Bone Marrow Transplantation (2001) 27, 341–343  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt Case report Four patients with AL amyloidosis treated with high-dose and autologous stem cell transplantation

G Reich1, Th Held2, W Siegert2, D Kampf3,BDo¨rken1 and G Maschmeyer1

Charite´ University Hospital, 1Campus Berlin-Buch, Department of Haematology, and Tumour , Campus Virchow-Klinikum, 2Department of Haematology and Oncology, and 3Department of (3), Humboldt University of Berlin, Germany

Summary: Case reports

Four patients with AL amyloidosis underwent high-dose Patient 1 chemotherapy and autologous stem cell transplantation at our institutions. Here, we report the clinical courses A 41-year-old woman was hospitalized for rapidly pro- and outcomes in these patients. Two patients with multi- gressive ankle oedema due to nephrotic syndrome. Twenty- organ amyloid deposits including cardiac involvement four hour proteinuria was 6.5 g, and creatinine clearance died within 12 days after high-dose chemotherapy. was normal. Serum cholesterol was 7.46 mmol/l and serum However, in the other two patients, one of whom was albumin 24 g/l. AL amyloidosis was proven on renal biopsy. Monoclonal lambda light chains were detected in suffering from amyloid-related cardiac failure, a sig- the urine by immune-fixation. Further investigation showed nificant improvement of organ function was achieved. no other organ involvement. Haematopoietic progenitor Bone Marrow Transplantation (2001) 27, 341–343. cells were mobilised from G-CSF (10 ␮g/kg/day for 4 Keywords: amyloidosis; high-dose chemotherapy; stem days), and 4.1 × 106 CD34-positive cells per kg were har- cell transplantation; toxicity; risk assessment vested by leucapheresis. In November 1997, the patient underwent high-dose chemotherapy with melphalan 200 mg/m2 followed by autologous stem cell transplan- tation (ASCT). Duration of severe neutropenia, defined as Patients with amyloid light chain (AL) amyloidosis have a granulocyte counts Ͻ0.5 × 109/l, was 4 days with no infec- very poor prognosis with a median survival of 13 months 1 tious complications. No platelet support was required. Non- from diagnosis. If cardiac involvement with progressive haematological toxicity consisted of grade III mucositis reduction of left ventricular ejection fraction is docu- treated with analgesics. 2 mented, the median survival is reduced to 5 months. The At 19 months post transplant, the patient is free from majority of patients succumb to cardiorespiratory failure, disease-specific symptoms. The twenty-four hour pro- renal failure and/or vascular bleeding. teinuria has reduced to 1 g and immune-fixation on urine Response to cytostatic treatment with alkylating agents, and plasma is negative. Serum albumin is 42 g/l, and the supplemented by glucocorticoids and/or colchicine, are cholesterol level 7.07 mmol/l. Renal sonography shows no minimally effective.2 Recently, high-dose chemotherapy pathological findings and no further organ involvement with haematopoietic stem cell support has been introduced has observed. in the treatment of patients with AL amyloidosis in order to improve organ function and prolong survival.3–5 We report the clinical courses and outcomes in four patients Patient 2 with AL amyloidosis treated with high-dose chemotherapy A 60-year-old man was admitted in December 1997 for and autologous stem cell transplantation. progressive dyspnoea (New York Heart Association grade 2) and ankle oedema. From April 1997 atrial fibrillation had been documented. Echocardiography showed the left ventricular ejection fraction (LVEF) to be reduced to 34%. Interventricular septum thickness was 15 mm. Twenty-four hour proteinuria was 8 g, and creatinine clearance was nor- mal. Plasma immune fixation was positive for lambda light chains. Biopsies of the rectal mucosa, liver and heart Correspondence: G Reich, Charite´ University Hospital, Campus Berlin- showed unequivocal involvement by AL amyloidoses. Buch, Robert-Ro¨ssle-Klinik, Department of , Oncology and Tumor Immunology, Humboldt University of Berlin, Lindenberger Weg From December 1997 to February 1998, the patient 80, 13125 Berlin, Germany received two cycles of chemotherapy consisting of conven- Received 24 July 2000; accepted 21 October 2000 tional-dose melphalan (16 mg/m2 day 1) and prednisolone AL amyloidosis treated with HDC and ASCT G Reich et al 342 60 mg/m2, days 1–4, according to Kyle et al.2 Because of (CO) diffusion capacity was normal. Two cycles of G-CSF, non-response and deterioration of clinical symptoms, high- each given as described above, were required to achieve a dose chemotherapy was scheduled. Progenitor cells were yield of 2.26 × 106 CD34-positive cells per kg from steady mobilised by G-CSF as described above, and 2.9 × 106 state. In February 1998, the patient received chemotherapy CD34-positive cells per kg were harvested by leukapher- with melphalan 200 mg/m2 followed by ASCT. Two days esis. In February 1998, the patient underwent chemotherapy after the chemotherapy the patient developed haematem- with melphalan 200 mg/m2 followed by ASCT. On day +8 esis. Prompt endoscopy of the upper gastrointestinal tract post transplant empiric antimicrobial was started revealed no bleeding source. On the day of ASCT haemop- for unexplained fever. Severe neutropenia was present from tysis occurred. Within 4 h the patient rapidly developed res- day +4, and a platelet transfusion was given on day +8. piratory failure caused by diffuse alveolar haemorrhage On day +10, rapidly progressive cardiorespiratory failure requiring mechanical ventilation. Adequate oxygenation necessitated mechanical ventilation and i.v. pressor support. was not achievable despite ventilation, and the patient Cardiac arrest caused by electromechanical dissociation expired. Autopsy showed significant lung involvement by refractory to resuscitation caused death on day +12 post amyloidosis resulting in diffuse alveolar bleeding and right transplant. Autopsy revealed acute myocardial infarction as ventricular cardiac failure. the main cause of death.

Discussion Patient 3 A 61-year-old man was hospitalized in December 1998 This report confirms that high-dose chemotherapy with because of hypotension, diarrhoea and paraesthesia of the autologous stem cell support offers a feasible and effective hands and feet. He was unable to continue working as a strategy for patients with advanced AL amyloidosis. How- teacher. Subcutaneus fat aspiration and biopsy of the rectal ever, patients with multi-organ involvement, including car- mucosa both revealed AL amyloidosis. Plasma immune diac amyloidosis, are at very high risk of treatment-related fixation was negative. Bone marrow biopsy showed periva- toxic death. Therefore, their exclusion from this treatment scular amyloid deposits and expression of lambda light modality is recommended by some authors.5,7,8 This rec- chains. Echocardiography and cardiac magnetic resonance ommendation causes a therapeutic dilemma, since these imaging (MRI) showed the typical findings of cardiac amy- patients have a median survival of 5 months when treated loidosis with reduction in systolic function.6 LVEF was with conventional-dose melphalan with prednisone.2 In reduced to 40%, and the interventricular septum thickness their preliminary report, Comenzo et al4 described 102 was 21 mm. The creatinine clearance was normal, and patients with AL amyloidosis and a median age of 61 years pathological urine protein excretion was not observed. Pro- treated with high-dose chemotherapy consisting of mel- genitor cells were mobilised by G-CSF as described above, phalan 100 or 200 mg/m2 in a randomized trial. With a and 2.2 × 106 CD34-positive cells per kg were harvested. median follow-up of 20 months, 70% of patients in the In February 1999, the patient underwent chemotherapy with high-dose melphalan group and 63% in the intermediate- melphalan 140 mg/m2 followed by ASCT. Duration of sev- dose melphalan group survived. Patients with cardiac ere neutropenia was 6 days, severe thrombocytopenia was involvement and LVEF reduced to less than 50%, renal not observed, and no transfusion of blood products was failure or pulmonary CO diffusion capacity of less than required. An episode of unexplained fever during neutrop- 50% underwent intermediate-dose melphalan therapy. enia promptly responded to first-line antibiotic treatment. Again, 20% of patients died within 100 days post treatment, Non-haematological toxicity was limited to grade III muco- and all these patients suffered from cardiac involvement, sitis. At 7 months post transplant, the patient’s blood press- or had more than two organ systems affected by amylo- ure has normalised, echocardiography and cardiac MRI idosis. When presenting his outcome analysis of high-dose show no signs of cardiac involvement and LVEF has melphalan and stem cell support in patients with vs those returned to normal. The patient continues to suffer from without cardiac involvement, Comenzo9 showed a 3-year stable paresthesia and diarrhoea, but he has returned to overall survival of 25% in 18 patients with cardiac work. amyloidosis. Saba et al10 published their observations on 11 patients Patient 4 with AL amyloidosis and cardiac involvement, nine of whom were eligible for high-dose chemotherapy. Three A 61-year-old man was hospitalized in December 1997 patients died from fatal cardiac arrhytmia or heart failure because of ankle oedema due to nephrotic sydrome, with after mobilisation with cyclophosphamide at a dose of a 24 h proteinuria of 16 g. Monoclonal lambda light chains 2.5 g/m2 plus G-CSF. During or shortly after high-dose were detected in urine and serum by immune fixation. Crea- chemotherapy with melphalan 140 mg/m2 and total body tinine clearance was normal. He suffered from dyspnoea irradiation, three further patients died from cardiac compli- NYHA 2 and hypotension. Renal, liver and bone marrow cations. The remaining three patients also developed histology revealed disseminated AL amyloidosis. Echocar- arrhythmias during neutropenia, but two of them achieved diography and cardiac MRI showed typical features of car- improved organ function documented after therapy, diac amyloidosis with a normal LVEF and impaired dias- resulting in a favourable treatment outcome in two of nine tolic relaxation. Chest radiography was suspicious of (22%) patients. Moreau et al5 studied the safety and feasi- pulmonary involvement. However, the carbon monoxide bility of high-dose chemotherapy followed by ASCT in 21

Bone Marrow Transplantation AL amyloidosis treated with HDC and ASCT G Reich et al 343 patients with systemic AL amyloidosis. The fatality rate If high-dose chemotherapy and ASCT in these patients due to toxicity within the first month post-transplant was is considered, they should be undertaken within controlled high, at 43%. Overall survival at 4 years was 57% for all clinical trials in which intensive care facilities and invasive study patients and 11% for those with more than two clini- cardiorespiratory support are available. Detailed patient cal manifestations such as renal failure, nephrotic syn- information and consent are also mandatory. drome, congestive heart failure, neuropathy or hepatome- galy. As a consequence, they recommended restricting stem cell mobilisation, high-dose therapy and stem cell support to patients without multiple-organ involvement by AL References amyloidosis. It may be interesting to analyse the impact of AL light 1 Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical chain amyloidosis in patients with multiple myeloma and laboratory features in 474 cases. Semin Hematol 1995; undergoing aggressive chemoradiotherapy with repeated 32: 45–59. high-dose melphalan, total body irradiation and autologous 2 Kyle RA, Gertz MA, Greipp PR et al. A trial of three regi- mens for primary amyloidosis: colchicine alone, melphalan stem cell transplantation. Reviewing their data on the out- and prednisolone, and melphalan, prednisolone and colchicine. come of ‘total therapy’ in patients with multiple myeloma, New Engl J Med 1997; 336: 1202–1207. 11 Desikan et al found no significant differences between 3 Comenzo RL, Sanchorawala V, Fisher C et al. Intermediate patients with (38%) or without (62%) amyloidosis docu- melphalan and blood stem cells mobilized with sequential mented by routine subcutaneous fat pad aspirates or organ- GM + G-CSF or G-CSF alone to treat AL (amyloid light directed biopsies in a series of 84 myeloma patients. chain) amyloidosis. Br J Haematol 1999; 104: 553–559. We conclude that high-dose chemotherapy may be effec- 4 Comenzo RL, Falk RH, Sanchorawala V et al. Treating AL tive in patients with AL amyloidosis, but that in patients amyloidosis with dose-intensive melphalan: outcomes in 102 with cardiac involvement or involvement of more than two patients. Blood 1998; 92 (Suppl. 1): 324a (Abstr. 1328). organ systems, a high rate of treatment-related compli- 5 Moreau P, Leblond V, Bourquelot P et al. Prognostic factors for survival and response after high-dose therapy and autolog- cations must be anticipated. At the same time, it must be ous stem cell transplantation in systemic AL amyloidosis: a emphasized that patients with congestive heart failure report on 21 patients. Br J Haematol 1998; 101: 766–769. caused by AL amyloidosis have a considerably poorer 6 Fattori R, Rocchi G, Celleti F et al. Contribution of magnetic median survival with only minimal benefit from conven- resonance imaging in the differential diagnosis of cardiac tional chemotherapy with melphalan and prednisone.2 To amyloidosis and symmetric hypertrophic cardiomyopathy. Am date, the best therapy for patients with cardiac involvement Heart J 1998; 136: 824–830. has not been determined. In one patient (No. 3) in our 7 Apperley JF, Gilmore J, Haynes A et al. Autografting for AL report, the potential benefit from high-dose chemotherapy, amyloidosis: recommendations for patient selection. Bone as shown by significant improvement of cardiac function, Marrow Transplant 1998; 21 (Suppl. 1): S212 (Abstr. 744). is clearly demonstrated. Although very preliminary, this 8 Moreau P. Autologous stem cell transplantation for AL amylo- idosis: a standard therapy? Leukemia 1999; 13: 1929–1931. observation corresponds well to the other reports cited 9 Comenzo RL. High-dose therapy for the treatment of primary showing survival rates of approximately 20–25% in this systemic amyloidosis. In: Schechter GP, Hoffman R, Schier high-risk subgroup of AL amyloidosis patients. Organ SL, Bajus JL (eds). Hematology 1999. American Society of improvement in case of cardiac amyloidosis is rarely Hematology Education Program Book 1999, pp 347–357. reported.12 Therefore, in most patients with only one organ 10 Saba N, Tsang R, Sutton DM et al. High treatment related system affected by AL amyloidosis, high-dose chemo- mortality in cardiac amyloid patients undergoing autologous therapy may be safe and effective, whereas just those stem cell transplant. Bone Marrow Transplant 1999; 24: patients with multi-organ involvement, in whom an 853–855. improvement of treatment options is urgently required, 11 Desikan KR, Dhodapkar, Hough A et al. Incidence and impact must be regarded as a high-risk group with respect to treat- of light chain associated (AL) amyloidosis on the prognosis of patients with multiple myeloma treated with autologous ment-related mortality. Because of the high treatment- transplantation. Leuk Lymphoma 1997; 27: 315–319. related mortality, we consider that there is no role for solid 12 Moreau P, Milpied N, de Faucal P et al. High-dose melphalan in cases of advanced cardiac or liver and autologous bone marrow transplantation for systemic AL amyloidosis prior to high-dose chemotherapy until more amyloidosis with cardiac involvement. Blood 1996; 87: clinical experience is available. 3063–3064.

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