Bone Marrow Transplantation (2001) 28, 637–642  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt Mini-review An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL

V Sanchorawala1,2, DG Wright1,2, DC Seldin1,2, LM Dember2,3, K Finn1,2, RH Falk2,4, J Berk2,5, K Quillen1,2 and M Skinner2,6

1Stem Cell Transplant Program of the Section of and , 2Amyloid Research and Treatment Program, Sections of 3Renal , 4Cardiology, 5Pulmonology and 6Rheumatology in the Department of Medicine, Boston University School of Medicine, Boston University Medical Center, Boston, MA, USA

Summary: complete hematologic responses. Bone Marrow Trans- plantation (2001) 28, 637–642. Primary or AL amyloidosis results from a plasma cell Keywords: AL amyloidosis; high-dose ; dyscrasia in which fibrillar light chain protein depo- stem cell transplantation sition leads to organ failure and death. Standard treat- ment for AL amyloidosis has been oral melphalan and prednisone. However, this form of treatment modifies the natural history of this lethal disease only marginally, Systemic amyloidosis is a multisystem disease caused by extending median survival from 13 months following widespread, pathologic, extracellular deposition of insol- diagnosis to 17 months. At Boston University Medical uble fibrillar proteins in organs and tissues. The process by Center, we have developed treatment protocols using which precursor proteins produce fibrils is multifactorial high-dose intravenous melphalan with autologous per- and differs among the various types of .1 ipheral blood stem cell transplantation (HDM/SCT) to Primary or ‘AL’ amyloidosis is the most common and treat AL amyloidosis, and we have treated over 200 arguably the most aggressive and lethal form of systemic patients with HDM/SCT during the past six years. This amyloidosis. In this disorder, amyloid protein deposits are extensive experience has shown that patients with AL derived from monoclonal immunoglobulin light chains amyloidosis, despite multisystem involvement and secreted by neoplastic plasma cell clones. Although the bur- compromised organ function can tolerate this aggressive den of clonal plasma cells in AL amyloidosis is generally form of treatment. Furthermore, HDM/SCT results in low, the accumulation of amyloid deposits in the , kid- durable hematologic responses in a substantial pro- neys, liver, GI tract and autonomic nervous system leads to portion of patients, and such responses are associated progressive disability, organ failure and death. The median with clinical improvement, decreased amyloid-related survival of untreated patients is 13 months from the time organ dysfunction, and prolonged survival. However, of diagnosis,2 with a considerably worse median survival toxicity from treatment is high (overall peri-transplant of 4 months for patients with congestive at mortality, 14%), particularly for those patients with clinically significant cardiac involvement. For this rea- diagnosis. Although long-term survival of untreated son, we believe a multidisciplinary management patients with AL amyloidosis (eg more than 10 years from approach is essential when using HDM/SCT for treat- diagnosis) can occur, such indolent progression of disease Ͻ 3 ment of AL amyloidosis. Based on our experience, we is rare ( 5%). Several prospective, randomized clinical believe that HDM/SCT is the treatment of choice for trials have shown that cyclic, low-dose oral melphalan and patients with AL amyloidosis who have a good perform- prednisone is beneficial, increasing the median survival of 4,5 ance status and limited cardiac involvement at the time patients to about 17 months. However, cyclic oral mel- of diagnosis. HDM/SCT offers the best chance for hema- phalan only rarely results in complete hematologic tologic remission, prolongation of survival, and reversal responses (eg elimination of the underlying plasma cell of amyloid-related disease. At the same time, we believe dyscrasia) or in reversal of amyloid-related organ dysfunc- that HDM/SCT should continue to be examined in the tion. Combination chemotherapy with VBMCP (vincristine, context of clinical trials, directed at developing carmustine, melphalan, cyclophosphamide and prednisone) approaches to broaden the applicability of this has also been studied in a randomized, prospective fashion by minimizing toxicity and to increase the likelihood of in this disorder but was found not to improve response rates or survival.6

Correspondence: V Sanchorawala, Boston University Medical Center, 88 East Newton Street, Boston, MA 02118, USA Stem cell transplantation in AL amyloidosis V Sanchorawala et al 638 Initial pilot studies of high-dose chemotherapy and tocols. Twenty of these patients began stem cell mobili- blood stem cell transplantation for the treatment of zation and collection but did not proceed to high-dose AL amyloidosis chemotherapy and transplant, either because of death (six patients) or complications (14 patients) during the initial High-dose intravenous melphalan chemotherapy and auto- phase of treatment. Of the 185 patients who completed logous peripheral blood stem cell transplantation has been chemotherapy and transplant, there were 22 deaths within 3 successful in inducing complete hematologic remissions months of treatment. This early mortality of 14% (28/205) and prolonging survival in multiple myeloma.7 Therefore, reflects the clinical fragility of this patient population, parti- it was logical to apply this approach to the treatment of cularly those with evidence of amyloid AL amyloidosis. who accounted for 70% (20/28) of the early deaths. The Amyloid Research and Treatment Program at Bos- One hundred and fifty-two patients completed high-dose ton University School of Medicine has had a long-standing melphalan and transplant prior to April 1999, for whom investigative interest in the pathophysiology and treatment there was the possibility of at least 1 year of follow up by of the various forms of systemic amyloidosis. In 1994, a April 2000. The median age of these 152 patients was 56 multidisciplinary clinical group was formed at Boston Uni- (range 29–80), with a male:female ratio of 1.5:1.0. Seventy- versity Medical Center to develop high-dose chemotherapy seven of these patients received full high-dose melphalan protocols for AL amyloidosis. This group was made up of (200 mg/m2) and 75 received modified high-dose treatment clinicians allied with the Amyloid Research and Treatment (100–140 mg/m2). Program, representing the disciplines of , neph- Of these 152 patients, 115 (76%) survived for at least 1 rology, , , and year following treatment and were evaluated for hemato- , together with hematologists in the Stem Cell logic and clinical responses. Hematologic CR was defined Transplant Program of the Section of Hematology and as absence of a monoclonal protein in serum and urine by Oncology. immunofixation electrophoresis together with a bone mar- We reported our initial experience with high-dose mel- row showing less than 5% plasma cells without phalan and stem cell transplantation (HDM/SCT) in five clonal dominance of ␬ or ␭ light chain isotypes. Forty- patients with AL amyloidosis in 1996.8 This pilot study seven percent (54/115) of patients evaluated at 1 year after showed that AL amyloidosis patients with significant sys- treatment were found to be in hematologic CR. Patients temic disease could be successfully treated with dose-inten- who received 200 mg/m2 of melphalan were more likely to sive chemotherapy. Furthermore, three of the five patients have a hematologic CR at 1 year (56%), than were those achieved a complete hematologic response, with disappear- who received modified high-dose melphalan (35%) (P = ance of their underlying clonal plasma cell disorder follow- 0.04). Furthermore, hematologic CRs have proven to be ing treatment. Moreover, all five patients experienced durable. Of the 54 patients with a hematologic CR at 1 reversal of amyloid-related organ dysfunction. year, only three to date have relapsed with reappearance of An expanded series of 25 patients was reported in 1998.9 their clonal plasma cell disorder; two patients relapsing at Among these 25 patients, hematologic complete responses 2 years and the third at 3 years. were observed in 13 of 21 evaluable patients (62%), and Median survival for the entire group of 152 patients 65% experienced improvement in amyloid-related organ treated prior to April 1999 has not as yet been reached dysfunction. (Table 1). Survival was influenced significantly by whether or not hematologic CR was evident at 1 year following treatment. Survival was also clearly influenced by whether Cumulative 6 year experience with high-dose or not patients had evidence of amyloid cardiomyopathy by chemotherapy and blood stem cell transplantation at ECHO or EKG at the time of treatment. The influence of Boston University Medical Center cardiac involvement on survival was apparent both for patients who achieved hematologic CR and for those who We have now treated over 200 patients with AL amylo- did not. idosis with HDM/SCT.10 The details of this series are being Amyloid-related organ response was also determined 1 reported elsewhere. Although patients have been treated on year following treatment. Response criteria were defined a number of separate protocols during the past 6 years, all as follows: renal, a 50% reduction in proteinuria without protocols have shared common eligibility criteria and treat- ment elements. In all cases, we have required a confirmed Table 1 Survival in 152 patients completing treatment prior to April tissue diagnosis of amyloidosis, clear evidence of a clonal 1999 plasma cell dyscrasia, age Ͼ18 years, and minimum meas- ures of performance status (SWOG 0–2), cardiac function 2 years (%) 3 years (%) 4 years (%) Ͼ у (LVEF 40%), pulmonary function (O2 saturation 95% on room air), and hemodynamic stability (baseline systolic Overall 65 60 60 blood pressure у90 mm Hg). Patients on hemodialysis or Non-cardiac 85 85 85 peritoneal dialysis for renal failure were not excluded if Hem CR 91 91 91 Non-CR 80 80 80 other eligibility criteria were met. There was also no set Cardiac 49 40 40 upper age limit. Hem CR 56 43 43 Between June 1994 and April 2000, 205 patients with Non-CR 41 38 38 AL amyloidosis began high-dose melphalan treatment pro-

Bone Marrow Transplantation Stem cell transplantation in AL amyloidosis V Sanchorawala et al 639 Table 2 Clinical responses at 1 year following treatment erally required oral or parenteral nutrition supplements in the pre- and post-transplant period. Hematologic CR (%) Hematologic non-CR (%) Nephrotic syndrome associated with renal amyloidosis has been observed not uncommonly to lead to severe Renal 71 10 hypoalbuminemia and edema or anasarca. We have found Hepatic 88 50 that albumin infusions to raise the serum albumin to greater Cardiac 68 31 Factor X 100 33 than 1.5 g/dl followed by loop diuretics have been effective in managing these complications. Hypoalbuminemia, autonomic insufficiency, hypoadren- alsim, and cardiac disease can lead to severe orthostatic deterioration in glomerular filtration rate;11 liver, a 50% hypotension in these patients. Thigh-high stockings, mido- reduction in alkaline phosphatase and/or reduction in liver drine and fludrocortisone have proven useful in managing span of at least 2 cm; cardiac, echocardiographic stabiliz- these problems. ation of cardiac disease (Ͻ2 mm increase in the wall thick- Cardiac disease has been observed to predispose patients ness and/or 20 g increase in left ventricle mass); factor X to atrial and ventricular as well as to symptoms deficiency, normalization of factor X levels.12 and signs of restrictive cardiomyopathy. Management of Improvements in all categories of organ involvement such patients in coordination with an experienced cardiolo- were observed as summarized in Table 2. In addition, most gist has proven to be critical. Amiodarone is often an effec- patients with autonomic and peripheral neuropathies experi- tive anti-arrhythmic, while beta blockers, calcium channel enced dramatic clinical improvements, although this has not blockers, and digoxin have often been poorly tolerated by been quantified. Such responses were observed in both the these patients. hematologic CR and non-CR groups. Deficiency of factor X, along with the poor endothelial and connective tissue integrity from amyloid deposition, is associated with an increased risk of cutaneous and mucosal Special problems of chemotherapy and transplant in bleeding, including disease-specific raccoon eye AL amyloidosis ecchymoses. Patients with factor X deficiency are at parti- cularly high risk of bleeding complications during periods Patients with AL amyloidosis typically have organ impair- of thrombocytopenia. Hence, we have found that screening ment that predisposes them to increased peri-transplant for factor X deficiency must be done prior to treatment. morbidity and mortality. Table 3 shows the frequency of This issue has been discussed in detail in a recent grade Ͼ2 toxicities (NCI Common Toxicity Criteria) publication.12 encountered in our group of patients. Unique clinical chal- Additional unusual problems that may be encountered in lenges with AL amyloidosis patients that warrant special these patients include difficulties with emergent endotra- mention relate to the management of nutrition, macroglos- cheal intubation in patients with macroglossia, spontaneous sia, orthostatic hypotension, volume status and cardiac splenic and esophageal rupture, and hypercoagulability in arrhythmias. association with nephrotic syndrome. Pretransplant assessment of gastrointestinal function and mucosal integrity has been essential. We have found that such assessment appropriately includes a detailed review of Patient selection gastrointestinal signs and symptoms, serial stool exams for occult blood loss, endoscopic studies to define if Patients who have received high-dose chemotherapy and indicated, and a complete assessment of coagulation status. stem cell transplantation in our phase I and II clinical trials Patients with poor nutrition because of gastrointestinal dys- represent a selected patient group. A retrospective review function and dysmotility, anorexia, or dysgeusia have gen- of the amyloid database from June 1994 to September 1999 at Boston University indicates that 39% of patients with a new diagnosis of AL amyloidosis were considered to be Table 3 Frequency of grade Ͼ2 toxicity ineligible for treatment on clinical trials of HDM/SCT due to poor performance status, severe cardiac involvement, or Toxicities Number of patients % multisystem organ failure. Sixteen percent did not pursue (of total group of 152) treatment because of non-medical reasons. However, 45% of patients were offered treatment, including patients of Nausea or vomiting 70 46 advanced age, on dialysis, and with evidence of cardiac Diarrhea 70 46 Mucositis 70 46 disease. Pulmonary edema 20 13 Peripheral edema 29 19 Ͼ Gastrointestinal bleeding 11 7 Age 65 years Non-gastrointestinal bleeding 11 7 Twenty-seven patients over the age of 65 were treated with Hepatic 21 14 2 Renal 27 18 intravenous melphalan at 100–200 mg/m with stem cell Metabolic 72 47 rescue. Two of 27 patients (7%) died due to peri-transplant Sepsis 25 16 toxicities within 3 months. Fifty-eight percent (11/19) of the surviving patients achieved a hematologic CR; 70% sur-

Bone Marrow Transplantation Stem cell transplantation in AL amyloidosis V Sanchorawala et al 640 vived for at least 1 year. These results are as favorable, if Conditioning was carried out with either melphalan and not more favorable, than those for our entire treatment TBI or melphalan alone. Four of 20 patients (20%) died as cohort. Thus, we find that HDM/SCT is tolerable and a result of treatment-related mortality. Twelve of 20 effective treatment for selected older patients. patients (60%) fulfilled criteria for hematologic or organ response. Thirteen patients survived with a follow-up of 3 Patients on dialysis to 26 months. Moreau et al15 recently reported on a multicenter study Patients on hemodialysis or peritoneal dialysis for end stage of 21 patients. They found an unexpectedly high treatment- renal disease (ESRD) were not excluded from our treatment related mortality rate of 43% (nine of 21), but 10 of the 12 protocols, if they met other eligibility criteria. We have survivors (83%) achieved a response. Their conditioning treated 12 patients with AL amyloidosis-associated ESRD regimen also consisted of high-dose melphalan alone or with intravenous melphalan 100–200 mg/m2. The outcomes with total body irradiation (TBI). of these patients will be reported in detail in a separate Gillmore et al16 also reported, in abstract form, 40 manuscript. Although some treatment-related toxicities patients who underwent high-dose melphalan therapy, with occurred more frequently in these patients, the CR rate and 37% treatment-related deaths. However, a clinical response 1 year survival rate did not differ between the ESRD and was seen in 53% of patients. non-ESRD patients. Based on our experience, we believe that ESRD, in and of itself, is not a contraindication to HDM/SCT. Current recommendations and future directions

Cardiac disease Our data and that from other centers indicate that, despite multisystem organ dysfunction, patients with AL amylo- A thickened ventricular septum has been proposed as an idosis can tolerate high-dose melphalan and autologous absolute contraindication to high-dose chemotherapy and stem cell transplantation. Moreover, dose-intensive chemo- transplantation.13,14 We have treated 26 high-risk patients therapy can induce complete hematologic responses in a with an interventricular septum thickness of у15 mm. Of substantial proportion of patients who complete treatment. these, 14 patients have died, five (14%) in the peritransplant Furthermore, complete hematologic responses in AL amy- setting and eight (31%) within 1 year of treatment. How- loidosis are associated with reversal of amyloid-related ever, 46% (12/26) patients have survived with follow-up of organ dysfunction and may lead to prolonged survival in 26–66 months. The median survival for this group is this disease, which is typically fatal within 2 years when slightly less than 2 years, with 64% surviving for 1 year, managed with standard oral chemotherapy regimens. We 49% for 2 years and 40% for 3 years. This compares very believe that a number of lessons can be learned from our favorably with the survival of patients with cardiac disease experience and from that of others, with regard to the use treated with oral melphalan and prednisone,4 for whom of HDM/SCT in the treatment of AL amyloidosis. median survival was 5 months, and survival at 1, 2 and 3 years was 35%, 23% and 21%, respectively. Thus, our Multidisciplinary patient management experience suggests that septal thickness alone does not assure a poor outcome. At the same time we continue to Over the past 6 years, we have treated a large number of believe that, patients with New York Heart Association AL amyloidosis patients with HDM/SCT including patients classification class III or class IV congestive heart failure, over 65, patients on dialysis, and patients with cardiac left ventricular ejection fraction of less than 40%, sympto- disease. While patient selection remains important in matic ventricular tachycardia, exertional syncope and achieving an acceptable outcome, we also believe that the thromboembolic events from atrial dysfunction are at such relatively low treatment-related mortality that we have high risk of developing lethal complications during observed, compared to that reported by others, is in part HDM/SCT that this form of treatment is inappropriate for attributable to the multidisciplinary approach to patient them. management carried out at our institution. Each patient is evaluated by a team of subspecialists who are familiar with the manifestations and treatment of amyloidosis. These sub- Experience with high-dose chemotherapy and stem specialists remain available to the transplant cell transplantation at other centers throughout therapy, and the amyloid clinical team meets regularly to review each patient’s progress during treat- Other centers have carried out pilot studies of high-dose ment. We encourage other transplant centers undertaking chemotherapy and stem cell transplantation for AL amylo- treatment of these complicated patients to adopt a similar idosis with varying results. Reported experience is shown multidisciplinary management approach. in Table 4. The Mayo Clinic recently reported their experience with Stem cell mobilization 23 patients entered on to treatment protocols from Nov- ember 1995 to September 1998.13 Their stem cell mobiliz- Stem cell mobilization has unusually high morbidity for ation regimen included a combination of cyclophosphamide these patients, because of their propensity for fluid reten- (3 g/m2) and growth factor; three patients did not proceed tion, edema, pleural effusions, hypoxemia, and severe with treatment because of complications of mobilization. hypotension. At present, we believe that stem cell mobili-

Bone Marrow Transplantation Stem cell transplantation in AL amyloidosis V Sanchorawala et al 641 Table 4 Reported experience of HDM/SCT

Patients treated Conditioning regimen Treatment-associated Hem CR Clinical response (n) mortality (%) (%)

Boston University10 205 HDM 14 47 a Mayo Clinic13 23 HDM or HDM/TBI 20 40 60% (12/20) Moreau et al15 21 HDM or HDM/TBI 43 30 83% (10/12) Gillmore et al16 40 HDM 37 40 53% (8/15) aSee details in Table 2. zation with G-CSF alone is the best approach. We have transplant vs cyclic oral melphalan with prednisone should treated seven patients with a combination of cyclophos- be done. A review of Mayo Clinic data has indicated that phamide (2.5–4.0 g/m2) along with growth factor for stem selection bias probably accounts for at least some of the cell mobilization; three of these patients experienced fatal differences in outcome for patients treated with HDM/SCT complications. The Mayo Clinic has also reported mor- when compared with historical controls treated with oral bidity associated with cyclophosphamide and growth factor cyclic melphalan and prednisone.18 In this review, it was mobilization regimens. Currently, we employ G-CSF 16 noted that the subgroup of patients less than age 70, without ␮g/kg/day given in a single dose or in two divided doses cardiac involvement, renal failure, or significant liver dis- for 3 days for stem cell mobilization. ease had a median survival of 45.6 months when treated with oral melphalan and prednisone – a survival which was Conditioning much better than that of all AL amyloidosis patients con- sidered together. However, in our experience, patients with- Conditioning regimens for multiple myeloma have out cardiac disease who underwent treatment with employed either melphalan alone or melphalan with TBI, HDM/SCT, achieved a 4 year survival of 85% (Table 1), with similar outcomes. However, there has been a sugges- and the median survival of this group has not been reached. tion of more toxicity with the addition of TBI. The Mayo We plan to carry out case-control studies to compare high- Clinic observed a higher incidence of mucositis as well as dose chemotherapy and stem cell transplant to standard- an increased need for total parenteral nutrition in patients dose melphalan and prednisone to further address this receiving total body irradiation.13 In a series of 10 patients, question. However, we currently believe that given our a higher risk of cardiorespiratory events was attributed to phase II experience, it may prove difficult to design an ethi- the use of TBI.17 Throughout, we have used melphalan cal trial of HDM/SCT vs standard oral melphalan and alone for conditioning, with dose modifications for patients prednisone. At the same time, we do not preclude the possi- older than 65 or with diminished cardiac function. How- bility that alternative protocols using dose-intensified ever, as described above, hematologic responses appear to chemotherapy with growth factor support alone without be dose-dependent. Future studies may explore the use of stem cell rescue, or using other therapeutic modalities, for other chemotherapy agents in combination with melphalan patients ineligible for HDM/SCT, will deserve evaluation to improve complete hematologic remission rates. in randomized studies.

Future trials Acknowledgements In the past, AL amyloidosis was a uniformly progressive and fatal disease, with long-term survival being a rare out- We gratefully acknowledge the numerous current and former col- come with oral melphalan and prednisone treatment. Devel- leagues in the Stem Cell Transplant Program, Amyloid Research opment of peripheral blood stem cell transplantation with and Treatment Program, Clinical Trials Office, and Clinical Lab- growth factor support has allowed for more aggressive oratories at Boston Medical Center who have assisted with the treatment of these patients and, as reviewed above, multidisciplinary evaluation and treatment of patients with AL HDM/SCT can result in durable complete remissions and amyloidosis. This work was supported in part by grants from the major improvements in organ function. Efforts in the future Food and Drug Administration FD-R-001346 and from the Gerry Foundation. Dr Seldin is a scholar of the Leukemia and Lym- should focus on improving supportive care to limit treat- phoma Society of America. ment-related morbidity and mortality, and on developing strategies to improve the hematologic CR rate. To this end, we are currently exploring tandem HDM/SCT in AL amy- References loidosis. A role for non-myeloablative allogeneic transplan- tation may also be defined in the future. 1 Falk RH, Comenzo RL, Skinner M. The systemic amylo- In spite of promising results, high-dose chemotherapy idoses. New Engl J Med 1997; 337: 898–909. and autologous stem cell transplant for AL amyloidosis is 2 Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical still a new therapy and should be carried out in the context and laboratory features in 474 cases. Semin Hematol 1995; of clinical trials. A crucial question is whether phase III 32:45–59. randomized trials of high-dose melphalan and stem cell 3 Kyle RA, Gertz MA, Greipp PR et al. Long-term survival (10

Bone Marrow Transplantation Stem cell transplantation in AL amyloidosis V Sanchorawala et al 642 years or more) in 30 patients with primary amyloidosis. Blood intensive intravenous melphalan and autologous blood stem 1999; 93: 1062–1066. cell transplant on AL amyloidosis-associated renal disease. 4 Skinner M, Anderson J, Simms R et al. Treatment of 100 Ann Intern Med 2001; 134: 746–753. patients with primary amyloidosis: a randomized trial of mel- 12 Choufani E, Sanchorawala V, Skinner M et al. Acquired factor phalan, prednisone and colchicine versus colchicine only. Am Xdeficiency in patients with AL amyloidosis: incidence, JMed1996; 100: 290–298. bleeding manifestations, and response to high dose therapy. 5 Kyle RA, Gertz MA, Greipp PR et al. A trial of three regi- Blood 2001; 96: 1885–1887. mens for primary amyloidosis: colchicine alone, melphalan 13 Gertz MA, Lacy MQ, Gastineau DA et al. Blood stem cell and prednisone, and melphalan, prednisone and colchicine. transplantation as therapy for primary systemic amyloidosis New Engl J Med 1997; 336: 1202–1207. (AL). Bone Marrow Transplant 2000; 26: 963–969. 6 Gertz MA, Lacy MQ, Lust JA et al. Prospective randomized 14 Gertz MA, Lacy MQ, Dispenzieri A. Myeloablative chemo- trial of melphalan and prednisone versus vincristine, carmus- therapy with stem cell rescue for the treatment of primary sys- tine, melphalan, cyclophosphamide, and prednisone in the temic amyloidosis: a status report. Bone Marrow Transplant treatment of primary systemic amyloidosis. J Clin Oncol 2000; 25: 465–470. 1999; 17: 262–267. 15 Moreau P, Leblond V, Bourquelot P et al. Prognostic factors 7 Attal M, Harousseau JL, Stoppa AM et al. A prospective ran- for survival and response after high-dose therapy and autolog- domized trial of autologous bone marrow transplantation and ous stem cell transplantation in systemic AL amyloidosis: a chemotherapy in multiple myeloma. New Engl J Med 1996; report on 21 patients. Br J Haematol 1998; 101: 766–769. 335:91–95. 16 Gillmore JD, Apperley JF, Craddock C et al. High-dose mel- 8 Comenzo RL, Vosburgh E, Simms RW et al. Dose-intensive phalan and stem cell rescue for AL amyloidosis. VIII Inter- melphalan with blood stem cell support for the treatment of national Symposium on Amyloidosis. Mayo Clinic: Rochester, AL amyloidosis: one-year follow-up in five patients. Blood MN. August 7–11, 1998, p 102. 1996; 88: 2801–2806. 17 Saba N, Tsang R, Sutton DM et al. High treatment-related 9 Comenzo RL, Vosburgh E, Falk RH et al. Dose-intensive mel- mortality in cardaic amyloid patients supports the use of less phalan with blood stem cell support for the treatment of AL intensive, non-cardiotoxic PBSC collection and induction regi- (amyloid light-chain) amyloidosis: survival and responses in mens. Blood 1998; 10 (Suppl. 1): 660a. 25 patients. Blood 1998; 91: 3662–3670. 18 Dispenzieri A, Lacy MQ, Kyle RA et al. AL amyloidosis is 10 Sanchorawala V, Wright DG, Dember LM et al. Five years a favorable independent prognostic factor for survival of 234 experience with high dose intravenous melphalan and autolog- patients with primary systemic amyloidosis (AL) functionally ous peripheral blood stem cell transplantation for the treatment eligible for peripheral blood stem cell transplantation. Proc of patients with AL amyloidosis. Blood 1999; 94: 396a. ASCO 1999; 18: 20a. 11 Dember LM, Sanchorawala V, Seldin DC et al. Effect of dose-

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