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ORIGINAL REPORTS
Hematologic Malignancies
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Outcome in Renal AL Amyloidosis After Chemotherapy
Abstract
Chemotherapy in AL (primary or light chain) amyloidosis is associated with improved survival, but its effect on renal outcome has not been examined systematically. The purpose of this study was to evaluate the effect of chemotherapy on clinical outcome among patients with renal AL amyloidosis.
We evaluated factors influencing survival among 923 patients with renal AL amyloidosis observed during a 21-year period, including 221 patients who became dialysis dependent. Factors associated with renal outcome were analyzed, including serum free light chain (FLC) response to chemotherapy using a simple subtraction formula applicable to all stages of chronic kidney disease. Patient survival and graft survival were analyzed in 21 renal transplantation recipients.
Median survival from diagnosis for the whole cohort was 35.2 months. Magnitude of FLC response with chemotherapy was strongly and independently associated with overall survival (P < .001) and renal outcome. Evaluable patients achieving more than 90% FLC response had a significantly higher rate of renal responses and lower rate of renal progression compared with patients achieving a 50% to 90% response, whose renal outcomes were, in turn, better than patients achieving less than 50% FLC response (P < .001). Median survival from dialysis dependence was 39.0 months, and median survival from renal transplantation was 89.0 months.
Renal outcome and overall outcome in AL amyloidosis are strongly associated with FLC response to chemotherapy and are best among patients achieving more than 90% suppression of the amyloidogenic monoclonal component. Survival on dialysis was substantially superior to that previously reported, and renal transplantation should be considered in selected patients with AL amyloidosis with end-stage renal disease.
The amyloidoses are disorders of protein folding, in which various unrelated proteins misfold and aggregate into fibrils that accumulate in tissues and disrupt organ function.1 Systemic AL (light chain) amyloidosis is caused by deposition of fibrils derived from monoclonal immunoglobulin light chains and is the most common and serious type.2 Organ involvement and clinical presentation of AL amyloidosis are heterogeneous, but renal dysfunction, which frequently progresses to end-stage renal disease (ESRD), is the most common clinical manifestation of the disease, and diagnosis of AL amyloidosis is commonly obtained through renal histology.3
The prognosis of untreated systemic AL amyloidosis is poor, with a survival time of approximately 12 months.4 Over the last 20 years, the use of cytotoxic chemotherapy to suppress production of amyloidogenic monoclonal immunoglobulin has improved outcomes5–9 such that median survival in AL amyloidosis now exceeds 3 years.10,11 However, prognosis is critically dependent on the pattern of amyloidotic organ involvement, with cardiac infiltration conferring a particularly poor prognosis.12,13
Consensus criteria to define organ involvement in AL amyloidosis and organ responses after chemotherapy were first published in 2005.14 Features at presentation that predict renal response15 and progression to dialysis have recently been reported,16 but modifiable factors that may influence renal outcome have been little studied, and findings in the small published series are conflicting.17,18 Furthermore, the few studies of renal replacement therapy in AL amyloidosis have mostly comprised small numbers of patients with dismal survival,18–20 which has led to AL amyloidosis being regarded as an absolute contraindication to renal transplantation in many renal units. Indeed, there is almost no literature to support its use even in carefully selected patients.21
We report here an analysis of clinical outcome among 923 patients with renal AL amyloidosis who were observed at a single national center over a period of 21 years. Factors associated with renal outcome were identified, including response to chemotherapy as assessed rigorously by serial serum free light chain (FLC) assays. We report unprecedented survival among 221 patients who commenced dialysis and compelling evidence supporting renal transplantation in selected patients.
In this study, we included all 923 patients who were diagnosed with renal AL amyloidosis and were assessed for the first time at the United Kingdom National Amyloidosis Centre (NAC) between March 1987 and May 2008. Renal involvement in AL amyloidosis was defined as non–Bence Jones proteinuria of more than 0.5 g/d according to the amyloidosis international consensus criteria.14 The diagnosis of AL amyloidosis was confirmed histologically in 853 patients and through a series of noninvasive investigations in the remaining 70 patients. In the absence of a histologic diagnosis of AL amyloidosis, the following criteria were required for inclusion in the study: amyloid deposition in the bones and viscera on iodine-123–labeled serum amyloid P component (SAP) scintigraphy; renal dysfunction fulfilling the amyloidosis international consensus criteria; evidence of a clonal B-cell dyscrasia; absence of amyloidogenic mutations in the genes encoding transthyretin, fibrinogen A α-chain, apolipoprotein A1, apolipoprotein A2, gelsolin, and lysozyme (to rule out hereditary forms of amyloidosis)22; and absence of a chronic inflammatory disorder or acute-phase response.
Patients underwent prospective protocolized assessments every 6 months at the NAC, with each assessment comprising clinical evaluation, tests of amyloidotic organ function including biochemical evaluation of renal and liver function, echocardiography, SAP scintigraphy,23 assessment of hematologic disease by serum FLC assay, and storage of serum samples at −30°C. Glomerular filtration rate was estimated according to Kidney Disease Outcomes Quality Initiative guidelines.24 For all patients whose baseline visit to the NAC was after January 2007, serial N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration was prospectively determined,25 and in patients who were first evaluated before this time, NT-proBNP was determined retrospectively from available archived serum samples. The study was approved by the Ethics Committee of the Royal Free Hospital, and patients provided informed consent.
For all patients whose baseline visit to the NAC was after December 2001, serial FLC concentration was prospectively monitored on blood samples scheduled monthly during periods of chemotherapy treatment and every 1 to 3 months during subsequent follow-up. For patients who were first evaluated before this time, FLC concentration was determined retrospectively wherever possible using archived serum samples obtained at the baseline NAC assessment and first follow-up visit 6 months later.
Healthy, polyclonal serum FLC concentrations increase progressively through advancing stages of chronic kidney disease (CKD),26 which impedes the monitoring of monoclonal light chain disorders. In this study, the value of the FLC monoclonal component was estimated by subtracting the concentration of the uninvolved light chain from that of the amyloidogenic light chain to obtain the FLC difference (dFLC), a strategy that has lately been validated in myeloma.27 The FLC response to chemotherapy was defined throughout the study as the percentage of the dFLC at baseline that remained at the time of analysis. To validate the method in AL amyloidosis, dFLC response was included as a covariate in the patient survival analysis. FLC response was time updated in analyses of patient and renal survival and was defined at 6 months from baseline in analyses of renal outcome by amyloidosis international consensus criteria.14
Risk factors for progression to dialysis were analyzed among the 752 patients with a baseline estimated glomerular filtration rate (eGFR) of ≥ 15 mL/min but not among the remaining 171 patients (Table 1). A separate analysis of factors influencing change in renal function from baseline according to the amyloidosis international consensus criteria and including both renal response and renal progression was undertaken in all 429 patients with follow-up renal data. Patients who died (n = 226) or started dialysis (n = 111) within 6 months of their baseline NAC visit and patients in whom there was no creatinine or proteinuria measurement recorded after 6 months from baseline (n = 157) were excluded from this analysis (Table 1). A 6-month time point from baseline was chosen because it corresponded to the first follow-up visit during which FLC response was routinely determined and also allowed sufficient time for occurrence of a potential change in renal function. Renal progression was defined as the earliest of the following: starting dialysis; 50% increase in proteinuria and increase by ≥ 1 g/d; or 25% increase in serum creatinine and follow-up creatinine more than 120 μmol/L.14 Renal response was defined as the earliest of the following: 50% decrease in proteinuria and decrease by ≥ 0.5 g/d as long as creatinine had not increased by 25%; or 25% reduction in serum creatinine as long as proteinuria had not increased by 50%.14
|
| Analysis | Criteria | No. of Patients |
|---|---|---|
| Factors influencing patient survival | ||
| Exclusion | None | 0 |
| Inclusion | All patients in the study | 923 |
| Factors influencing progression to dialysis | ||
| Exclusion | All patients with eGFR < 15 mL/min at baseline | 171 |
| Inclusion | All patients with eGFR ≥ 15 mL/min at baseline | 752 |
| Factors influencing change in renal function (amyloidosis international consensus criteria) | ||
| Exclusion | Patients who died before 6 months of follow-up | 226 |
| Patients who experienced progression to dialysis before 6 months of follow-up | 111 | |
| Patients without follow-up renal data at or after 6 months | 157 | |
| Inclusion | All patients with follow-up renal data at or after 6 months | 429 |
| Factors influencing patient survival from commencement of dialysis | ||
| Exclusion | Patients who did not receive dialysis | 702 |
| Inclusion | All patients who received dialysis | 221 |
| Factors influencing patient and renal allograft survival from renal transplantation | ||
| Exclusion | Patients who did not receive renal transplantation | 902 |
| Inclusion | All patients who received renal transplantation | 21 |
Abbreviation: eGFR, estimated glomerular filtration rate.
Patient follow-up was censored at date of last clinic visit before May 2008. Kaplan-Meier analyses and Cox regression were used to investigate factors associated with overall survival of all patients in the cohort. Cox regression models were also fitted to identify independent predictors of progression to dialysis dependence among 752 patients with eGFR ≥ 15 mL/min at baseline; predictors of either a renal response or a renal progression among 429 patients; and predictors of survival from commencement of dialysis among 221 patients (Table 1). All factors that were of statistical and/or clinical significance (P < .20) in univariate analyses were included in multivariable analyses. Cut points were chosen by their clinical relevance (alkaline phosphatase, bilirubin, albumin, CKD stage, and proteinuria) or based on previously published work in amyloidosis (NT-proBNP and FLC concentration). The log-rank test was used to compare difference in stratified Kaplan-Meier survival analyses.
Baseline demographics and clinical characteristics of the patients are listed in Table 2. The cohort of 923 patients was observed for a median of 22.4 months (interquartile range [IQR], 7.3 to 49.0 months) after diagnosis. A total of 530 patients (57.4%) died. The Kaplan-Meier median survival time from diagnosis for the whole cohort was 35.2 months (95% CI, 28.0 to 42.0 months; Fig 1A). Median time from diagnosis to baseline NAC visit was 2.8 months (IQR, 1.4 to 5.8 months).
|
| Demographic or Clinical Characteristic | No. of Patients(N = 923) | % |
|---|---|---|
| Male sex | 524 | 56.8 |
| Age, years | ||
| Median | 62 | |
| IQR | 55-70 | |
| Time from diagnosis to baseline evaluation, months | ||
| Median | 2.8 | |
| IQR | 1.4-5.8 | |
| Year of amyloid diagnosis | ||
| Before 2000 | 312 | 33.8 |
| 2001-2004 | 377 | 40.9 |
| 2005-2008 | 234 | 25.4 |
| Amyloid load by SAP scan | ||
| Small | 434 | 47.1 |
| Moderate | 222 | 24.1 |
| Large | 216 | 23.4 |
| Missing | 51 | 5.5 |
| Received pretreatment with chemotherapy | 329 | 35.7 |
| Chronic kidney disease stage | ||
| 1 | 141 | 15.3 |
| 2 | 263 | 28.5 |
| 3 | 256 | 27.7 |
| 4 | 92 | 10.0 |
| 5 | 146 | 15.8 |
| Missing | 25 | 2.7 |
| Dialysis started | ||
| Before first visit | 94 | 10.2 |
| Within 6 months of first visit | 42 | 4.6 |
| After 6 months from first visit | 85 | 9.2 |
| Serum albumin, g/L | ||
| < 25 | 332 | 36.0 |
| 26-35 | 354 | 38.4 |
| > 35 | 221 | 23.9 |
| Missing | 16 | 1.7 |
| 24-Hour urine protein (BJP not included), g | ||
| 0.5-3 | 264 | 28.6 |
| 3.1-10 | 520 | 56.3 |
| > 10 | 109 | 11.8 |
| Missing | 30 | 3.3 |
| NT-proBNP, pmol/L | ||
| 0-35 (0-300 pg/mL) | 97 | 10.5 |
| 36-150 (301-1,273 pg/mL) | 95 | 10.5 |
| 151-400 (1,274-3,387 pg/mL) | 76 | 8.2 |
| > 400 (> 3,387 pg/mL) | 145 | 15.7 |
| Missing | 510 | 55.3 |
| Amyloidogenic light chain | ||
| λ | 77.3 | |
| κ | 22.7 | |
| Laboratory markers at first visit | ||
| Hemoglobin, g/dL | ||
| Median | 12.5 | |
| IQR | 11.1-14.0 | |
| Serum creatinine, μmol/L | ||
| Median | 106 | |
| IQR | 78-192 | |
| Creatinine clearance, mL/min | ||
| Median | 54.4 | |
| IQR | 28.5-81.6 | |
| eGFR, mL/min | ||
| Median | 56 | |
| IQR | 27-79 | |
| 24-hour urine protein, g | ||
| Median | 5.1 | |
| IQR | 2.5-7.6 | |
| Serum albumin, g/L | ||
| Median | 28 | |
| IQR | 23-35 | |
| Bilirubin, U/L | ||
| Median | 7 | |
| IQR | 5-11 | |
| Alkaline phosphatase, U/L | ||
| Median | 107 | |
| IQR | 76-175 | |
| Systolic blood pressure, mmHg | ||
| Median | 125 | |
| IQR | 110-145 | |
| Diastolic blood pressure, mmHg | ||
| Median | 76 | |
| IQR | 68-85 | |
| Standing systolic blood pressure, mmHg | ||
| Median | 123 | |
| IQR | 109-140 | |
| Standing diastolic blood pressure, mmHg | ||
| Median | 76 | |
| IQR | 66-86 | |
| λ light chain in λ patients, mg/L | ||
| Median | 99.1 | |
| IQR | 37.5-283.5 | |
| κ light chain in κ patients, mg/L | ||
| Median | 18.7 | |
| IQR | 9.7-52.7 | |
Abbreviations: IQR, interquartile range; SAP, serum amyloid P component; BJP, Bence Jones proteinuria; NT-proBNP, N-terminal pro–B-type natriuretic peptide; eGFR, estimated glomerular filtration rate.
Fig 1. Kaplan-Meier survival from diagnosis in systemic AL amyloidosis. (A) Median survival time among 923 patients was 35.2 months (interquartile range, 28.0 to 42.2 months). (B) Survival from diagnosis stratified by N-terminal pro–B-type natriuretic peptide (NT-proBNP). Survival was significantly better among patients with baseline NT-proBNP less than 150 pmol/L (< 1,273 pg/mL) compared with patients with NT-proBNP more than 150 pmol/L (> 1,273 pg/mL; median survival, 97.0 v 35.9 months, respectively; P < .001, log-rank test).
NT-proBNP concentration at baseline was strongly associated with survival (Fig 1B), and NT-proBNP more than 150 pmol/L (1,273 pg/mL) remained significantly associated with mortality in multivariable analyses (P < .001). There was a clear decreasing trend between risk of death and magnitude of FLC response to chemotherapy, with a hazard ratio (HR) for death of 0.73 (95% CI, 0.57 to 0.92; P = .01) for patients achieving a 50% to 90% FLC response and 0.27 (95% CI, 0.18 to 0.39; P < .001) for patients achieving more than 90% FLC response compared with patients achieving less than 50% FLC response. Other baseline factors associated with increased mortality were older age, lower urine protein, bilirubin more than 21 μmol/L, alkaline phosphatase more than 130 U/L, systolic blood pressure less than 120 mmHg, lower serum albumin, and higher amyloidogenic serum FLC concentration (Table 3).
|
| Factor | Total No. of Patients (N = 923) | Patients Who Died | Univariable Analysis | Multivariable Analysis | |||||
|---|---|---|---|---|---|---|---|---|---|
| No. | % | HR | 95% CI | P | HR | 95% CI | P | ||
| Dialysis (time updated) | |||||||||
| No | 829* | 476* | 57.4 | 1 | .02 | 1 | .06 | ||
| Yes | 94 | 54 | 57.4 | 1.29 | 1.04 to 1.59 | 0.77 | 0.58 to 1.01 | ||
| Sex | |||||||||
| Male | 524 | 314 | 59.9 | 1.27 | 1.07 to 1.51 | .01 | 1.20 | 1.00 to 1.43 | .05 |
| Female | 399 | 216 | 54.1 | 1 | 1 | ||||
| FLC response (time updated) | |||||||||
| < 50% | NA† | 1 | — | 1 | — | ||||
| 50%-90% | 0.70 | 0.55 to 0.88 | .05 | 0.73 | 0.57 to 0.92 | .01 | |||
| > 90% | 0.31 | 0.21 to 0.44 | .003 | 0.27 | 0.18 to 0.39 | < .001 | |||
| Missing | 1.27 | 1.00 to 1.62 | < .001 | 0.82 | 0.63 to 1.08 | .16 | |||
| Year of baseline evaluation | |||||||||
| Before 2002 | 356 | 255 | 71.6 | 1.15 | 0.96 to 1.37 | .12 | 0.60 | 0.48 to 0.76 | < .001 |
| 2002 or later | 567 | 275 | 48.5 | 1 | 1 | ||||
| Age at diagnosis, per 10 years higher | 1.22 | 1.12 to 1.33 | < .001 | 1.22 | 1.11 to 1.33 | < .001 | |||
| NT-proBNP at baseline, pmol/L | |||||||||
| 0-35 | 101 | 25 | 24.8 | 0.22 | 0.14 to 0.35 | < .001 | 0.33 | 0.20 to 0.53 | < .001 |
| 36-150 | 96 | 34 | 35.4 | 0.39 | 0.26 to 0.58 | 0.40 | 0.26 to 0.61 | ||
| 151-400 | 78 | 32 | 41.0 | 0.49 | 0.33 to 0.74 | 0.56 | 0.37 to 0.85 | ||
| > 400 | 148 | 83 | 56.1 | 1 | 1 | ||||
| Missing‡ | 500 | 356 | 71.2 | 1.22 | 0.96 to 1.56 | 1.15 | 0.88 to 1.51 | ||
| Baseline FLC concentration, mg/L | |||||||||
| 0-150 | 291 | 116 | 39.9 | 1 | < .001 | 1 | < .001 | ||
| 151-500 | 273 | 155 | 56.8 | 1.96 | 1.54 to 2.49 | 1.79 | 1.39 to 2.30 | ||
| > 500 | 190 | 123 | 64.7 | 2.27 | 1.76 to 2.93 | 2.30 | 1.76 to 3.01 | ||
| Missing | 169 | 136 | 80.5 | 3.99 | 3.10 to 5.12 | 3.04 | 2.27 to 4.07 | ||
| CKD stage at baseline | |||||||||
| 1-3 | 660 | 375 | 56.8 | 1 | .005 | 1 | .002 | ||
| 4-5 | 242 | 140 | 57.9 | 1.26 | 1.04 to 1.53 | 0.87 | 0.68 to 1.12 | ||
| Missing | 21 | 15 | 71.4 | 1.96 | 1.17 to 3.28 | 2.47 | 1.42 to 4.30 | ||
| 24-hour urine protein at baseline, g | |||||||||
| 0-3 | 264 | 166 | 62.9 | 1.37 | 1.13 to 1.65 | < .001 | 1.34 | 1.08 to 1.66 | < .001 |
| 3-10 | 520 | 289 | 55.6 | 1 | 1 | ||||
| > 10 | 109 | 56 | 51.4 | 0.78 | 0.59 to 1.04 | 0.60 | 0.44 to 0.82 | ||
| Missing | 30 | 19 | 63.3 | 1.94 | 1.22 to 3.08 | 1.76 | 1.03 to 3.00 | ||
| Bilirubin at baseline, U/L | |||||||||
| 0-21 | 836 | 472 | 56.5 | 1 | < .001 | 1 | .004 | ||
| > 21 | 65 | 46 | 70.8 | 2.16 | 1.59 to 2.92 | 1.52 | 1.08 to 2.13 | ||
| Missing | 22 | 12 | 54.5 | 1.12 | 0.63 to 1.98 | 4.09 | 1.26 to 13.24 | ||
| Albumin at baseline, g/L | |||||||||
| < 20 | 129 | 90 | 68.8 | 1.49 | 1.16 to 1.90 | .01 | 2.73 | 2.04 to 3.63 | < .001 |
| 20-29 | 363 | 212 | 58.4 | 1.22 | 1.01 to 1.48 | 1.56 | 1.27 to 1.92 | ||
| > 30 | 419 | 221 | 52.7 | 1 | 1 | ||||
| Missing | 12 | 7 | 58.3 | 1.08 | 0.51 to 2.30 | 0.62 | 0.14 to 2.75 | ||
| ALP at baseline, U/L | |||||||||
| 0-130 | 581 | 307 | 52.8 | 1 | < .001 | 1 | < .001 | ||
| > 130 | 326 | 214 | 65.6 | 1.81 | 1.52 to 2.16 | 1.76 | 1.45 to 2.14 | ||
| Missing | 16 | 9 | 56.3 | 1.03 | 0.53 to 2.01 | 0.33 | 0.06 to 1.89 | ||
| Systolic BP at baseline, mmHg | |||||||||
| < 120 | 243 | 140 | 57.6 | 1 | < .001 | 1 | < .001 | ||
| > 120 | 323 | 132 | 40.9 | 0.63 | 0.49 to 0.79 | 0.72 | 0.56 to 0.93 | ||
| Missing | 357 | 258 | 72.3 | 1.55 | 1.26 to 1.91 | 1.48 | 1.18 to 1.86 | ||
Abbreviations: HR, hazard ratio; FLC, free light chain; NA, not applicable; NT-proBNP, N-terminal pro–B-type natriuretic peptide; CKD, chronic kidney disease; ALP, alkaline phosphatase; BP, blood pressure.
*Numbers refer to patients who received dialysis at any time during follow-up.
†NA since time updated, and patients may move from one FLC response category to another.
‡Despite missing NT-proBNP data in 500 patients, there was no statistical difference in survival between the missing and < 35 pmol/L (< 300 pg/mL) categories. See Table 2 for NT-proBNP categories in pg/mL.
Among 752 patients with an eGFR of ≥ 15 mL/min at baseline, 98 (13.0%) experienced progression to ESRD and received dialysis after a Kaplan-Meier median time of 26.8 months. Independent factors at baseline associated with progression to dialysis were higher CKD stage (CKD stage 3: HR, 2.06; 95% CI, 1.22 to 3.49; CKD stage 4: HR, 7.07; 95% CI, 4.01 to 12.47, v CKD stage 2; P < .001) and lower serum albumin (HR, 3.04; 95% CI, 1.57 to 5.88 for albumin < 20 v > 30 g/L; P = .003). FLC response was also significantly associated with progression to dialysis; patients with a 50% to 90% response (HR, 0.63; 95% CI, 0.39 to 1.00; P = .05) and patients with a more than 90% response (HR, 0.24; 95% CI, 0.12 to 0.49; P = .001) were less likely to experience progression to dialysis compared with patients with less than 50% response.
Among 429 patients evaluable for renal outcome by amyloidosis international consensus criteria, progression of renal disease from baseline occurred in 235 patients (54.8%), and renal responses occurred in 140 patients (32.6%). Interestingly, CKD stage at baseline did not significantly influence chance of renal response, with 27.3%, 33.5%, 33.6%, and 27.8% of patients with CKD stages 1, 2, 3, and 4, respectively, achieving a renal response. The Kaplan-Meier median time from baseline NAC visit to renal progression was 23.8 months (95% CI, 18.8 to 33.5 months). In univariate analyses, FLC response at 6 months from baseline (HR, 0.32; 95% CI, 0.20 to 0.52 for > 90% v < 50% response), 24-hour urine protein (HR, 1.62; 95% CI, 1.15 to 2.27 for urine > 10 v < 3 g), and serum albumin (HR, 2.47; 95% CI, 1.71 to 3.58 for albumin < 20 v > 30 g/L) were associated with an increased risk of renal progression. Factors significantly associated with renal response and renal progression in multivariable analyses are listed in Table 4. Importantly, achieving more than 90% FLC response at 6 months was associated with an almost four-fold increase in the chance of renal response (P < .001) and a 68% reduction in the chance of renal progression (P < .001) when compared with an FLC response of 0% to 50%. In sensitivity analyses, renal outcome was significantly better among patients with an FLC response of more than 90% compared with patients with an FLC response of 50% to 90% (P < .001 for renal progression; P < .001 for renal response).
|
| Factor | Renal Progression | Renal Response | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total No. of Patients | Patients With Renal Progression | HR | 95% CI | P | Total No. of Patients | Patients With Renal Response | HR | 95% CI | P | |||
| No. | % | No. | % | |||||||||
| FLC response at 6 months | ||||||||||||
| 0%-49% | 120 | 77 | 64.2 | 1 | < .001 | 120 | 23 | 19.2 | 1 | < .001 | ||
| 50%-90% | 163 | 97 | 59.5 | 0.76 | 0.56 to 1.04 | 163 | 48 | 29.4 | 1.64 | 0.99 to 2.71 | ||
| > 90% | 65 | 21 | 32.3 | 0.32 | 0.19 to 0.52 | 46 | 41 | 89.1 | 3.95 | 2.36 to 6.63 | ||
| Missing | 81 | 40 | 49.4 | 0.52 | 0.35 to 0.78 | 81 | 28 | 34.6 | 1.76 | 0.98 to 3.16 | ||
| CKD stage | ||||||||||||
| 1 | 88 | 39 | 44.3 | 0.68 | 0.47 to 1.01 | .003 | Excluded* | |||||
| 2 | 164 | 88 | 53.7 | 1 | ||||||||
| 3 | 119 | 71 | 59.7 | 1.24 | 0.90 to 1.71 | |||||||
| 4 | 37 | 23 | 62.2 | 1.76 | 1.09 to 2.84 | |||||||
| 5 | 14 | 9 | 64.3 | 1.71 | 0.84 to 3.45 | |||||||
| Missing | 7 | 5 | 71.4 | 2.27 | 0.91 to 5.69 | |||||||
| Serum albumin, g/L | ||||||||||||
| < 20 | 54 | 42 | 77.8 | 2.74 | 1.76 to 4.27 | < .001 | 54 | 9 | 16.7 | 0.33 | 0.16 to 0.69 | .01 |
| 20-29 | 169 | 101 | 59.8 | 1.90 | 1.37 to 2.63 | 169 | 43 | 25.4 | 0.57 | 0.38 to 0.85 | ||
| ≥ 30 | 202 | 88 | 43.6 | 1 | 202 | 86 | 42.6 | 1 | ||||
| Missing | 4 | 4 | 100 | 2.11 | 0.72 to 6.16 | 4 | 2 | 50.0 | 0.58 | 0.08 to 3.99 | ||
NOTE. Two hundred thirty-five (54.8%) of 429 patients experienced renal progression, and 140 (32.6%) of 429 patients experienced renal response. Among 253 patients who were not pretreated, HR for renal progression was 0.67 (95% CI, 0.44 to 1.02) among 50% to 90% FLC responders and 0.26 (95% CI, 0.14 to 0.50) for greater than 90% FLC responders compared with less than 50% FLC responders (P < .001). HR for renal response among patients who were not pretreated was 1.56 (95% CI, 0.77 to 3.13) for 50% to 90% FLC responders and 4.29 (95% CI, 2.15 to 8.57) for greater than 90% FLC responders compared with less than 50% FLC responders (P < .001).
Abbreviations: HR, hazard ratio; FLC, free light chain; CKD, chronic kidney disease.
*Excluded from multivariable analyses; P = .67 in univariable analyses.
Two hundred twenty-one (23.9%) of 923 patients with renal AL amyloidosis received dialysis during the course of their disease, 127 only after their first visit to our center. One hundred fourteen (51.6%) of 221 dialysis-dependent patients died, and the median survival time from commencement of dialysis, which was unaltered by censoring at renal transplantation, was 39.0 months (95% CI, 29.8 to 43.9 months; Fig 2A). Survival stratified by year of commencement of dialysis is shown in Figure 2B. Serum albumin less than 25 g/L (P = .04) and alkaline phosphatase more than 130 U/L at commencement of dialysis (P = .02) were significantly associated with mortality in multivariable analyses.
Fig 2. Kaplan-Meier survival from commencement of dialysis in systemic AL amyloidosis. (A) Median survival time among all patients (n = 221) from start of dialysis was 39.0 months. (B) Patients who started dialysis after 2002 survived for significantly longer than did patients starting dialysis before 2002 (median survival, 43.6 v 29.8 months, respectively; P = .05).
Twenty-one (9.5%) of 221 dialysis patients underwent renal transplantation, including three living and 18 deceased donor grafts. Median follow-up time from renal transplantation was 50 months (IQR, 21.3 to 77.3 months). Median estimated patient survival from transplantation was 89 months (95% CI, 57 to 160 months). One- and 5-year patient survival rates were 95.2% and 71.4%, respectively. There were no graft failures as a result of recurrent amyloid, but nine patients died with functioning renal transplantations, including two patients who died from progressive extrarenal amyloid. The other seven deaths were from infection (n = 4), GI hemorrhage (n = 1), and unknown cause (n = 2). At 5 years from transplantation, there was scintigraphic evidence of recurrent amyloid in six functioning renal allografts, accompanied in five patients by proteinuria.
This study, comprising long-term follow-up of a uniquely large cohort of 923 patients with renal AL amyloidosis, demonstrates prolonged survival and superior renal outcomes among patients who achieved greater than 90% reduction in their dFLC value after chemotherapy. The substantial survival advantage associated with an FLC response demonstrated here is completely consistent with previous studies in AL amyloidosis,7,28 and therefore, the present series validates the use of the dFLC method in this disease. As CKD progresses, the concentrations of healthy polyclonal and abnormal monoclonal FLCs increase progressively, reflecting reduced renal clearance and metabolism and invalidating the use of absolute FLC measurements for tracking hematologic response in patients with renal disease. In contrast, the validity of dFLC measurements throughout all stages of CKD enabled us to estimate the proportion of the amyloidogenic monoclonal light chain present at baseline that remained after chemotherapy, which demonstrated, to our knowledge for the first time, a compelling and substantial relationship between magnitude of FLC response to chemotherapy and renal outcome. FLC response at 6 months from baseline was independently associated with both improvement in renal function and renal progression among evaluable patients in this series, with a more than 90% response conferring a near four-fold chance of renal response and a greater than three-fold reduction in chance of renal progression compared with a less than 50% FLC response (P < .001). Other factors independently associated with renal progression and/or requirement for dialysis included lower eGFR, lower serum albumin, and heavier proteinuria at presentation, consistent with previous reports.16 However, it is important to recognize that management and outcome of individual patients is also governed by tolerability and toxicity of treatment and that the design of the present study did not ascertain renal progression or deaths that may have resulted from counterproductive attempts to translate a clonal partial response to complete response with additional chemotherapy. It is also important to appreciate that the degree to which the monoclonal light chain concentration needs to be suppressed to facilitate improvement in amyloidotic organ dysfunction differs not only between individuals but also between different organs within the same individual. Therefore, the present findings do not imply that chemotherapy should necessarily target a more than 90% FLC response in all patients with renal AL amyloidosis, but subject to prospective validation, the present findings support this general objective in the absence of undue toxicity from chemotherapy, guided by serial FLC measurements using the simple dFLC method. The low proportion of patients reaching dialysis in this cohort compared with other series likely reflects the markedly different inclusion criteria; one cannot directly compare patients with renal AL amyloidosis according to amyloidosis international consensus criteria with patients who present with dominant renal AL amyloidosis.
Independent factors associated with death in this series, along with a less than 50% FLC response to chemotherapy, were older age, higher absolute baseline amyloidogenic FLC concentration, and lower serum albumin at presentation. In addition, systolic blood pressure less than 120 mmHg, higher NT-proBNP, and alkaline phosphatase and bilirubin outside the normal range at presentation, which are likely to reflect amyloidotic involvement of the autonomic nerves, heart, and liver respectively, were associated with poorer survival.
Median survival time from commencement of dialysis among 221 patients was more than 3 years, considerably longer than previously reported,16,18–20 and was 43.6 months for patients starting after 2002. The reasons for the prolonged survival on dialysis compared with other series, as well as the improved survival on dialysis among those commencing after 2002, remain unclear but, in the absence of evidence that the criteria for instituting dialysis differ or have changed over time respectively, are likely to reflect a combination of improved supportive management, improved dialysis techniques, and better chemotherapy treatments for AL amyloidosis.
Some renal units continue to exclude all patients with systemic AL amyloidosis from consideration for renal transplantation as a result of the multisystem nature of the disease and the perceived risk of allograft failure from amyloid recurrence.29 Less than 10% of patients reaching ESRD underwent renal transplantation in this series. Selection criteria for renal transplantation included absence of overt myeloma, a hematologic response to chemotherapy sufficient to prevent amyloid accumulation by serial SAP scintigraphy, and little or no clinically significant extrarenal amyloidosis, as well as willingness of the local renal unit to list the patient.21 Among this group of carefully selected patients, median estimated survival time from renal transplantation was 89.0 months. Graft loss from recurrent amyloid did not occur in any patient, and all deaths were in the context of a functioning renal allograft, suggesting that patients without clinically significant extrarenal amyloidosis should routinely be considered for renal transplantation, particularly if chemotherapy has resulted in a good hematologic response.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Arthur R. Bradwell, The Binding Site (C) Consultant or Advisory Role: None Stock Ownership: Arthur R. Bradwell, The Binding Site Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Julian D. Gillmore
Provision of study materials or patients: Helen J. Lachmann, Ashutosh D. Wechalekar, Simon D.J. Gibbs, Nancy L. Wassef, Arthur R. Bradwell, Philip N. Hawkins, Julian D. Gillmore
Collection and assembly of data: Jennifer H. Pinney, Nancy L. Wassef, Julian D. Gillmore
Data analysis and interpretation: Jennifer H. Pinney, Loveleen Bansi, Julian D. Gillmore
Manuscript writing: Jennifer H. Pinney, Helen J. Lachmann, Loveleen Bansi, Ashutosh D. Wechalekar, Janet A. Gilbertson, Dorota Rowczenio, Prayman T. Sattianayagam, Simon D.J. Gibbs, Emanuela Orlandi, Nancy L. Wassef, Arthur R. Bradwell, Philip N. Hawkins, Julian D. Gillmore
Final approval of manuscript: Jennifer H. Pinney, Helen J. Lachmann, Loveleen Bansi, Ashutosh D. Wechalekar, Janet A. Gilbertson, Dorota Rowczenio, Prayman T. Sattianayagam, Simon D.J. Gibbs, Emanuela Orlandi, Nancy L. Wassef, Arthur R. Bradwell, Philip N. Hawkins, Julian D. Gillmore
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Acknowledgment
We thank our many colleagues for referring and caring for the patients; A. Hughes, E. Pyart, D. Gopaul, and D. Hutt for their care of the patients at the National Amyloidosis Centre; T. Hunt for reviewing the histology; and J. Berkeley for expert preparation of the manuscript.
