., K. A. and K. C. analyzed the data. H. O. performed the research/study, analyzed the data, designed the study and interpreted the results. Funding: The authors declare no external funding for this study. Conflict of interest: The authors declare no conflicts of interest. Received 20 September 2014; revision 9 December 2014; accepted 10 December 2014.
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Key words: adjuvant chemotherapy, amyloid light-chain amyloidosis, bortezomib, cirrhosis, dexamethasone, liver transplant
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: E150–E155
Bortezomib and dexamethasone for AL amyloidosis
cell transplantation have been reported.6,7 Here, we present the first case of successful treatment of progressive liver failure secondary to systemic AL amyloidosis with bortezomib- and dexamethasone-based chemotherapy following LT.
CASE REPORT
A
65-YEAR-OLD JAPANESE woman complaining of persistent jaundice for 2 months was referred to our hospital for the treatment of progressive liver failure of unknown etiology. Laboratory tests revealed the following results: hepatitis virus, negative; tumor markers, negative; autoantibodies, negative; total bilirubin level, 20.0 mg/dL; prothrombin time and international normalized ratio, 1.51; alkaline phosphatase level, 1435 U/L; creatinine level, 3.03 mg/dL; platelet count, 254 000/μL; calcium, 4.5 mEq/mL; immunoglobulin G, 849 mg/dL; immunoglobulin M, 47 mg/dL; and N-terminal pro-brain natriuretic peptide level, 7421 pg/ mL. Her Model for End-Stage Liver Disease score was 33. Enhanced computed tomography confirmed a diffusely enlarged liver without tumor growth, along with substantial ascites and pleural effusion. The patient had experienced melena 2 days before the LT. Gastroscopy revealed diffusely multifocal oozing without any hemorrhagic disease, such as tumors, ulcers or varices, in the upper gastrointestinal tract. Echocardiography revealed enlargement of the right side of the heart and fluid decompensation due to heart and renal failure. The myocardial wall moved normally and the left ventricular ejection fraction was 63%. The progressive hepatic dysfunction and accompanying hepatorenal syndrome required hemodialysis filtration twice as a bridge to the LT. As there were no alternative therapies, emergency living donor LT was performed. After the LT, partial
(a)
Liver
(b)
E151
gastrectomy was required, owing to active bleeding in the stomach. The removed portion of the liver weighed 1880 g, and was greenish in color, diffusely enlarged, elastic and slightly soft. The resected stomach contained an elastic and soft tumor lesion, which was thought to be the source of the bleeding (Fig. 1). The patient’s postoperative course was uneventful, with an immediate improvement in her renal function after the LT permitting discontinuation of the dialysis. Twelve days postsurgery, the patient’s creatinine level was 0.52 mg/dL. On the same day, echocardiography revealed that the left ventricular posterior wall thickness was still 12.2 mm, which suggested the possibility of cardiac amyloidosis, according to the 10th International Symposium on Amyloid and Amyloidosis.8 The patient did not experience melena or hematemesis after the LT. Congo red staining revealed diffuse amyloid deposits in the liver and gastric mucosa (Fig. 2), and immunohistology revealed monoclonal immunoglobulin light chains. Further tests revealed a serum κ-type light-chain level of 3210 mg/L (normal, 2.42–18.92 mg/L) and a λ-type light-chain level of 10.7 mg/L (normal, 4.44– 26.18 mg/L), yielding a κ : λ ratio of 300:1 (normal, 0.248–1.804:1). Postoperative flow cytometry of the bone marrow cells revealed that the proportion of CD38+CD138+ monoclonal plasma cells was 7.2% (Fig. 3). Based on these findings, the patient was diagnosed with AL amyloidosis (κ-type) secondary to symptomatic myeloma. On day 45 post-surgery, the patient underwent chemotherapy with bortezomib (1.6 mg/kg bodyweight) and dexamethasone (16.5 mg/kg bodyweight) on days 1, 4, 8 and 11 for treatment of the AL amyloidosis. After one course, the circulating free light chains disappeared, and the serum κ : λ ratio decreased markedly to 2.17:1. Twenty days after beginning chemotherapy, the patient developed mild anemia and thrombocytopenia without
Stomach
Figure 1 Isolated specimens. (a) The explanted liver. (b) The resected stomach containing an elastic and soft tumor lesion (arrow).
© 2014 The Japan Society of Hepatology
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Hepatology Research 2015; 45: E150–E155
R. Nakano et al.
(a)
Figure 2 Histopathological findings. (a) Histological liver findings showing widespread amyloid deposits (Congo red; original magnifications: upper panel, ×4; lower panel, ×20). (b) Histological stomach findings showing amyloid deposits in the resected gastric mucosa (Congo red; original magnifications: upper panel, ×4; lower panel, ×20).
Liver
(b)
x4
x4
x20
x20
CD138PE 10 0 10 1 10 2 10 3 10 4
any signs of myeloma. Accordingly, the chemotherapy regimen was adjusted to weekly administration of bortezomib (2.1 mg/kg bodyweight) and dexamethasone (16.5 mg/kg bodyweight). One week later, the chemotherapy was discontinued due to the patient developing a skin rash and diarrhea. The patient was discharged 83 days after the LT. At the last follow up (22 months after the LT), the patient was healthy, with normal liver function, good renal function and a creatinine level of 0.78 mg/dL. No circulating free light chains were detected. Moreover, liver biopsy revealed a normal liver structure with very few amyloid deposits, and endoscopic biopsy speci-
10 0 10 1 10 2 10 3 10 4 CD38 FITC
Figure 3 Flow cytometry of the bone marrow cells on day 37 after the liver transplant. The cell population contained 7.2% CD38+CD138+ plasma cells. FITC, fluorescein isothiocyanate.
© 2014 The Japan Society of Hepatology
Stomach
mens from the stomach revealed a marked reduction in the amyloid deposition (Fig. 4). Hence, chemotherapy with bortezomib and dexamethasone appears to be a potential initial therapeutic option for this disorder.
DISCUSSION
T
O OUR KNOWLEDGE, this is the first case report of a patient with hepatic AL amyloidosis undergoing LT followed by bortezomib and dexamethasone chemotherapy that subsequently led to amelioration of the disease. LT alone does not improve the prognosis of AL amyloidosis, because the abnormal amyloid protein is produced by a proliferative plasma cell clone in the bone marrow.9 However, LT combined with newer chemotherapy regimens, such as those containing a proteasome inhibitor, may represent an effective treatment for patients with decompensated hepatic AL amyloidosis without any other severe organ dysfunction. Despite the recent advances in the management of AL amyloidosis, approximately 30% of patients die within 1 year of diagnosis.10 Particularly important predictors of poor prognosis are liver dysfunction, congestive heart failure, the free immunoglobulin light-chain level at diagnosis and the number of involved organs.3,5,11–13 In this case, the patient’s prognosis was dismal, and a liver biopsy should be performed before the LT in similar cases. However, in this case, a liver biopsy could not be
Bortezomib and dexamethasone for AL amyloidosis
Hepatology Research 2015; 45: E150–E155
(a)
Liver
(b)
x4
x4
x20
x20
E153
Stomach
Figure 4 Biopsy results at the final follow up. (a) Liver biopsy showing very few amyloid deposits in Glisson’s sheath (arrow) (Congo red; original magnifications: upper panel, ×4; lower panel, ×20). (b) Stomach biopsy showing very few amyloid deposits (Congo red; original magnifications: upper panel, ×4; lower panel, ×20).
performed, owing to the following reasons: (i) the patient showed symptoms of bleeding tendency with substantial ascites; and (ii) the computed tomography revealed no signs of neoplastic hepatic substitution. If we had initially been aware of this diagnosis, the decision to perform living donor LT for such an advanced case of AL amyloidosis with heart and renal failure would have been considered controversial. However, as we were unaware of this condition at that time, LT was considered the only option to save the patient’s life. Therefore, we must carefully weigh the risks and benefits of this procedure when deciding on the eligibility for LT in the future, especially in the living donor setting. Based on our findings, LT may represent a potential salvage treatment option for hepatic AL amyloidosis in the absence of significant secondary extrahepatic disease, and several groups have reported patients with AL amyloidosis who were treated with LT (Table 1). However, as LT alone does not affect the production of amyloid protein, additional therapeutic strategies, including chemotherapy and stem cell transplantation, are required after the LT.6,7,14–16 The indications for LT followed by chemotherapy include patients with liver failure due to AL amyloidosis without any other severe organ dysfunction and patients without an opportunity for stem cell transplantation. Aggressive therapy consisting of high-dose melphalan followed by autologous stem cell transplan-
tation has been shown to be effective in treating AL amyloidosis, although only a few patients are eligible for this treatment modality.10 Alternatively, bortezomib is a reversible proteasome inhibitor that has shown significant activity in patients with myeloma,17 and a recently developed bortezomib-based regimen has shown promising activity and manageable toxicity in patients with AL amyloidosis.18,19 Lamm et al. have reported that, among 26 patients with AL amyloidosis who received this regimen, the overall response rate was 54%, with eight patients achieving complete hematological remission.18 In another study of 94 patients with AL amyloidosis, a hematological response was achieved in 71% of patients and complete response was achieved in 25% of patients. The authors concluded that this regimen was active in AL amyloidosis, induced rapid responses and provided high rates of hematological and organ responses. In addition, the toxicity of this regimen was limited and the adverse events could be managed.19 Therefore, this regimen could be effective and well tolerated in patients with AL amyloidosis after LT, as in our patient, who was administrated chemotherapeutic drugs comprising bortezomib and dexamethasone. Throughout the follow-up period, her immunoglobulin free light-chain levels remained within the normal range. However, special attention should be paid to the degree of amyloid deposition in the grafted liver, as our
© 2014 The Japan Society of Hepatology
M M M M M F F F F F
54
44
61 31 66
63 56 29 60 50
41 65
Sattianayagam et al., 20107
Binotto et al., 201115
Hirano et al., 201316 Our patient
© 2014 The Japan Society of Hepatology 10.6 20.0
– – – – –
– – –
–
–
15.2 29.6
T-Bil (mg/dL)
ALP, alkaline phosphatase; GI, gastrointestinal; T-Bil, total bilirubin.
Lymph node Heart, GI tract
None None Kidney, heart, autonomic nerve system Kidney, heart Heart None GI tract Heart
None
None
Spleen rupture None
Extrahepatic organ involvement
– 1435
– – – – –
– – –
–
–
4020 1565
ALP (mg/dL)
– 3.0
– – – – –
– – –
–
–
2.1 2.5
Creatinine (mg/dL)
Chemotherapy None Stem cell transplant None Stem cell transplant, chemotherapy None Chemotherapy
None Stem cell transplant, chemotherapy Stem cell transplant, renal transplant Stem cell transplant, chemotherapy Chemotherapy None None
Treatment of amyloidosis
Not available – – – Melphalan and dexamethasone – Bortezomib and dexamethasone
Not available – –
Not available
–
– Melphalan
Regimen of chemotherapy
2 14
24 0 5 4 60
11 11 5
68
150
18 28
Follow up (months)
Dead Alive
Dead Dead Dead Dead Alive
Dead Dead Dead
Alive
Alive
Alive Alive
Outcome
R. Nakano et al.
F F
M M
61 65
Nowak et al., 200014 Kumar et al., 20026
Sex
Age
Reports
Table 1 Characteristics and outcome among reports with systemic AL amyloidosis who underwent liver transplantation
E154 Hepatology Research 2015; 45: E150–E155
Hepatology Research 2015; 45: E150–E155
Bortezomib and dexamethasone for AL amyloidosis
follow-up period was relatively short and the disease course was not characteristic. In conclusion, this report describes the first case of systemic AL amyloidosis that was successfully treated using bortezomib- and dexamethasone-based chemotherapy after LT that was performed for acute liver failure. The successful outcome indicates that LT followed by chemotherapeutic strategies can halt ongoing amyloid production in hepatic AL amyloidosis. However, the eligibility for LT in cases of hepatic AL amyloidosis should be carefully assessed.
9 10
11
12
REFERENCES 1 Chopra S, Rubinow A, Koff RS, Hepatic CAS. amyloidosis. A histopathologic analysis of primary (AL) and secondary (AA) forms. Am J Pathol 1984; 115: 186–93. 2 Ikeda S, Hanyu N, Hongo M et al. Hereditary generalized amyloidosis with polyneuropathy. Clinicopathological study of 65 Japanese patients. Brain 1987; 110: 315–37. 3 Kumar SK, Gertz MA, Lacy MQ et al. Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score. Mayo Clin Proc 2011; 86: 12–8. 4 Gertz MA. Immunoglobulin light chain amyloidosis: 2013 update on diagnosis, prognosis, and treatment. Am J Hematol 2013; 88: 416–25. 5 Gertz MA, Zeldenrust SR. Treatment of immunoglobulin light chain amyloidosis. Curr Hematol Malig Rep 2009; 4: 91–8. 6 Kumar KS, Lefkowitch J, Russo MW et al. Successful sequential liver and stem cell transplantation for hepatic failure due to primary AL amyloidosis. Gastroenterology 2002; 122: 2026–31. 7 Sattianayagam PT, Gibbs SD, Pinney JH et al. Solid organ transplantation in AL amyloidosis. Am J Transplant 2010; 10: 2124–31. 8 Gertz MA, Comenzo R, Falk RH et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from
13
14
15
16
17
18
19
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the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18–22 April 2004. Am J Hematol 2005; 79: 319–28. Gertz MA, Kyle RA. Primary systemic amyloidosis – a diagnostic primer. Mayo Clin Proc 1989; 64: 1505–19. Gertz MA. Immunoglobulin light chain amyloidosis: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 2011; 86: 180–6. Kumar S, Dispenzieri A, Katzmann JA et al. Serum immunoglobulin free light-chain measurement in primary amyloidosis: prognostic value and correlations with clinical features. Blood 2010; 116: 5126–9. Park MA, Mueller PS, Kyle RA, Larson DR, Plevak MF, Gertz MA. Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients. Medicine (Baltimore) 2003; 82: 291–8. Kumar S, Dispenzieri A, Lacy MQ et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 2012; 30: 989–95. Nowak G, Westermark P, Wernerson A, Herlenius G, Sletten K, Ericzon BG. Liver transplantation as rescue treatment in a patient with primary AL kappa amyloidosis. Transpl Int 2000; 13: 92–7. Binotto G, Cillo U, Trentin L et al. Double autologous bone marrow transplantation and orthotopic liver transplantation in a patient with primary light chain (AL) amyloidosis. Amyloid 2011; 18 (Suppl 1): 132–4. Hirano K, Ikemura M, Mizuno S et al. Two cases with hepatic amyloidosis suspected of having primary sclerosing cholangitis. Hepatol Res 2013; 43: 911–6. Richardson PG, Sonneveld P, Schuster MW et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487–98. Lamm W, Willenbacher W, Lang A et al. Efficacy of the combination of bortezomib and dexamethasone in systemic AL amyloidosis. Ann Hematol 2011; 90: 201–6. Kastritis E, Wechalekar AD, Dimopoulos MA et al. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol 2010; 28: 1031–7.
© 2014 The Japan Society of Hepatology
doi: 10.1111/hepr.12462
Case Report
Treatment of hepatic amyloid light-chain amyloidosis with bortezomib and dexamethasone in a liver transplant patient Ryosuke Nakano,1 Masahiro Ohira,1 Kentaro Ide,1 Kohei Ishiyama,1 Tsuyoshi Kobayashi,1 Hiroyuki Tahara,1 Hirotaka Tashiro,1 Yoshiaki Kuroda,2 Tatsuo Ichinohe,2 Koji Arihiro,3 Kazuaki Chayama4 and Hideki Ohdan1 1 Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, 2Department of Hematology and Oncology, Research Center for Radiation Casualty Medicine, Research Institute for Radiation Biology and Medicine, 3Department of Pathology, Graduate School of Biomedical Sciences, and 4Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
Hepatic amyloid light-chain (AL) amyloidosis is characterized by abnormal deposition of amyloid fibrils in the liver. As this precursor protein is produced by a proliferative plasma cell clone in the bone marrow, liver transplantation (LT) does not affect the disease’s progression. Here, we describe the successful treatment using bortezomib- and dexamethasonebased chemotherapy, following LT, of hepatic AL amyloidosis in a 65-year-old woman with progressive liver failure. The patient presented with progressive hepatic dysfunction accompanied by hepatorenal syndrome requiring hemodialysis, and living donor LT was successfully performed. Histology revealed amyloid deposits in the liver and stomach, and
serum immunofixation revealed AL amyloidosis (κ-type). The patient began chemotherapy on day 45 after the LT, and remission was achieved after one course. She was subsequently discharged 83 days after the LT, with normal liver and renal function, and no clinical evidence of recurrent disease was observed at the latest follow up (22 months post-LT).
INTRODUCTION
the extracellular matrix and vessel walls of various organs.1 Liver transplantation (LT) is a therapeutic option for patients with familial amyloid polyneuropathy; as the liver produces most of the amyloid precursors, LT resolves the condition by eliminating production of the precursor protein.2 However, in amyloid light-chain (AL) amyloidosis, the precursor protein is produced by a proliferative plasma cell clone in the bone marrow. Thus, LT alone has no effect on the production of the precursor protein, as the plasma cell clone persists in the bone marrow. Accordingly, the prognosis of hepatic AL amyloidosis is poor, with a median survival from diagnosis of only 10–14 months.3 Systemic AL amyloidosis patients should be considered for stem cell transplantation, although only a minority are eligible, or for trials of systemic chemotherapy.4 Moreover, although no standard treatment for hepatic AL amyloidosis exists,5 several cases of successful LT for hepatic AL amyloidosis followed by curative stem
S
YSTEMIC AMYLOIDOSIS IS a group of diseases that are characterized by deposition of amyloid fibrils in
Correspondence: Dr Masahiro Ohira, Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. Email: [email protected] Author contribution: R. N. and M. O. performed the research/ study, analyzed the data and wrote the manuscript. K. I., K. I., T. K., H. T. and H. T. performed the research/study and analyzed the data. Y. K., T. I., K. A. and K. C. analyzed the data. H. O. performed the research/study, analyzed the data, designed the study and interpreted the results. Funding: The authors declare no external funding for this study. Conflict of interest: The authors declare no conflicts of interest. Received 20 September 2014; revision 9 December 2014; accepted 10 December 2014.
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Key words: adjuvant chemotherapy, amyloid light-chain amyloidosis, bortezomib, cirrhosis, dexamethasone, liver transplant
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: E150–E155
Bortezomib and dexamethasone for AL amyloidosis
cell transplantation have been reported.6,7 Here, we present the first case of successful treatment of progressive liver failure secondary to systemic AL amyloidosis with bortezomib- and dexamethasone-based chemotherapy following LT.
CASE REPORT
A
65-YEAR-OLD JAPANESE woman complaining of persistent jaundice for 2 months was referred to our hospital for the treatment of progressive liver failure of unknown etiology. Laboratory tests revealed the following results: hepatitis virus, negative; tumor markers, negative; autoantibodies, negative; total bilirubin level, 20.0 mg/dL; prothrombin time and international normalized ratio, 1.51; alkaline phosphatase level, 1435 U/L; creatinine level, 3.03 mg/dL; platelet count, 254 000/μL; calcium, 4.5 mEq/mL; immunoglobulin G, 849 mg/dL; immunoglobulin M, 47 mg/dL; and N-terminal pro-brain natriuretic peptide level, 7421 pg/ mL. Her Model for End-Stage Liver Disease score was 33. Enhanced computed tomography confirmed a diffusely enlarged liver without tumor growth, along with substantial ascites and pleural effusion. The patient had experienced melena 2 days before the LT. Gastroscopy revealed diffusely multifocal oozing without any hemorrhagic disease, such as tumors, ulcers or varices, in the upper gastrointestinal tract. Echocardiography revealed enlargement of the right side of the heart and fluid decompensation due to heart and renal failure. The myocardial wall moved normally and the left ventricular ejection fraction was 63%. The progressive hepatic dysfunction and accompanying hepatorenal syndrome required hemodialysis filtration twice as a bridge to the LT. As there were no alternative therapies, emergency living donor LT was performed. After the LT, partial
(a)
Liver
(b)
E151
gastrectomy was required, owing to active bleeding in the stomach. The removed portion of the liver weighed 1880 g, and was greenish in color, diffusely enlarged, elastic and slightly soft. The resected stomach contained an elastic and soft tumor lesion, which was thought to be the source of the bleeding (Fig. 1). The patient’s postoperative course was uneventful, with an immediate improvement in her renal function after the LT permitting discontinuation of the dialysis. Twelve days postsurgery, the patient’s creatinine level was 0.52 mg/dL. On the same day, echocardiography revealed that the left ventricular posterior wall thickness was still 12.2 mm, which suggested the possibility of cardiac amyloidosis, according to the 10th International Symposium on Amyloid and Amyloidosis.8 The patient did not experience melena or hematemesis after the LT. Congo red staining revealed diffuse amyloid deposits in the liver and gastric mucosa (Fig. 2), and immunohistology revealed monoclonal immunoglobulin light chains. Further tests revealed a serum κ-type light-chain level of 3210 mg/L (normal, 2.42–18.92 mg/L) and a λ-type light-chain level of 10.7 mg/L (normal, 4.44– 26.18 mg/L), yielding a κ : λ ratio of 300:1 (normal, 0.248–1.804:1). Postoperative flow cytometry of the bone marrow cells revealed that the proportion of CD38+CD138+ monoclonal plasma cells was 7.2% (Fig. 3). Based on these findings, the patient was diagnosed with AL amyloidosis (κ-type) secondary to symptomatic myeloma. On day 45 post-surgery, the patient underwent chemotherapy with bortezomib (1.6 mg/kg bodyweight) and dexamethasone (16.5 mg/kg bodyweight) on days 1, 4, 8 and 11 for treatment of the AL amyloidosis. After one course, the circulating free light chains disappeared, and the serum κ : λ ratio decreased markedly to 2.17:1. Twenty days after beginning chemotherapy, the patient developed mild anemia and thrombocytopenia without
Stomach
Figure 1 Isolated specimens. (a) The explanted liver. (b) The resected stomach containing an elastic and soft tumor lesion (arrow).
© 2014 The Japan Society of Hepatology
E152
Hepatology Research 2015; 45: E150–E155
R. Nakano et al.
(a)
Figure 2 Histopathological findings. (a) Histological liver findings showing widespread amyloid deposits (Congo red; original magnifications: upper panel, ×4; lower panel, ×20). (b) Histological stomach findings showing amyloid deposits in the resected gastric mucosa (Congo red; original magnifications: upper panel, ×4; lower panel, ×20).
Liver
(b)
x4
x4
x20
x20
CD138PE 10 0 10 1 10 2 10 3 10 4
any signs of myeloma. Accordingly, the chemotherapy regimen was adjusted to weekly administration of bortezomib (2.1 mg/kg bodyweight) and dexamethasone (16.5 mg/kg bodyweight). One week later, the chemotherapy was discontinued due to the patient developing a skin rash and diarrhea. The patient was discharged 83 days after the LT. At the last follow up (22 months after the LT), the patient was healthy, with normal liver function, good renal function and a creatinine level of 0.78 mg/dL. No circulating free light chains were detected. Moreover, liver biopsy revealed a normal liver structure with very few amyloid deposits, and endoscopic biopsy speci-
10 0 10 1 10 2 10 3 10 4 CD38 FITC
Figure 3 Flow cytometry of the bone marrow cells on day 37 after the liver transplant. The cell population contained 7.2% CD38+CD138+ plasma cells. FITC, fluorescein isothiocyanate.
© 2014 The Japan Society of Hepatology
Stomach
mens from the stomach revealed a marked reduction in the amyloid deposition (Fig. 4). Hence, chemotherapy with bortezomib and dexamethasone appears to be a potential initial therapeutic option for this disorder.
DISCUSSION
T
O OUR KNOWLEDGE, this is the first case report of a patient with hepatic AL amyloidosis undergoing LT followed by bortezomib and dexamethasone chemotherapy that subsequently led to amelioration of the disease. LT alone does not improve the prognosis of AL amyloidosis, because the abnormal amyloid protein is produced by a proliferative plasma cell clone in the bone marrow.9 However, LT combined with newer chemotherapy regimens, such as those containing a proteasome inhibitor, may represent an effective treatment for patients with decompensated hepatic AL amyloidosis without any other severe organ dysfunction. Despite the recent advances in the management of AL amyloidosis, approximately 30% of patients die within 1 year of diagnosis.10 Particularly important predictors of poor prognosis are liver dysfunction, congestive heart failure, the free immunoglobulin light-chain level at diagnosis and the number of involved organs.3,5,11–13 In this case, the patient’s prognosis was dismal, and a liver biopsy should be performed before the LT in similar cases. However, in this case, a liver biopsy could not be
Bortezomib and dexamethasone for AL amyloidosis
Hepatology Research 2015; 45: E150–E155
(a)
Liver
(b)
x4
x4
x20
x20
E153
Stomach
Figure 4 Biopsy results at the final follow up. (a) Liver biopsy showing very few amyloid deposits in Glisson’s sheath (arrow) (Congo red; original magnifications: upper panel, ×4; lower panel, ×20). (b) Stomach biopsy showing very few amyloid deposits (Congo red; original magnifications: upper panel, ×4; lower panel, ×20).
performed, owing to the following reasons: (i) the patient showed symptoms of bleeding tendency with substantial ascites; and (ii) the computed tomography revealed no signs of neoplastic hepatic substitution. If we had initially been aware of this diagnosis, the decision to perform living donor LT for such an advanced case of AL amyloidosis with heart and renal failure would have been considered controversial. However, as we were unaware of this condition at that time, LT was considered the only option to save the patient’s life. Therefore, we must carefully weigh the risks and benefits of this procedure when deciding on the eligibility for LT in the future, especially in the living donor setting. Based on our findings, LT may represent a potential salvage treatment option for hepatic AL amyloidosis in the absence of significant secondary extrahepatic disease, and several groups have reported patients with AL amyloidosis who were treated with LT (Table 1). However, as LT alone does not affect the production of amyloid protein, additional therapeutic strategies, including chemotherapy and stem cell transplantation, are required after the LT.6,7,14–16 The indications for LT followed by chemotherapy include patients with liver failure due to AL amyloidosis without any other severe organ dysfunction and patients without an opportunity for stem cell transplantation. Aggressive therapy consisting of high-dose melphalan followed by autologous stem cell transplan-
tation has been shown to be effective in treating AL amyloidosis, although only a few patients are eligible for this treatment modality.10 Alternatively, bortezomib is a reversible proteasome inhibitor that has shown significant activity in patients with myeloma,17 and a recently developed bortezomib-based regimen has shown promising activity and manageable toxicity in patients with AL amyloidosis.18,19 Lamm et al. have reported that, among 26 patients with AL amyloidosis who received this regimen, the overall response rate was 54%, with eight patients achieving complete hematological remission.18 In another study of 94 patients with AL amyloidosis, a hematological response was achieved in 71% of patients and complete response was achieved in 25% of patients. The authors concluded that this regimen was active in AL amyloidosis, induced rapid responses and provided high rates of hematological and organ responses. In addition, the toxicity of this regimen was limited and the adverse events could be managed.19 Therefore, this regimen could be effective and well tolerated in patients with AL amyloidosis after LT, as in our patient, who was administrated chemotherapeutic drugs comprising bortezomib and dexamethasone. Throughout the follow-up period, her immunoglobulin free light-chain levels remained within the normal range. However, special attention should be paid to the degree of amyloid deposition in the grafted liver, as our
© 2014 The Japan Society of Hepatology
M M M M M F F F F F
54
44
61 31 66
63 56 29 60 50
41 65
Sattianayagam et al., 20107
Binotto et al., 201115
Hirano et al., 201316 Our patient
© 2014 The Japan Society of Hepatology 10.6 20.0
– – – – –
– – –
–
–
15.2 29.6
T-Bil (mg/dL)
ALP, alkaline phosphatase; GI, gastrointestinal; T-Bil, total bilirubin.
Lymph node Heart, GI tract
None None Kidney, heart, autonomic nerve system Kidney, heart Heart None GI tract Heart
None
None
Spleen rupture None
Extrahepatic organ involvement
– 1435
– – – – –
– – –
–
–
4020 1565
ALP (mg/dL)
– 3.0
– – – – –
– – –
–
–
2.1 2.5
Creatinine (mg/dL)
Chemotherapy None Stem cell transplant None Stem cell transplant, chemotherapy None Chemotherapy
None Stem cell transplant, chemotherapy Stem cell transplant, renal transplant Stem cell transplant, chemotherapy Chemotherapy None None
Treatment of amyloidosis
Not available – – – Melphalan and dexamethasone – Bortezomib and dexamethasone
Not available – –
Not available
–
– Melphalan
Regimen of chemotherapy
2 14
24 0 5 4 60
11 11 5
68
150
18 28
Follow up (months)
Dead Alive
Dead Dead Dead Dead Alive
Dead Dead Dead
Alive
Alive
Alive Alive
Outcome
R. Nakano et al.
F F
M M
61 65
Nowak et al., 200014 Kumar et al., 20026
Sex
Age
Reports
Table 1 Characteristics and outcome among reports with systemic AL amyloidosis who underwent liver transplantation
E154 Hepatology Research 2015; 45: E150–E155
Hepatology Research 2015; 45: E150–E155
Bortezomib and dexamethasone for AL amyloidosis
follow-up period was relatively short and the disease course was not characteristic. In conclusion, this report describes the first case of systemic AL amyloidosis that was successfully treated using bortezomib- and dexamethasone-based chemotherapy after LT that was performed for acute liver failure. The successful outcome indicates that LT followed by chemotherapeutic strategies can halt ongoing amyloid production in hepatic AL amyloidosis. However, the eligibility for LT in cases of hepatic AL amyloidosis should be carefully assessed.
9 10
11
12
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