Nephrol Dial Transplant (2016) 31: 1284 1289 doi: 10.1093/ndt/gfv328 Advance Access publication 30 November 2015 Original Article The impact of dialysis on the survival of patients with immunoglobulin light chain (AL) amyloidosis undergoing autologous stem cell transplantation Nelson Leung 1,2, Shaji K. Kumar 1, Siobhan V. Glavey 3, Angela Dispenzieri 1, Martha Q. Lacy 1, Francis K. Buadi 1, Suzanne R. Hayman 1, David Dingli 1, Prashant Kapoor 1, Steven R. Zeldenrust 1, Stephen J. Russell 1, John A. Lust 1, William J. Hogan 1, S. Vincent Rajkumar 1, Dennis A. Gastineau 1, Taxiarchis V. Kourelis 1, Yi Lin 1, Wilson I. Gonsalves 1, Ronald S. Go 1 and Morie A. Gertz 1 1 Division of Hematology, Mayo Clinic, Rochester, MN, USA, 2 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA and 3 Department of Haematology, National University of Ireland, Galway Correspondence and offprint requests to: Nelson Leung; E-mail: leung.nelson@mayo.edu ABSTRACT Background. Acute renal failure requiring dialysis is associated with high mortality during autologous stem cell transplantation (ASCT). This study examined the association between acute renal failure and mortality in immunoglobulin light chain (AL) amyloidosis during ASCT. Methods. Between 1996 and 2010, 408 ASCT patients were evaluated. Data were collected from electronic medical records. Results. Dialysis was performed on 72 (17.6%) patients. Eight patients started dialysis >30 days prior to ASCT (Group II), 36 started ±30 days after ASCT (Group III) and 28 initiated dialysis >1 month after ASCT (Group IV). Patients who never dialyzed were assigned to Group I. There were no significant age or sex differences. Median overall survival (OS) had not been reached in Groups I and II but was 7.0 months in Group III and 48.5 months in Group IV (P < 0.001). Treatment-related mortality (TRM) was observed in 44.4% of the patients in Group III, 6- fold higher than the next highest group (P < 0.001). The most common causes of TRM were cardiac and sepsis. In the multivariate analysis, only hypoalbuminemia (<2.5 g/dl, P < 0.001) and estimated glomerular filtration rate (egfr) <40 ml/min/ 1.73 m 2 (P < 0.001) were independently associated with starting dialysis within 30 days of ASCT. Conclusions. The study found significant differences in the OS depending on when the acute renal failure occurred. Patients who required dialysis within 30 days of ASCT had the highest rate of TRM. Screening with serum albumin and egfr may reduce the risk. Keywords: amyloidosis, creatinine, hypoalbuminemia, stem cell transplant BACKGROUND Systemic immunoglobulin light chain amyloidosis (AL) is a fatal form of plasma cell dyscrasia [1]. The misfolding and deposition of monoclonal immunoglobulin light chains in the extracellular space cause progressive organ failure, leading to death of the patient. Without effective treatment, median survival was as short as 13 months from diagnosis [2]. Treatment with melphalan and prednisone or high-dose dexamethasone produced only limited hematologic response, which translated to limited benefit in overall survival (OS, 18 months) [2 4]. On the other hand, high-dose melphalan followed by autologous stem cell transplantation (ASCT) achieved a complete hematologic response (CR) in 40% of the patients, which improved the OS to 4.6 years [5]. A recent update of the study showed that the OS had increased further to 6.3 years [6, 7]. In a separate study, OS was not reached in patients with CR, was 107 months with partial response and was 32 months with no response (P < 0.001) [8]. The Author 2015. Published by Oxford University Press Downloaded from onhttps://academic.oup.com/ndt/article-abstract/31/8/1284/2237982 behalf of ERA-EDTA. All rights reserved. 1284
Despite the benefits, ASCT also has its drawbacks. The most concerning is the high treatment-related mortality (TRM). Early on, this had been reported as high as 40% in some centers [9]. In a randomized trial comparing ASCT to melphalan dexamethasone, poorer short-term outcomes in patients randomized to ASCT were attributed to the high TRM observed [10]. Patients considered high risk by the Mayo Clinic criteria were most at risk. It was clear from the randomized study that ASCT should not be performed in high-risk patients. Screening with cardiac biomarkers cardiac troponin T (ctnt) and N-terminal pro-brain natriuretic peptide (NTproBNP) had greatly reduced TRM for AL amyloidosis patients [11 13]. However, not all of the risk has been eliminated [14]. Since cardiac biomarker screening excludes patients with significant cardiac involvement from ASCT, most of the patients now undergoing ASCT have predominately renal involvement [14]. Acute kidney injury (AKI) has been shown to be associated with high rates of mortality in patients undergoing hematopoietic stem cell transplantation, particularly if dialysis is required [15, 16]. Renal involvement is one of the strongest risk factors for dialysis in AL patients [17]. Previous studies have identified several risk factors associated with the development of AKI, but these were not specific for the need of dialysis[18, 19]. This retrospective study was undertaken to investigate the risk factors contributing to the development of acute renal failure and its relationship to survival in AL patients undergoing ASCT. MATERIALS AND METHODS Patients with AL who underwent ASCT between March 1996 and January 2010 were identified from the Stem Cell Transplantation database. Amyloid was diagnosed by demonstration of Congo red birefringence in tissue biopsy. Amyloid typing was performed by immunohistochemistry, demonstrating light chain restriction. Later, typing by liquid chromatography tandem mass spectrometry was performed for the majority of patients [20]. Organ involvement was assessed based on the criteria by the International Society of Amyloidosis [21]. Patient characteristics were obtained from the database and electronic medical records. This study was approved by the Institutional Review Board at the Mayo Foundation in accordance with the Declaration of Helsinki and the Health Insurance Portability and Accountability Act guidelines. Prior to July 2001, stem cells were mobilized with cyclophosphamide (1.5 g/m 2 ) priming followed by either granulocyte or granulocyte macrophage colony stimulating factor (5 g/kg/day) or with growth factor alone. After July 2001, cyclophosphamide was eliminated from the protocol. Conditioning with melphalan (140 mg/m 2 ) with total body irradiation (TBI) (12 Gy) or melphalan of 200 mg/m 2 was used until January 1999. After January 1999, only melphalan (100 200 mg/m 2 ) was used for conditioning. The melphalan dose was routinely reduced to 140 mg/m 2 for patients with renal impairment and other serious comorbidities. All patients underwent conditioning for 2dayspriortoASCT.SinceTBIisnolongerused,patients who underwent TBI for conditioning were excluded from the study. TRM was defined as death of any cause prior to Day 100 of ASCT. Serum albumin was measured by serum protein electrophoresis. Patient characteristics and laboratory data were collected from the electronic medical record. Laboratory data were obtained at the time of diagnosis. Patients were separated into groups based on the timing of their dialysis. Patients who never received dialysis were placed into Group I, those who received dialysis prior to Day 30 were in Group II, patients who started dialysis ±30 days of ASCT were in Group III and Group IV patients required dialysis after Day 30 of ASCT. The timing of dialysis was analyzed to determine its association with OS and TRM. The estimated glomerular filtration rate (egfr) was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula [22]. Parameters with significant associations were then investigated in a multivariate analysis. Similar analysis was also performed to detect associations with the need for dialysis. Statistical calculations were performed using the JMP software package version 8.0 (SAS Institute, Cary, NC). Pearson s chi-square tests were performed on categorical data. Two-sample t-tests and Wilcoxon ranksum tests were used to compare continuous variables. Variables with a P-value <0.05 were considered significant. Multivariate analysis was performed with a Cox proportional hazards model. Survivals were analyzed using the Kaplan Meier methods from the time of ASCT and compared using the log-rank test. RESULTS Between March 1996 and January 2010, 428 patients underwent ASCT for AL amyloidosis at our institution. No one was lost to follow-up. Seventeen patients were excluded for having TBI as part of their conditioning, two for having heart transplant prior to ASCT and one patient declined consent for the study. ASCT was frontline treatment for 62.7% of the patients in this study. High-dose steroids and alkylator-based therapies were started in 21.6% and 7.7% of patients, respectively, prior to ASCT. Most of these patients received only one cycle of chemotherapy while waiting for ASCT. Others received immunomodulatory drugs (thalidomide and lenalidomide, 4.7%), bortezomib (0.7%) and other therapies (2.6%) prior to ASCT. Neither receiving prior therapy nor the type of therapy had any impact on the OS (P = 0.53). Dialysis was performed on 72 (17.6%) patients. Eight patients who started dialysis >30 days prior to ASCT were assigned to Group II. Thirty-six patients who started within 30 days of ASCT were in Group III and 28 who initiated dialysis >1 month after ASCT were assigned to Group IV. None of the 336 patients in Group I ever received dialysis. No significant differences were noted in the age and sex of the three groups that needed dialysis versus the patients in Group I (Table 1). The median follow-up for survival patients was 52 months. The median survival from ASCT for the entire cohort was 97.9 months. The shortest OS was that of Group III. The median OS from ASCT had not been reached in Groups I and II and was only 7.0 months in Group III and 48.5 months in Group IV (Figure 1A). The OS of Group III [P 0.001, relative risk (RR), 2.57, 95% confidence interval (CI), 1.58 4.01] and Dialysis and treatment-related mortality in AL amyloidosis 1285
Table 1. Baseline patient characteristics I II III IV P-value N 336 8 38 28 Age (years) 57 (25 75) 59 (53 70) 58 (31 73) 59 (42 67) 0.62 Sex (male, %) 58.3 87.5 61.1 57.1 0.41 albumin (g/dl) 2.8 (0.8 4.4) 2.9 (1.5 3.8) 2.1 (1.0 3.7) 1.9 (0.9 3.7) <0.001 Alk phos (U/L) 88 (36 1014) 84 (61 320) 98 (28 1395) 94 (49 646) 0.40 B2m (μ/ml) 2.5 (1.0 10.1) 24.7 (9.8 35.1) 3.2 (1.0 15.2) 2.8 (1.0 5.7) <0.001 Scr (mg/dl) 1.0 (0.4 2.6) 7.9 (3.7 12) 1.4 (0.8 5.6) 1.2 (0.7 2.1) <0.001 egfr (ml/min/1.73 m 2 ) 66 (20 178) 7 (4 17) 51 (8 88) 59 (30 90) <0.001 Proteinuria (g/day) 2.9 (0.0 21.4) 10.66 (0.6 35.4) 6.6 (0.1 26.2) 7.0 (0.0 21.5) <0.001 ctnt (ng/ml) 0.01 (0.0 1.0) 0.06 (0.01 0.15) 0.01 (0.01 0.35) 0.01 (0.01 0.24) <0.001 NTproBNP (pg/ml) 520 (17.5 17 330) 8467 (1089 35 000) 1065 (50.3 6849) 1537 (40.6 8008) 0.002 CRP (mg/l) 0.4 (0.01 40.4) 1.4 (0.2 9.5) 0.4 (0.03 13.1) 0.4 (0.05 5.9) 0.31 Time to dialysis (days) 171 ( 700 69) 14 ( 16 30) 876 (70 3106) Alk phos, alkaline phosphatase; B2m, beta-2-microglobulin; Scr, serum creatinine; egfr, estimated glomerular filtration rate; ctnt, cardiac troponin T; N-TproBNP, N terminal pro-brain natriuretic peptide; CRP, C-reactive protein. Values are given as median (95% CI). FIGURE 1: (A) Overall survival from ASCT based on dialysis initiation. Patients in Group I never required dialysis. Dialysis was initiated >30 days prior to ASCT in Group II. Group III patients initiated dialysis ±30 days of ASCT and Group IV patients had dialysis started >30 days after ASCT. The median OS was not reached in Groups I and II and was 7.5 months in Group III and 48.5 months in Group IV. The median OS was significantly shorter for Group III (P < 0.001) and Group IV (P = 0.004) when compared with Group I but not Group II (P = 0.5). (B) Analysis was repeated with patients with cardiac involvement excluded. The median OS was not reached by Groups I and II and was 22.6 months in Group III and 80.3 months in Group IV (P < 0.001). Group IV (P = 0.008, RR 2.02, 95% CI 1.21 3.19) was significantly shorter than that of Group I. Similar results were noted when patients with cardiac involvement (echocardiographic evidence was used prior to the availability of the cardiac biomarkers) were excluded from analysis (Figure 1B). The OS was not different between Groups I and II (P = 0.5). The OS after the start of dialysis was also significantly different among the three groups of dialysis patients. It had not been reached by patients in Group II and it was 6.5 months in Group III and 14.9 months in Group IV (P = 0.046). Cause of death for patients in Groups II, III and IV was extracted from the medical records and correspondence. The TRM for the entire cohort was 9.8%. All patients from Group II died of consequences of progressive AL, and no patient had TRM. In Group III, 71.4% of the deaths were TRM. The cause of death included cardiac (n = 5), sepsis (n = 7), acute liver failure (n = 1), intracranial hemorrhage (n = 1) and hemorrhagic shock from gastrointestinal and vaginal hemorrhage (n =1). The other 28.6% of deaths occurred after Day 100. The cause included pulmonary embolism and sepsis (n = 1), failure to thrive and depression (n = 1), unknown (n = 1) and progression of AL (n = 3). Progression of AL was responsible for 85.7% of deaths in Group IV. The other two patients died of complications from line-related sepsis (4.8%) and of unknown causes. One patient from Group IV suffered TRM as a result of hemorrhagic colitis from AL. Recovery of renal function and dialysis independence occurred in 11 (15.3%) patients. All were from Group III. Seven (9.7%) patients who did not recover renal function received a kidney transplant after ASCT. Two were from Group II, three from Group III and two from Group IV. Dialysis independence either by recovery of renal function or kidney transplantation was significantly associated with better survival. The median survival of all patients who required dialysis was 48.2 months, but the patients who did not achieve dialysis independence had a median survival of just 30.0 months (Figure 2, P < 0.001). On univariate analysis, parameters that were associated with inferior OS were elevated ctnt (P < 0.001), elevated NTproBNP (P = 0.03) and the need for dialysis after Day 30 1286 N. Leung et al.
Table 2. Treatment-related mortality by dialysis group Group I II III IV TRM (%) 6.9 0 44.4 3.6 I versus 0.44 <0.001 0.50 II versus 0.018 0.59 III versus <0.001 First row lists the percentage of TRM by group. Rows 2 4 display the P-values comparing the TRM between groups. FIGURE 2: Overall survival from ASCT based on recovery of renal function. Of the 72 patients who required dialysis, 11 recovered renal function (RR) and 7 received kidney transplantation (KTx). The median OS of patients who did not recover renal function (NR) was 30 months (P = 0.001). of ASCT (P < 0.001). Only requirement of dialysis after Day 30 (Groups III and IV) and NTproBNP remained independent predictors of inferior OS in the multivariate analysis (P < 0.001 for both). The best cut-off of NTproBNP using a receiver operating characteristic (ROC) curve for survival was 1325 pg/ml. The RR was 4.47 (95% CI 2.45 7.84) for starting dialysis after Day 30 of ASCT and 4.31 (95% CI 2.49 7.76) for elevated NTproBNP. Further investigation of the patients who required dialysis after Day 30 found that by log-rank test the patients in Groups III and IV had similar OSs (P = 0.45); however, the median survival when analyzed by Wilcoxon test showed a significant difference (7.0 months versus 48.5 months, P = 0.02, Figure 1A). This proposed that the events were not equally distributed after ASCT between the two groups. Indeed, the TRM was significantly higher in Group III than in Group IV (44.4% versus 3.57%, respectively, P < 0.001, Table 2). In a logistic regression model, the requirement of dialysis within 30 days of ASCT (P = 0.002) and elevated NTproBNP (P < 0.001) were independently associated with TRM. Since dialysis within 30 days of ASCT was associated with the highest risk of early death and TRM, additional analyses were performed to evaluate the risk factors associated with Group III patients. In the univariate analysis, significant differences were noted in Group III patients in terms of their alkaline phosphatase (P = 0.02), serum creatinine (P < 0.001), albumin (P < 0.001), creatinine clearance (P < 0.001), proteinuria (P < 0.001), β2-microglobulin (P < 0.001) and egfr (P < 0.001) when compared with patients in Group I. In a logistic regression model, only egfr (P < 0.001) and albumin (P < 0.001) remained significantly different. Using the ROC, the cut-off, for egfr was <55 ml/min/1.73 m 2 (P < 0.001) and 2.5 g/dl (P < 0.001) for albumin. Unfortunately, 46% of the patients had an egfr below the cut-off, making the cut-off not very useful. The risk of dialysis within 30 days of ASCT was then evaluated over the entire range of egfr. The risk increased significantly when egfr was <40 ml/min/1.73 m 2. In a logistic regression model, the egfr cut-off of <40 ml/min/1.73 m 2 was compared with Table 3. Risk of dialysis and treatment related mortality Risk factors 0 1 2 P-value Dialysis (%) 2.0 10.0 43.8 <0.001 TRM (%) 7.1 9.4 28.1 0.001 The risk of requiring dialysis ±30 days of ASCT or TRM by the number of pretransplant risk factors (serum albumin <2.5 mg/dl and egfr <40 ml/min/1.73 m 2 ). an egfr of <55 ml/min/1.73 m 2 and <40 ml/min/1.73 m 2 was superior [P = 0.001, odds ratio (OR) 4.57, CI 1.80 12.39] versus (P = 0.04, OR 2.95, CI 1.08 8.11). The lower cut-off of <40 ml/min/1.73 m 2 also produced more comparable ORs (OR 8.83, 95% CI 3.97 20.26, P < 0.001; albumin, OR 8.04, 95% CI 3.50 20.70, P < 0.001) when compared with the cut-off of <55 ml/min/1.73 m 2 (OR 6.14, 95% CI 2.79 14.77, P < 0.001; albumin OR 8.42, 95% CI 3.76 20.96, P < 0.001). Using the new cutoff for egfr, a model was constructed with an egfr <40 ml/ min/1.73 m 2 and hypoalbuminemia (<2.5 mg/dl). Patients with zero, one or two risk factors had 2.04, 10.04 and 43.8% risk, respectively, of requiring dialysis within 30 days of ASCT. Using the same model, patients with zero, one or two risk factors had 7.1, 9.4 and 28.1% chance of TRM, respectively (Table 3). DISCUSSION ASCT was the first highly effective therapy for patients with AL [5]. Even with the advent of newer therapies with novel agents, data still support the use of ASCT in selected patients with AL [23]. This is in large part due to recent advances that reduced TRM, making ASCT safer [24]. While tremendous improvement has been made with cardiac biomarkers, AKI remains an issue. Studies have shown that AKI requiring dialysis in patients undergoing hematopoietic stem cell transplantation imposes a mortality rate as high as 80% regardless of the source of the stem cells [16]. In AL, the risk of requiring dialysis at any point after diagnosis is 8-fold higher in those with renal involvement versus those without [17]. Since patients with significant cardiac involvement are no longer selected for ASCT, the patients most often selected for ASCT are the ones with renal involvement. Lower creatinine clearance, higher proteinuria, cardiac involvement, age and urinary sediment have been found to be associated with AKI during ASCT, but the association could not be made with dialysis since the number was too small in these studies [18, 19]. In addition, the mortality was not well defined. Thus this study was undertaken to better evaluate these two issues. This study found that not only did acute renal failure requiring dialysis have a significant impact on the survival of AL Dialysis and treatment-related mortality in AL amyloidosis 1287
patients, but the timeing was also important. Patients who required dialysis within 30 days of ASCT had the worst OS. On the other hand, patients who started dialysis at least 30 days prior to ASCT had similar survival as those who were never dialyzed. This phenomenon had also been reported in patients with multiple myeloma and a small study with AL patients [25 27]. Aside from the need for dialysis after Day 30, the only other independent predictor of OS was NTproBNP. The need for dialysis after Day 30 negated the impact of elevated ctnt in this study. This study also found that the patients who required dialysis within 30 days of ASCT were more likely to suffer TRM. The worst OS was noted in Group III patients. TRM occurred in 44.4% of these patients and was responsible for 71.4% of the deaths. The difference in TRM could not be completely explained by cardiac biomarkers since NTproBNP was not significantly different between the two groups. Moreover, high TRM was noted when the patients with cardiac involvement were excluded in the subgroup analysis. However, in the multivariate model, NTproBNP was an independent predictor of TRM when dialysis was required within 30 days of ASCT. The need for dialysis replaced ctnt. It is interesting to note that Group II patients had the highest ctnt and NTproBNP but the lowest TRM in this study. This brings up the possibility that both biomarkers were affected by renal failure and they no longer had thesameprognosticsignificance once the patient was on dialysis. Patients in Group III had greater than six times the TRM as those in Group IV and Group I. Low egfr and hypoalbuminemia were found to be independently associated with the need fordialysiswithin30daysofasct.thepatientswithboth risk factors had the highest risk of dialysis in this study. Hypoalbuminemia was most likely a reflection of proteinuria since it cancelled out the effects of proteinuria in the multivariate models. For patients exhibiting both of these risk factors, ASCT should be avoided. Once the patient was on stable dialysis, the risk appeared to lessen and ASCT could be reconsidered. Recently, a new staging system has been proposed for renal involvement in AL patients by the Pavia group [28]. In their model, proteinuria >5 g/day and egfr <50 ml/min/1.73 m 2 were independent predictors of poor renal outcome. Despite differences in our endpoints, our findings are actually quite similar. In our study, serum albumin was more predictive of dialysis requirement within 30 days of ASCT, whereas proteinuria in their study was better for predicting dialysis after diagnosis. The methodology may also have contributed to the minor differences. The albumin value in our study was obtained from serum protein electrophoresis, whereas it was not specified in theirs. Our original cut-off for egfr was similar to theirs, but it was reduced to improve clinical correlation and discrimination. Regardless, it is important to recognize that these differences are more statistical than clinical. The take-home message from both studies is that patients with the more nephrotic syndrome and renal impairment have the worse renal outcomes. A limitation of this study is the retrospective methodology. This is especially pertinent when interpreting the benefits of a kidney transplant. Patients who received a kidney transplant were generally required to have a complete hematologic response, to be healthy enough for the surgery and had to have lived long enough to acquire the kidney. The ability to receive a kidney transplant itself represents a major selection bias and it is impossible for a retrospective study to determine its true benefit. In addition, the use of cardiac biomarker for screening became standard in mid-2009 at our institution. This could have altered some of the results since our study cut-off date was January 2010. In conclusion, despite new therapeutic options, ASCT remains a treatment option for certain patients with AL amyloidosis. This is especially true for patients with limited access to novel agents. The current study found that acute renal failure within 30 days of ASCT was highly associated with TRM. An egfr <40 ml/min/1.73 m 2 and serum albumin <2.5 g/dl were found to be highly associated with the need for dialysis during this period. With fewer and fewer severe cardiac AL patients undergoing ASCT, these new risk factors may become increasingly important to screen the severe renal AL patients. Our results support larger studies for confirmation. The goal is to reduce TRM even further during ASCT, making the procedure even safer. ACKNOWLEDGEMENTS We thank the JABBS Foundation, Predolin Foundation and Mr. and Mrs. Ted Kirshenbaum for their generous support. CONFLICT OF INTEREST STATEMENT M.A.G. has honoraria from Celgene, Novartis, Millenium, Med Learining, Onyx, ISIS and Sanofi. 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