Trends in day 100 and 2-year survival after auto-sct for AL amyloidosis: outcomes before and after 2006

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1 (2011) 46, & 2011 Macmillan Publishers Limited All rights reserved /11 ORIGINAL ARTICLE Trends in day 100 and 2-year survival after auto-sct for AL amyloidosis: outcomes before and after 2006 MA Gertz 1, MQ Lacy 1, A Dispenzieri 1, SK Kumar 1, FK Buadi 1, D Dingli 1, N Leung 2, WJ Hogan 1 and SR Hayman 1 1 Division of Hematology, Mayo Clinic, Rochester, MN, USA and 2 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA The role of auto-sct in the management of Ig light-chain (AL) amyloidosis remains undefined. In this study, we report 422 patients who received auto-sct for AL amyloidosis to compare outcomes of patients treated before January 2006 with those treated from January 2006 to 1 December Day 100 all-cause mortality decreased over this time period from 12 to 7% (P ¼ 0.09). Survival at 2 years increased from 78 to 82%. The major determinants of early mortality (before day 100) were the presence of cardiac involvement by amyloid with increased levels of cardiac biomarkers, lower serum albumin, higher serum creatinine and a higher number of organs involved. On multivariate survival analysis, higher levels of serum troponin T and N-terminal pro-brain natriuretic peptide were the only predictors of early mortality after auto-sct. Improved supportive care and refined patient selection have improved the safety margin of patients undergoing auto-sct; short-term mortality showed a more than 40% decrease after (2011) 46, ; doi: /bmt ; published online 11 October 2010 Keywords: amyloidosis; cardiac failure; chemotherapy; auto-sct; survival Introduction The role of auto-sct in the management of Ig light-chain (AL) amyloidosis remains undefined. 1,2 In the only prospective randomized study that compared auto-sct with traditional-dose chemotherapy consisting of melphalan and dexamethasone, median survival in the melphalan plus dexamethasone arm was significantly longer (56.9 vs 22.2 months; P ¼ 0.04). 3 In that study, all-cause mortality at day 100 for patients undergoing auto-sct was 30%, with most patients dying of complications related to cardiac amyloid involvement. In a review of outcomes from multiple centers, the median survival of patients with amyloidosis selected for SCT exceeded 80 months. 4,5 Reviews from Mayo Clinic, 6 Boston Medical Center 5 and Memorial Sloan-Kettering Cancer Center (New York, NY, USA) 7 showed median survivals of 86 months, 55 months and not reached, respectively, which suggests major differences in patient selection criteria for transplant. If auto-sct is to provide any value to patients with AL amyloidosis, the high treatment-related mortality that has been reported, which is far higher than that in patients with multiple myeloma, must be decreased. 8,9 Several factors distinguish auto-sct in patients with amyloidosis from that in patients with a hematological malignancy. 10 Patients with a hematological malignancy frequently have significant tumor burdens in the BM, but tend to have well-preserved organ function. In patients with amyloidosis, the converse is true. The BM shows almost no disease, with an average tumor burden of 5% in plasma cells, 11,12 whereas organ dysfunction is frequently severe. As a consequence, patient selection and the center s experience in the application of myeloablative therapy become paramount in preventing unacceptable levels of treatment-related mortality. 13,14 The prognostic value of cardiac biomarkers, 15 serum creatinine 16 and serum albumin, 17 as well as echocardiographic assessment of interventricular septal thickness, 18 in patients undergoing auto-sct was beginning to be better understood in the early 2000s. This understanding helped our auto-sct group to refine patient selection criteria to better determine those patients in whom the procedure may not be safe. Although this understanding increased gradually over time, by early 2006, our group had developed a consensus of selection criteria for auto-sct. In this study, we aimed to analyze our institution s entire population of patients with AL amyloidosis who underwent auto-sct to determine any changes that have occurred in outcomes from the inception of the program through 2005, compared with outcomes over the past 4 years. Correspondence: Dr MA Gertz, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. gertz.morie@mayo.edu Received 12 May 2010; revised 30 July 2010; accepted 11 August 2010; published online 11 October 2010 Patients and methods This study was approved by the Mayo Clinic Institutional Review Board. We retrospectively searched our patient

2 database for the records of all patients with AL amyloidosis, who underwent auto-sct from March 1996 to 1 December 2009 at Mayo Clinic in Rochester, Minnesota, MN, USA. Criteria for auto-sct eligibility were as follows: physiological age 70 years or younger (or robust elderly ); performance score of 2 or less; troponin T value less than 0.06 ng/ml (introduced in June 2006); creatinine clearance 30 ml/min (unless on chronic dialysis); New York Heart Association class I or II (unless on chronic dialysis); and not more than two organs that are significantly involved. We analyzed two groups of patients by the date of auto-sct. The first cohort ranges from the date of the first auto-sct on 8 March 1996 to 30 December 2005 ( Pre-2006 auto-sct group); the second cohort consists of patients who underwent auto-sct from 6 January 2006 to 1 December 2009 ( Post-2006 auto-sct group). No patients were excluded from this analysis. Melphalan conditioning chemotherapy (p200 mg/m 2 ) was administered on days 2 and 1, with half the dose given on each day. Decisions regarding dosage reduction were based on age, creatinine level and ejection fraction. 10 Before 2007, the conditioning dose was decreased for patients with creatinine levels of 2.0 mg per 100 ml or higher; this threshold creatinine level has since been decreased to 1.7 mg per 100 ml. Apheresis in the patient population was with growth factor only without chemotherapy priming. Initially, we administer a single dose of 10 mcg/kg of G-CSF per day for 4 days. On day 4, if the CD34 þ cell count is 10/mL or greater, apheresis commences. If day 1 yield is less than CD34 þ cells/kg, plerixafor is added. If the yield after day 1 is less than CD34 þ cells/kg, plerixafor is added further. If CD34 þ cell count is o10/ml on day 4, we add plerixafor 240 mcg/kg (160 mcg/kg if creatinine clearance is o50 ml/ min), and cells are collected on day 5 if CD34 þ cell count is 10/mL or greater. The minimum acceptable number of CD34 þ cells for safe transplantation is CD34 þ cells/kg. Apheresis was performed by processing L of blood in 4-h sessions. The lowest number of stem cells infused was CD34 þ cells/kg. Most patients were treated and received conditioning chemotherapy and stem-cell infusions as outpatients. Standard post-auto-sct supportive care, which included prophylactic fluoroquinolone antibiotics, fluconazole and acyclovir, was used for all patients. Patients were admitted to the hospital only if they had intractable mucositis, dehydration or decrease in performance status. The primary end point of the study was survival at day 100. All deaths were considered through day 100 without regard to cause, and death related to therapy was not distinguished from death due to progressive amyloidosis. No patients were lost to follow-up, and all patients were considered evaluable for survival. All patients gave written consent for research use of their data. Statistical analysis Survival was analyzed and compared between groups with the Kaplan Meier method. Differences between groups were analyzed with Kruskal Wallis rank-sum testing for continuous variables and the Fisher exact test for discrete variables. Variables that were significant on univariate analysis at Po0.2 were then entered into a proportional hazards model, with the least significant variables entered first. Statistical analysis was performed using JMP 8.0 software (SAS Institute Inc, Cary, NC, USA). All probabilities reported are two-tailed. Po0.05 was considered significant. Results In this study, 422 consecutive patients with AL amyloidosis received auto-sct during the study period. All patients had biopsy-proven amyloidosis. In most patients, the diagnosis could be established by Congo red staining of a s.c. fat aspirate or BM biopsy specimen. Visceral amyloid biopsies showed positive results in the sural nerve (n ¼ 5), kidney (n ¼ 232), myocardium (n ¼ 53) and liver (n ¼ 20). However, the classification of organ involvement was based exclusively on clinical criteria, as defined by consensus and modified by the addition of cardiac biomarkers. 19 The dose of conditioning chemotherapy administered was 200 mg/m 2 melphalan in 278 patients (66%) and less than 200 mg/m 2 in 144 (34%). The median number of CD34 þ cells collected was cells/kg (interquartile range, cells/kg). Of the 422 patients, 265 received auto-sct before 1 January 2006 (Pre-2006 auto-sct) and 157 received auto- SCT after 1 January 2006 (Post-2006 auto-sct) (Table 1). The only patient characteristics that were significantly different between the two groups were a lower serum alkaline phosphatase level and a higher serum b 2 -microglobulin level in the Post-2006 auto-sct group. The number of organs involved, echocardiographic evidence of amyloid involvement and values of cardiac biomarkers were not different between the groups. Day 100 all-cause mortality in the Pre- and Post-2006 auto-sct groups is shown in Figure 1. In the Pre-2006 auto-sct group, 32 patients (12.1%) died before day 100, whereas in the Post auto-sct group, 11 patients (7.0%) died before day 100. This represents a mortality reduction of 42%, but the comparison between the groups did not achieve statistical significance (P ¼ 0.09). When extending the analysis to 2 years after auto-sct, the percentages of patients surviving were 82% for the Post-2006 auto-sct group and 78% for the Pre-2006 auto-sct group (Figure 2). Univariate analysis of patients who did (n ¼ 379) and did not survive (n ¼ 43) through day 100 showed factors that predicted survival (Table 2). Predictors of early death included the presence of cardiac amyloid involvement by criteria established by consensus; 19 lower values of serum albumin; higher values of serum creatinine, serum N-terminal pro-brain natriuretic peptide, serum troponin T and serum b 2 -microglobulin; increased interventricular septal thickness defined by echocardiography; higher number of organs involved; and conditioning with less than 200 mg/m 2 of melphalan. The analysis was repeated separately for the Post-2006 auto-sct group and the Pre auto-sct group. In the Post-2006 auto-sct group, factors that were significantly different between those who survived through day 100 (n ¼ 146) and those who did not 971

3 972 Table 1 Patient characteristics Characteristics Patient group a P-value Pre-2006 SCT (n ¼ 265) Post-2006 SCT (n ¼ 157) Age, years 56.8 ( ) 58.2 ( ) 0.08 Men 157 (59.2) 94 (59.8) 0.92 Amyloid involvement Renal 179 (67.5) 114 (72.6) 0.33 Cardiac 132 (49.8) 79 (50.3) 0.54 Liver 43 (16.2) 15 (9.6) 0.06 IVS thickness, mm 12 (10 14) 12 (10 15) EF, % 65 (60 70) 64 (60 68) 0.16 No. of organs involved (48) 69 (44) 2 99 (37) 66 (42) (14) 22 (14) Conditioning dose o200 mg/m 2 melphalan 84 (31.7) 60 (38.2) 0.20 Albumin, g per 100 ml 2.8 ( ) 2.6 ( ) 0.15 Creatinine, mg per 100 ml 1.1 ( ) 1.0 ( ) 0.12 NT-proBNP, pg/ml 671 (181 3,425) 717 (165 1,976) 0.47 Troponin T, ng/ml 0.01 ( ) 0.01 ( ) 0.42 Alkaline phosphatase, U/L 93 (72 145) 84 (67 107) b 2 M, mg/l 2.51 ( ) 2.75 ( ) o0.001 Urine total protein, g per day 3.38 ( ) 3.81 ( ) 0.22 Abbreviations: b 2 M ¼ b 2 -microglobulin; EF ¼ ejection fraction; IVS ¼ interventricular septum; NT-proBNP ¼ N-terminal pro-brain natriuretic peptide. a Values are number of patients (%) or median (interquartile range) Patients surviving, % 90 Post-2006 SCT Pre-2006 SCT Patients surviving, % Post-2006 SCT Pre-2006 SCT Time, mo Figure 1 Kaplan Meier curves showing all-cause mortality through day 100 in patients with AL amyloidosis who underwent auto-sct before and after 2006 (P ¼ 0.09). Note that the survival scale ranges from 80 to 100% Time, mo Figure 2 Kaplan Meier curves showing survival through 24 months in patients with AL amyloidosis who underwent auto-sct before and after 2006 (P ¼ 0.09). Note that the survival scale ranges from 70 to 100%. (n ¼ 11) were interventricular septal thickness (12 vs 14 mm, P ¼ 0.009) and serum values of creatinine (1.0 vs 1.25 mg per 100 ml, P ¼ 0.03), N-terminal pro-brain natriuretic peptide (588 vs 3633 pg/ml, P ¼ 0.01) and troponin T (0.01 vs ng/ml, P ¼ 0.006). In the Pre-2006 auto-sct group, factors that were significantly different between those who survived through day 100 (n ¼ 233) and those who did not (n ¼ 32) were interventricular septal thickness (12 vs 14 mm, P ¼ 0.003), frequency of cardiac involvement by consensus criteria (47 vs 75%, P ¼ 0.004), one-organ involvement (52 vs 22%, P ¼ 0.001) and serum values of albumin (2.86 vs 2.22 g per 100 ml, P ¼ 0.007), troponin T (0.01 vs ng/ml, Po0.001), b 2 -microglobulin (2.44 vs 3.11 mg/l, P ¼ 0.001) and 24-h urine total protein (3.31 vs 6.24 g/d, P ¼ 0.04). On multivariate analysis of the entire cohort, only two features predicted decreased survival: the presence of cardiac amyloid involvement by consensus criteria (P ¼ 0.004) and higher serum troponin T level (P ¼ 0.04). If the parameter of cardiac amyloid involvement was removed from the statistical model, the only feature that predicted early death was higher serum troponin T value (P ¼ 0.008). Discussion Mortality rates associated with auto-sct in AL amyloidosis range from 5% to nearly 40% Efforts to improve survival in patients with amyloidosis have been facilitated

4 Table 2 Group differences by survival duration 973 Characteristics Survival group a P-value Early death (n ¼ 43) Survived 100 d (n ¼ 379) Age, years 56.2 ( ) 57.5 ( ) 0.78 Men 27 (63) 224 (59) 0.74 Amyloid involvement Renal 33 (77) 260 (69) 0.30 Cardiac 32 (74) 179 (47) Liver 10 (23) 48 (13) 0.06 IVS thickness, mm 14 (12 16) 12 (10 14) EF, % 66 (56 70) 65 (60 69) 0.94 No. of organs involved (23) 187 (49) 2 21 (49) 144 (38) (28) 48 (13) Conditioning dose o200 mg/m 2 melphalan 22 (51.1) 122 (32) 0.02 Albumin, g per 100 ml 2.3 ( ) 2.7 ( ) 0.01 Creatinine, mg per 100 ml 1.2 ( ) 1.1 ( ) NT-proBNP, pg/ml 3,061 ( ) 579 ( ) Troponin T, ng/ml 0.03 ( ) 0.01 ( ) Alkaline phosphatase, U/L 88 (74 182) 88 (69 127) 0.21 b 2 M, mg/l 3.05 ( ) 2.51 ( ) Urine total protein, g per day 6.1 ( ) 3.5 ( ) 0.08 Abbreviations: b 2 M ¼ b 2 -microglobulin; EF ¼ ejection fraction; IVS ¼ interventricular septum; NT-proBNP ¼ N-terminal pro-brain natriuretic peptide. a Values are number of patients (%) or median (interquartile range). by the introduction of novel agents for the treatment of amyloidosis, including thalidomide, 23 lenalidomide 24 and bortezomib. 25 Melphalan dexamethasone has been established as a highly effective regimen in patients who are not considered candidates for auto-sct. 26 The median reported survival of 5.1 years using oral chemotherapy in that study makes it difficult to determine the exact role of auto- SCT, if any, in managing AL amyloidosis. In the early days of SCT, before long-term follow-up was available, impressively high hematological and organ response rates were demonstrated that were, to that point, not seen with melphalan prednisone therapy. 27 However, when compared with the melphalan prednisone era, several differences have been introduced in the ways in which treatment efficacy is assessed. The most important change was the development of the Ig free light-chain assay, which allowed a more accurate determination of hematological response Reports on the efficacy of melphalan and prednisone may underestimate the true response rates because none of the studies included light-chain measurements. 31,32 Response rates with novel agent-based therapy are extremely high and rival those seen with auto-sct. 33 It is, therefore, fair to ask whether auto-sct, given its higher risk, should remain a standard of care for amyloidosis. At Mayo Clinic, not more than 20 25% of patients seen in consultation are eligible for consideration of auto-sct. The exclusions most typically are related to age, New York Heart Association class III or IV cardiac failure, chronic kidney disease stage IV, significant three-organ involvement and previous cumulative melphalan exposure, making successful stem-cell procurement highly unlikely. To effectively assess the role of auto-sct, all efforts must be taken to properly select patients to minimize treatmentrelated mortality. If treatment-related mortality remains around 15%, it will be extremely difficult to power a study to detect an advantage over standard chemotherapy, which has treatment-related mortalities less than 5%. 34 Experience of the treatment center has been shown to be an important predictor of outcome after auto-sct in amyloidosis. The Center for International Blood and Marrow Transplant Research reported that outcomes after SCT were directly related to the years of experience a center had in performing transplants. 35 Day-30 treatment-related mortality after high-dose chemotherapy and SCT was 18%. 35 Day-100 mortality was not reported in that study, but in our study, day-30 all-cause mortality was 5.5% (23/ 422): 6.4% (17/265) before 2006 and 3.8% (6 of 157) after 2006, which also represents a 40% decrease in all-cause mortality. Moreover, the introduction of cardiac biomarkers has allowed refinement in patient selection and serves as an increasingly sensitive method for predicting cardiac risk Our experience over 14 years showed a decrease in day 100 all-cause mortality by nearly 40%. However, this did not achieve statistical significance, most likely because the study was underpowered, with only 11 deaths occurring over a 4-year period. Our findings on univariate analysis of parameters that predict survival are not new. 39 In previous reports, decreased dose of melphalan, 10,40 number of organs involved, 41 levels of cardiac biomarkers, 42 serum b 2 - microglobulin, 43 albumin 44 and creatinine 45 have all been reported to affect overall survival. Our results of multivariate analysis demonstrating that only cardiac biomarkers are significant in predicting outcome have also been previously reported. 46 However, long-term data that show decreased mortality because of knowledge of predictors of poor outcome have helped in refining patient selection. The risk of death after auto-sct can now be identified on

5 974 the basis of certain risk factors, and patients with these risk factors can be excluded from participation in auto- SCT trials. We found no differences in clinical characteristics between the earlier and later treatment groups to validate our claim that patient selection has changed and thus has decreased early mortality. In effect, we are comparing a group with 11 deaths with a group with 32 deaths numbers we believe are too small to detect a statistically significant difference. Although the only official change in our selection criteria was the addition of a cutoff for troponin T values, our tolerance for a physiological age of 70 years has become stricter and our willingness to classify an organ as significantly involved has increased. As a consequence, the fraction of patients receiving auto-sct at Mayo Clinic has decreased by about 5%. Refinement in supportive care also may have an important role in survival because improved supportive measures contribute to the decreased early mortality. The current threshold for troponin T values above which we do not consider SCT to be safe is 0.06 ng/ml. 37 Because AL amyloidosis has a very poor prognosis, what constitutes acceptable treatment-related mortality is a question of philosophy and not science. Treatment-related mortality for auto-sct in patients with multiple myeloma is less than 2%. 47 The sixfold increased mortality in patients with amyloidosis represents a substantial difference. Others have reported high treatment-related mortality for patients with AL amyloidosis treated with novel agents. In a trial of lenalidomide and dexamethasone, 17% died before the completion of three cycles, 48 and pretreatment cardiac biomarker levels were an important predictor of ability to tolerate any form of therapy. The decrease in treatment-related mortality and the improved 2-year survival we report herein are encouraging and represent a justification for the continued exploration of the role of auto-sct in AL amyloidosis. This study does not demonstrate that auto-sct is a superior technique to novel agent-based therapy. This question can only be answered by ongoing prospective randomized trials. It is also difficult to distinguish how much of the decreased mortality is related to improvements in supportive care that occur because of gains in experience in the management of these complex patients or whether improved patient selection, such as excluding patients with advanced cardiac disease based on cardiac biomarkers, is responsible for the improved outcomes. 37 In conclusion, survival at day 100 and at 24 months in patients with AL amyloidosis receiving auto-sct has improved since the beginning of 2006 when compared with the earlier time period. 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