Bone Marrow Transplantation (2002) 30, 279–285  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Amyloidosis Toxic : a life-threatening of high-dose therapy and autologous stem cell transplantation among patients with AL amyloidosis

BM Hayes-Lattin, PT Curtin, WH Fleming, JF Leis, DE Stepan, S Schubach and RT Maziarz

Adult Bone Marrow Transplant Program, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA

Summary: with autologous transplantation in patients with amylo- idosis and focuses on the complication of toxic megacolon. AL amyloidosis is a plasma cell disorder in which tissue deposition of immunoglobulin light chains leads to organ dysfunction. Recent reports of high-dose therapy Patients and methods with autologous stem cell transplantation for amylo- idosis suggest higher response rates and extended sur- Four patients received high-dose therapy and autologous vival compared to those seen with conventional chemo- stem cell transplantation at Oregon Health and Science Uni- therapy. However, substantial treatment-related toxicity versity. Two patients were treated for primary AL amylo- has been observed. This case series describes our insti- idosis, one for multiple myeloma with AL amyloidosis, and tutional experience with autologous transplantation in one patient for multiple myeloma who was later found to four patients with amyloidosis with an emphasis on have AL amyloidosis (see details in Table 1). unique gastrointestinal toxicities, including toxic mega- colon. Patient 1 Bone Marrow Transplantation (2002) 30, 279–285. doi:10.1038/sj.bmt.1703627 A 57-year-old man presented with 18 months of progress- Keywords: AL amyloidosis; high-dose chemotherapy; ive hand and finger swelling, nail changes, and skin fra- stem cell transplantation; toxic megacolon gility. His history was also notable for macroglossia with obstructive sleep apnea, and bilateral carpal tunnel release surgeries. A skin biopsy confirmed AL amyloid deposition. Serum protein electrophoresis (SPEP) did not reveal a AL amyloidosis is monoclonal plasma cell disorder charac- monoclonal protein, but a bone marrow biopsy showed terized by tissue deposition of immunoglobulin light chains, 16% lambda-restricted plasma cells without evidence leading to dysfunction of organs including the heart, kid- of amyloid deposition and a 24 h urine collection showed neys, gastrointestinal (GI) tract, liver, soft tissues and 800 mg of Bence-Jones proteinuria. No lytic lesions were nerves. In one series of 474 patients, the median survival identified on bone survey. 1 after diagnosis was 13.2 months without treatment. Con- The patient was treated with vincristine, adriamycin, and ventional therapies aimed at the underlying plasma cell dis- dexamethasone (VAD) chemotherapy, followed by cyclo- order have produced modest gains, with response rates of phosphamide, etoposide and decadron (CED) chemo- 30% and an extension of median survival by only 6 therapy and G-CSF stem cell mobilization by which 37.3 2,3 months. Over the past several years, trials of high-dose ϫ 106 CD34+ cells/kg were collected and cryopreserved. therapy and autologous stem cell transplantation have Six months after the initiation of primary therapy, the reported response rates up to 55–100% and a median sur- patient received high-dose therapy with busulfan 4 mg/kg 4–16 vival exceeding 12 to 24 months. These data have led four times a day for 3 days, melphalan 50 mg/m2 daily for clinicians to increasingly consider AL amyloidosis as an 2 days, and thiotepa 250 mg/m2 daily for 2 days, followed indication for autologous transplantation. Unfortunately, by autologous transplant with 19.3 ϫ 106 CD34+ cells/kg. substantial treatment-related toxicity has been reported in The duration of severe neutropenia was 10 days, compli- patients with amyloidosis undergoing autologous transplan- cated by and grade 3 mucositis (NCI scale17). Within tation. This series describes our institutional experience 2 weeks of transplant, the patient had responded with near complete resolution of macroglossia and dermopathy. On day +14, he developed watery , which responded Correspondence: Dr RT Maziarz, Oregon Health and Science University, to treatment with tincture of opium and pulsed steroids for 18 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA possible autologous graft-versus-host disease. However, Received 18 December 2001; accepted 25 March 2002 on day +18, the diarrhea returned with frank . Toxic megacolon after transplant for amyloidosis BM Hayes-Lattin et al 280 Table 1 Patient characteristics

Age at Sex Transplant Amyloid Pre-transplant Stem cell Conditioning Outcome transplant diagnosis involvement therapy mobilization regimen

58 M Multiple myeloma Skin (biopsy), GI VAD ϫ 5 cycles CED with G-CSF Busulfan Toxic megacolon, with AL amyloidosis (macroglossia, Melphalan died day +81 biopsy), bone Thiotepa marrow (biopsy) 52 M AL amyloidosis Renal (biopsy), bone G-CSF, Melphalan Multi-organ system marrow (biopsy), G-CSF/GM-CSF failure, died day +20 liver (enlargement, alk phos), peripheral nerves (symptoms) 56 M Multiple myeloma GI (biopsy), bone Oral melphalan and CED with G-CSF Busulfan Toxic megacolon, marrow (biopsy) prednisone, VAD ϫ Thiotepa died 14 months post- 4 cycles, TBI transplant with cyclophosphamide ϫ relapse 3 cycles 65 M AL amyloidosis GI (macroglossia, VAD ϫ 3 cycles Cyclophosphamide Melphalan Mucositis, alive 20 oral biopsy), skin, with G-CSF months post- renal (proteinuria) transplant, partial remission

Assays for ova and parasites, bacterial and viral pathogens, platelet transfusion support with gradual recovery, and was and C. difficile toxin were negative. Colonoscopy revealed discharged on day +25. ulceration and biopsies showed changes consistent with He was re-admitted on day +28 with fever and dehy- chronic ischemic and focal amyloid deposition in dration. Blood cultures revealed a coagulase-negative vessel walls (Figure 1). The patient received red cell and Staphylococcal species, which was treated with intravenous and removal of his central catheter. The persisted and he developed abdominal cramping with wat- ery diarrhea and distention of the bowel of up to 8 cm on radiographs. He was treated with narcotic withdrawal, bowel rest, intravenous fluids, and additional empiric anti- biotics. A tagged WBC scan showed persistent tracer activity in the distal transverse colon, but a CT scan showed only mild ascites without visible abscess formation. Again, multiple stool cultures and C. difficile toxin assays were negative. Over 1 week, his diarrhea slowed and he remained afebrile after stopping the antibiotics. On day +33, the patient developed new lower with urinary symptoms and was found to have adenoviral cys- titis. With controlled diarrhea on bowel rest and total par- enteral nutrition, he was discharged from the hospital on day +50, but continued to suffer persistent and vom- iting with any oral intake. On day +78, he developed acute jaundice and multiple new subcutaneous masses. He declined further treatment and died 81 days post transplant. A post-mortem examination was not performed.

Patient 2 A 51-year-old man presented with hypertension and pro- teinuria, which were treated medically. One year later, he noted intermittent nausea and vomiting with anorexia and an intervening 62-pound weight loss. He also complained of persistent lower extremity edema, easy bruising, decreased exercise tolerance, paresthesias in his feet, and Figure 1 Colitis. Colonoscopy to evaluate bloody diarrhea 18 days after autologous transplantation for multiple myeloma with AL amyloidosis several episodes of diarrhea lasting several days at a time. revealed colitis with deep (a) and linear (b) ulcerations. Biopsies con- The serum creatinine was 1.9 mg/dl. A 24 h urine collection firmed presence of amyloid deposition. revealed a creatinine clearance of 80 ml/min and pro-

Bone Marrow Transplantation Toxic megacolon after transplant for amyloidosis BM Hayes-Lattin et al 281 teinuria of 12.9 g. Renal biopsy showed negative Congo patient received therapy for multiple myeloma with oral red staining, but positive staining of mesangial deposits melphalan and prednisone. Three years later, after rising with anti-lambda light chain antibodies. Electron serum paraprotein levels, he was treated with VAD chemo- microscopy revealed fibrillary glomerular deposits with therapy and achieved only a partial response followed by ultrastructural features and dimensions consistent with three cycles of intermediate-dose cyclophosphamide, which amyloid. A bone marrow biopsy demonstrated normal reduced his bone marrow involvement to 11% plasma cells. cellularity and composition with aggregates of small He underwent hematopoietic stem cell mobilization using eosinophilic nodules which stained positively with Congo CED chemotherapy with G-CSF, and 8.3 ϫ 106 CD34+ red and were faintly birefringent, consistent with amyloid. cells/kg were harvested by leukopheresis. There was no detectable monoclonal protein in serum or Four years from initial diagnosis, he received high-dose urine. He had palpable hepatomegaly and an isolated elev- therapy with busulfan 4 mg/kg in divided daily doses for ation of the serum alkaline phosphatase. An echocardiog- 2 days, thiotepa 200 mg/m2 daily for 2 days, and total body ram showed normal myocardial wall thickness and normal irradiation (TBI) 1.5 cGy twice daily for 3 days, followed systolic function. Several months after diagnosis, he by autologous stem cell transplantation. At the time of underwent primary stem cell mobilization with G-CSF with transplantation, the serum creatinine was 1.1 mg/dl. Post a poor collection, followed by repeat mobilization with transplant, the patient developed severe mucositis and gas- combination G-CSF and GM-CSF by which 6.5 ϫ 106 trointestinal bleeding, requiring transfusion support. He CD34+ cells/kg were collected. developed a neutropenic fever on day +1, and was empiri- The patient proceeded to high-dose therapy 1 month cally covered with broad-spectrum antibiotics until neutro- later, receiving melphalan 200 mg/m2, followed by autolog- phil recovery on day +10. Blood and urine cultures ous transplant. On admission, his creatinine had increased remained negative. On day +11, he suffered new abdominal to 3.0 mg/dl. His early post-transplant course was marked cramping, nausea with vomiting, and increased diarrhea. by neutropenic fever and grade 3 mucositis. On day +5, he His abdomen was firm and distended with mild diffuse ten- developed oliguric renal failure. A renal ultrasound showed derness, and an abdominal X-ray revealed up to 10 cm echogenic kidneys without signs of obstruction and an ech- dilation of the ascending and transverse colon without obvi- ocardiogram was normal. Therapy with aggressive ous obstruction (Figure 2). This complication was treated diuretics, albumin infusions, and low-dose dopamine did with narcotic withdrawal, bowel rest and decompression by not control progressive volume overload, and on day +7he a nasogastric tube. By day +12, he became newly febrile was transferred to the intensive care unit for initiation of continuous veno-venous hemofiltration (CVVH). His course was complicated by hypotension requiring vaso- pressor support and new onset atrial fibrillation with rapid ventricular response. The patient’s mental status deterio- rated, and, with worsening mucositis, he was intubated for airway protection. Right heart catheterization showed a decreased systemic vascular resistance and elevated cardiac output consistent with . He developed new fevers, worsening hypotension, and increasing bilateral pulmonary infiltrates, co-incidental with neutrophil recovery. An abdominal source of the sepsis was suspected, with pro- gressive abdominal distention with rigidity and dilated loops of bowel up to 6 cm on abdominal radiographs. Cul- tures failed to demonstrate an infectious pathogen and despite broad-spectrum antibiotics, the patient’s multi- organ failure progressed. He was supported with antibiotics, vasopressors, CVVH, mechanical ventilation, and total par- enteral nutrition with no improvement. On day +20, support was withdrawn and the patient expired. A post-mortem examination was not performed.

Patient 3 A 56-year-old man was evaluated for nephrosis with renal insufficiency. A renal biopsy showed active chronic inter- stitial nephritis with eosinophilia and interstitial hemorrh- age. Electron microscopy findings were nondiagnostic with an inflammatory infiltrate in the interstitium. An SPEP revealed a monoclonal kappa light chain, a UPEP con- firmed presence of Bence-Jones proteins, and a subsequent Figure 2 Megacolon. Abdominal radiographs revealed colonic disten- bone marrow biopsy showed large aggregates of plasma tion of up to 10 cm in a patient after autologous transplant with abdominal cells with 17% of these showing kappa-restriction. The cramping, diarrhea and fever.

Bone Marrow Transplantation Toxic megacolon after transplant for amyloidosis BM Hayes-Lattin et al 282 and was restarted on broad-spectrum antibiotics. A colonos- bocytopenia requiring transfusion support, grade 3 mucos- copy revealed edematous and friable mucosa with a granu- itis, and culture-negative neutropenic fever covered with lar appearance and multiple ulcerations. Colonic biopsies broad-spectrum antibiotics. He did not experience any revealed the presence of bi-refringent material in associ- further tachyarrhythmias. ation with the muscularis mucosa, consistent with amylo- Two months post-transplantation, a bone marrow biopsy idosis and mucosal changes secondary to local amyloid- revealed no amyloid deposits but persistent disease with 5– related vasculopathy. Assays for ova and parasites, bacterial 10% lambda-restricted plasma cells, and he was started on and viral pathogens, and C. difficile toxin were repeatedly maintenance therapy with thalidomide 100 mg daily. By 13 negative. The patient required continuous hospitalization months post transplantation, his proteinuria had continued with continued bowel dysfunction, abdominal distention, to decrease to 117 mg in 24 h and his bone marrow showed and return of fevers when off antibiotics. He was dis- similar findings. The patient reported significant improve- charged from the hospital on day +76 post transplant, but ment in tongue swelling and body stiffness. He had continued to have abnormal abdominal radiographs for returned to his normal activities. another 2 months. Two repeat colonoscopy exams showed similar findings. Retrospective analysis of pre-transplant bone marrow biopsies and a pre-transplant colon and Discussion duodenal biopsy all failed to demonstrate involvement with amyloid, but a bone marrow examination prior to hospital In this series of four patients who received high-dose ther- discharge did show amyloid deposits. apy and autologous stem cell transplantation, two were After discharge, he required 6 additional weeks of par- treated for primary AL amyloidosis, one for multiple myel- enteral nutrition, and by 10 months post transplant he con- oma with AL amyloidosis, and one patient was later found tinued to suffer poor appetite with weight loss. Twelve to have AL amyloidosis complicating multiple myeloma months post transplant, he developed increased urinary (Table 1). Two of the four patients died within 3 months Bence-Jones protein with a stable serum creatinine of 0.9 of transplantation, one of multi-organ system failure and mg/dl, followed by recurrent pleural transudates of unclear one of probable progressive disease in the setting of sig- etiology. Ultimately, the patient died 14 months after trans- nificant colitis. Of the two patients surviving Ͼ100 days, plantation with sepsis after an attempted pleurodesis. A one had severe colitis with megacolon and biopsy-proven post-mortem examination was not performed. amyloid-related vasculopathy, later dying with relapse and . Both patients surviving the transplantation pro- Patient 4 cedure had partial hematologic and amyloid-involved organ disease remissions. A 62-year-old man experienced progressive tongue swell- Several groups have reported on the use of high-dose ing. Within 1 year, he was treated for obstructive sleep therapy with autologous stem cell transplantation in treating apnea with uvuloplasty and continuous positive airway AL amyloidosis (Table 2). In total, these results would sug- pressure nocturnal ventilation. He also developed carpal gest response rates of approximately 50%. However, the tunnel syndrome and had bilateral surgical releases. He total observed rate of 100 day treatment-related mortality complained of easy bruising including periorbital was 18%, without stratification based on organs affected ecchymoses, and stiffness with skin thickening of the by amyloid. In contrast, toxic death rates of only 5% after cheeks, shoulders, and hands leading to the inability to tie autologous transplantation are typical for patients with mul- his own shoes. An oral biopsy confirmed the presence of tiple myeloma.19–21 While the data for amyloidosis may be submucosal AL amyloid deposition. The serum creatinine skewed by selective case reporting of adverse events, out- was 0.8 mg/dl, total protein 4.7 g/dl, albumin 3.2 g/dl, and comes in the largest series show similar mortality rates. SPEP negative for a monoclonal protein. A 24 h urine col- Early deaths are often from cardiac causes or multi-organ lection showed 984 mg of mostly lambda Bence-Jones pro- failure. tein. No lytic lesions were found on bone survey. A bone Substantial morbidity has also been reported after high- marrow biopsy showed normal cellularity with 10–15% dose therapy in patients with amyloidosis, including a few lambda-restricted plasma cells, and no evidence of amyloid published reports detailing substantial GI toxicity. In 1992, deposition. An echocardiogram showed mild left atrial Mehta et al22 described a case of massive GI bleeding 3 enlargement and normal left ventricular function. There days after an abbreviated course of high-dose therapy and were no specific findings to suggest a restrictive myopathic allogeneic transplantation for multiple myeloma with amy- process. After diagnosis, the patient was treated with three loidosis of the bowel. In an autologous transplantation ser- cycles of VAD chemotherapy, followed by stem cell mobil- ies, Dember et al9 observed mucositis in 53%, elevation in ization with cyclophosphamide and G-CSF, and 41.8 ϫ 106 liver enzymes or bilirubin levels in 13%, and GI bleeding CD34+ cells/kg were collected. This chemotherapy was in 10% of 65 patients. A fatal case of gastrointestinal per- complicated by neutropenic fever and paroxysmal atrial foration with amyloid infiltration occurring 4 days after fibrillation. A repeat echocardiogram showed no myocar- autologous transplantation was reported by Schulenburg et dial abnormalities to suggest amyloid infiltration. al.23 Gertz et al8,10 described GI toxicity in five of 20 One month later, he underwent high-dose therapy with patients (25%) surviving autologous transplantation, with melphalan 200 mg/m2 followed by autologous stem cell four requiring prolonged enteral and/or parenteral nutrition transplantation. His post-transplantation course was compli- including one with severe gastrointestinal bleeding. Com- cated by severe neutropenia for 10 days, anemia and throm- enzo et al24 stated ‘the degree of gastrointestinal toxicity

Bone Marrow Transplantation Toxic megacolon after transplant for amyloidosis BM Hayes-Lattin et al 283 Table 2 Published series of autologous transplants for amyloidosis

Author/Ref. No. of patients 100 day treatment- Overall survival No. Follow-up Hematologic Amyloid organ related mortality (intention-to- evaluable response disease treat) improvement

Majolino32 1 1/1 (100%) CMV 0 at 74 days 1 74 days PR at 2 weeks Not reported pneumonitis Van Buren33 3 (one syngeneic) 0/3 (0%) 2/2 (100%) at 24 2 12 months 2/2 (100%) 2/2 (100%) PR Lokhorst6 months CR Moreau14 1 (May 1993) 0 1/1 (100%) at 17 1 17 months 1/1 (100%) 1/1 (100%) PR months CR Gillmore34 16 (too early to 1/16 (6%) GI bleed Not reported 0 N/A N/A N/A analyze) Amoura4 9 3/9 (33%) ARF, 5/9 (55%) median 5 Mean Not 4/5 (80%), 1/5 sepsis, arrhythmia 12.6 months 8.9 months reported CR, 3/5 PR Moreau 21 (June 1993 9/21 (43%) Multi- 12/21 (57%) at 12 Median 3/12 (25%) 10/12 (83%) (IFM)5 March 1997) organ failure, median 14 14 months CR PR+CR bleeding, months arrhythmia Schulenburg23 1 1/1 (100%) GI 0 at 4 days 0 N/A N/A N/A perforation Patriarca15 1 0 1/1 (100%) at 22 1 22 months 1/1 (100%) 1/1 (100%) PR months CR Saba29 9 7/9 (78%) (3 2/9 (22%) at Ͼ6 2 Not Not reported 2/2 (100%) PR during months after reported mobilization) referral arrhythmia, CHF, hypotension Sezer16 1 0 1/1 (100%) at 3 1 3 months 1/1 (100%) 1/1 (100%) renal months CR and cardiac PR Gertz8,10 23 (3 never 4/20 (20%) 13/23 (57%) 20 Median 8/20 (40%) 12/20 (60%) PR transplanted) pneumonia, multi- median 16 Ͼ13 months CR organ system months failure, sudden death Reich13 4 2/4 (50%) acute 2/4 (50%) at 7 2 7 and 19 1/2 (50%) 2/2 (100%) PR MI, diffuse alveolar and 19 months months PR hemorrhage Sanchorawala11 205 (20 never 22/185 (12%) 115/152 (76%) 115 at Ͼ12 months 54/115 (47%) 18/50 (36%) renal Comenzo7,24 transplanted) at >12 months Ͼ12 months CR CR at 12 months Dember9 (Dember)

Total 295 50/272 (18%) 154/225 (68%) 162 72/155 (46%) 53/96 (55%)

with 200 mg/m2 of melphalan is striking,’ with nausea and transplantation setting, amyloid deposition can lead to a vomiting in 83%, diarrhea in 65%, mucositis in 91%, and variety of GI symptoms, and has been associated with spon- GI bleeding in 22% of patients. In reviewing the use of taneous bowel perforation26 and fatal GI hemorrhage.27 autologous transplantation for amyloidosis, Sanchorawala Pathophysiologically, amyloid infiltration may directly con- et al11 agreed that ‘pretransplant assessment of gastrointes- tribute to the generation of toxic megacolon by injuring the tinal function and mucosal integrity has been essential’. mucosa and by impairing the smooth muscle and myenteric The GI toxicities observed at our institution included not nerve plexus needed to maintain normal gut motility. In only severe mucositis and GI bleeding, but also clinical patient 1, the early, rapid, and marked regression of macro- presentations of toxic megacolon, with non-obstructive glossia may have reflected systemic decreases in GI tissue colonic dilatation, fever and other signs of systemic tox- infiltration, leading to thinning of the gut wall and contribu- icity.25 The degree of toxicity was severe. One patient was ting to mucosal breakdown. Other potential factors con- considered for total and another had persistent tributing to the development of toxic megacolon in this bowel dysfunction for nearly 5 months. These patients did group of patients include the use of vincristine in pre-trans- not have a history of underlying inflammatory bowel dis- plantation therapy, and the use of thiotepa in the condition- ease and no infectious causes for the colitis were identified. ing regimen, both of which may be toxic to the autonomic Biopsies revealed acute inflammation consistent with toxic nerves controlling gut motility.28 megacolon, but were also notable for focal vascular amy- In addition to treatment-related GI toxicities, other organ loid deposition and associated mucosal injury. In the non- systems may be substantially compromised after high-dose

Bone Marrow Transplantation Toxic megacolon after transplant for amyloidosis BM Hayes-Lattin et al 284 therapy in patients with amyloidosis. Multiple investigators Acknowledgements have documented episodes of profound renal and cardiac insufficiency, with edema, volume overload, and vascular We thank the staff of the Adult Bone Marrow Transplantation leak syndromes.4,5,8,9,12,29 This description is similar to the Program at Oregon Health and Sciences University, particularly course of patient 2 in our series. Cardiac arrhythmias and coordinators Anne Kratz, RN and Florence Seelig, RN. sudden death are also relatively frequent in this patient population.4,5,8,9,12,13,29 A retrospective analysis of 21 patients revealed that the number of clinical manifestations References of amyloidosis pre-transplantation was predictive for sur- vival, with a toxic death rate of Ͼ75% in patients with two 1 Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical or more organ dysfunctions.5 In addition to the number of and laboratory features in 474 cases. Semin Hematol 1995; affected organ systems, the presence of symptomatic car- 32:45–59. diac involvement has statistically correlated with poorer 2 Skinner M, Anderson J, Simms R et al. Treatment of 100 overall survival rates.24 patients with primary amyloidosis: a randomized trial of mel- The high rates of toxicity observed with high-dose ther- phalan, prednisone, and colchicine versus colchicine only. Am apy for primary amyloidosis have led to questions about the JMed1996; 100: 290–298. 3 Kyle RA, Gertz MA, Greipp PR et al. A trial of three regi- impact of amyloidosis on outcomes in patients undergoing mens for primary amyloidosis: colchicine alone, melphalan autologous transplantation for multiple myeloma. In a ser- and prednisone, and melphalan, prednisone, and colchicine. ies of 84 myeloma patients, no differences were found in New Engl J Med 1997; 336: 1202–1207. disease characteristics, event-free survival, or overall sur- 4 Amoura Z, Leblond V, Azar N et al. High dose therapy and vival in the 38% found to have amyloid deposits.30 How- autologous stem cell transplantation (ASCT) for systemic ever, these findings have been criticized because most of amyloidosis (AL): report of 9 cases (abstract). Arthritis Rheum the patients with documented amyloidosis were discovered 1998; 41: S234. after routine subcutaneous fat pad aspirates, with only 5 Moreau P, Leblond V, Bourquelot P et al. Prognostic factors seven biopsies of symptomatic organs. Saba et al29 noted for survival and response after high-dose therapy and autolog- fatal arrhythmias and refractory stem cell infusion-related ous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. Br J Haematol 1998; 101: 766–769. hypotension occurring in six of nine patients transplanted 6 Lokhorst HM, Verdonck LF. Intensive therapy in AL amylo- for predominantly cardiac AL amyloidosis, but in none of idosis and light-chain deposition disease (letter). Ann Intern over 100 patients transplanted for myeloma. Med 1995; 123: 553. Based on the high degree of toxicity observed, clinicians 7 Comenzo RL, Falk RH, Sanchorawala V et al. Treating AL must remain critical when evaluating the role of high-dose amyloidosis (AL) with dose-intensive melphalan: outcomes in therapy and autologous transplantation in treating amylo- 102 patients. Blood 1998; 92: 324a. idosis. The long-term survival with stem cell transplan- 8 Gertz MA, Lacy MQ, Dispenzieri A. Myeloablative chemo- tation is not yet known, and the population found to be therapy with stem cell rescue for the treatment of primary sys- eligible might have relatively ‘good risk’ amyloidosis, temic amyloidosis: a status report. Bone Marrow Transplant including extended survival without transplantation. In a 2000; 25: 465–470. 9 Dember LM, Sanchorawala V, Seldin DC et al. Effect of dose- retrospective analysis of patients seen at the Mayo Clinic intensive intravenous melphalan and autologous blood stem- from 1983 to 1997, the median survival of the 229 patients cell transplantation on al amyloidosis-associated renal disease. who would have met standard eligibility criteria for trans- Ann Intern Med 2001; 134: 746–753. plantation was 42 months.31 10 Gertz MA, Lacy MQ, Gastineau DA et al. Blood stem cell In conclusion, high-dose therapy and autologous stem transplantation as therapy for primary systemic amyloidosis cell transplantation is feasible in a selected subset of (AL). Bone Marrow Transplant 2000; 26: 963–969. patients with AL amyloidosis, with generation of hematol- 11 Sanchorawala V, Wright DG, Seldin DC et al. An overview ogic and amyloid-involved organ disease remissions. Pre- of the use of high-dose melphalan with autologous stem cell vious authors have identified patients with involvement of transplantation for the treatment of AL amyloidosis. Bone fewer than two symptomatic organ systems and no cardiac Marrow Transplant 2001; 28: 637–642. 19,24 12 Comenzo RL, Vosburgh E, Falk RH et al. Dose-intensive mel- as benefiting most from this treatment. How- phalan with blood stem-cell support for the treatment of AL ever, based on the experiences outlined above, particular (amyloid light-chain) amyloidosis: survival and responses in attention to the presence of GI involvement with amylo- 25 patients. Blood 1998; 91: 3662–3670. idosis appears prudent, as significant morbidity and mor- 13 Reich G, Held T, Siegert W et al. Four patients with AL amy- tality has been documented in these patients. Careful review loidosis treated with high-dose chemotherapy and autologous of prior GI symptoms is fundamental to pre-transplantation stem cell transplantation. Bone Marrow Transplant 2001; 27: evaluations to identify those at risk for intestinal amyloid. 341–343. Other strategies to detect amyloid may include routine 14 Moreau P, Milpied N, de Faucal P et al. High-dose melphalan radiographs or rectal biopsies, in which abnormalities may and autologous bone marrow transplantation for systemic AL be found even in asymptomatic patients.26,27 However, the amyloidosis with cardiac involvement. Blood 1996; 87: 3063–3064. clinical utility is limited by lack of available data to assess 15 Patriarca F, Geromin A, Fanin R et al. Improvement of amy- an individual’s transplantation risk based on positive rectal loid-related symptoms after autologous stem cell transplan- biopsies without symptoms. Finally, clinicians should be tation in a patient with hepatomegaly, macroglossia and pur- aware of toxic megacolon as a potential complication of pura. Bone Marrow Transplant 1999; 24: 433–435. high-dose therapy in amyloidosis. 16 Sezer O, Schmid P, Shweigert M et al. Rapid reversal of neph-

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