Abstract
High-dose melphalan and autologous stem cell transplantation (HDM/SCT) have been used in patients with immunoglobulin light chain (AL) amyloidosis for over 2 decades now with durable responses, prolonged survival, and decreasing treatment-related mortality. Historically, patients with poorer baseline functional status, advanced age, renal compromise, and cardiac involvement have been treated with a risk-adapted modified conditioning dose of melphalan (mHDM) of 100 to 140 mg/m2 before SCT. In part because of these baseline characteristics, patients receiving mHDM/SCT have had poorer outcomes compared with patients receiving full-dose melphalan at 200 mg/m2. With the advent of novel therapeutic agents such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for the treatment of AL amyloidosis, it is imperative to understand the long-term effects of mHDM/SCT. Here we report the long-term outcomes of 334 patients with AL amyloidosis treated with mHDM/SCT. Median overall survival was 6.1 years and median event-free survival 4.3 years, with median overall survival reaching 13.4 years for patients who had achieved a hematologic complete response (CR). Overall hematologic response rate was 69%, and treatment-related mortality was 3% after 2010. Thus, mHDM/SCT leads to prolonged survival and favorable outcomes, especially if a hematologic CR is achieved.
Keywords: Stem cell transplantation, AL amyloidosis, Overall survival, Hematologic response, Melphalan dose
INTRODUCTION
In immunoglobulin light chain (AL) amyloidosis, amyloid fibril deposits, derived from immunoglobulin light chains produced by a clonal plasma cell dyscrasia, accumulate in extracellular tissues and damage vital organs. High-dose melphalan and autologous stem cell transplantation (HDM/SCT) have been shown to induce durable hematologic and clinical remissions in selected patients with AL amyloidosis and to prolong survival substantially when hematologic remissions are achieved. To reduce treatment-related complications, a lower dose of melphalan conditioning, hereafter called modified HDM (mHDM), has been used for patients who are of advanced age, frail, and/or have organ dysfunction associated with AL amyloidosis. The dose of melphalan can vary from 100 to 200 mg/m2 based on a risk-adapted approach, described by Comenzo and Gertz [1] to reduce treatment-related morbidity and mortality associated with HDM/SCT.
We previously reported on our experience of 312 patients treated with HDM/SCT in 2004 [2], and this series was updated in 2011 with 421 patients [3]. We also reported on the outcome of 629 patients with AL amyloidosis treated with HDM/SCT for a >20-year period to address remission durability and long-term results [4]. Of 543 assessable patients, 40.3% achieved a hematologic complete response (CR) after SCT. Hematologic CR occurred in 44.9% patients who received full-intensity (200 mg/m2) HDM compared with 33.8% patients who received mHDM (100 to 140 mg/m2) (χ2, P = .0091). Median overall survival (OS) was 10.5 years for those receiving full-intensity HDM compared with 5.2 years for patients receiving mHDM (P < .0001). A Center for International Blood and Marrow Transplant Research study also showed a reduced risk of hematologic relapse with higher doses of melphalan [5], as did a report from the Mayo Clinic [6].
On the other hand, a study of 143 patients with AL amyloidosis from Memorial Sloan Kettering Cancer Center (MSKCC) showed no impact of the dose of melphalan on event-free survival (EFS) (P =.26) or OS (P =.11) on a multivariate analysis [7]. This was at least in part due to the availability of novel agents for consolidation that increased CR after mHDM/SCT [7]. Moreover, with better patient selection, supportive care, and risk stratification in the last decade, treatment-related mortality (TRM) associated with HDM/SCT has greatly improved [8,9].
Although the full-intensity melphalan conditioning dose of 200 mg/m2 has been associated with responses and prolonged survival, the role of mHDM/SCT has been called into question [5]. Yet, taking into account that conditioning with mHDM has historically been recommended for older or more compromised patients, often because of more advanced heart involvement or renal dysfunction, it is difficult to ascertain if these patients’ inferior outcomes are due to a less effective SCT conditioning regimen or the underlying frailty of this patient population.
With the introduction of novel agents, including proteasome inhibitors, immunomodulatory drugs, and antiCD38 monoclonal antibodies, it becomes even more imperative to understand the efficacy of mHDM. We now report the long-term outcomes of patients with AL amyloidosis who underwent mHDM/SCT over a 23-year period.
METHODS
Patients
Three hundred thirty-four consecutive patients (238 patients from Boston University/Boston Medical Center (BMC) and 96 patients from MSKCC) with biopsy-proven AL amyloidosis who underwent mHDM/SCT between the years 1994 and 2017 were included in this study. All patients had provided informed consent for the use of their medical records, and the Institutional Review Boards of the respective institutions approved this study. Data were extracted from a prospectively maintained database, and patient charts were reviewed to ensure data completeness and accuracy. Data transfer agreements were generated between the 2 institutions in accordance with the compliance office.
Treatment Schedule
Peripheral blood stem cells were collected by leukapheresis after mobilization using granulocyte colony-stimulating factor. Melphalan was given in 2 equally divided doses on days –3 and 2 or as a single dose on day –2, and stem cells were infused on day 0. Two hundred eighty-nine patients (87%) received mHDM at a dose of 140 mg/m2, and 45 patients (13%) received a dose of 100 mg/m2. Twenty-seven patients (8%) received melphalan at a dose of 100 mg/m2 on a clinical trial, as previously described [10]. Another 14 patients (4%) received melphalan at a dose of 100 mg/m2 as part of the Southwest Oncology Group clinical trial S0115 [11].
Selection Criteria for SCT
Eligibility criteria for SCT were quite broad and largely unchanged over the years: biopsy-proven amyloid disease, evidence of a plasma cell dyscrasia, at least 1 major organ affected by amyloid disease, absence of heart failure or arrhythmia resistant to medical management, uncontrolled angina, myocardial infarction within 6 months before enrollment, New York Heart Association class III or IV heart failure, lung diffusion capacity of 50% or more of predicted, supine systolic blood pressure of 90 mm Hg or greater, and total bilirubin level <2 mg/dL. Patients were considered ineligible for the full-intensity HDM at 200 mg/m2 and instead offered mHDM if they were over age 65, with advanced cardiac involvement (left ventricular ejection fraction <45%), with poor functional status (Eastern Cooperative Oncology Group score >2) as evaluated by the 6-minute walk test and/or stair climb test, or if the stem cell collection yield was <2.5 ×· 106 CD34+ cells/kg, as previously described [3]. Selection criteria were similar between the 2 institutions, except for the following: (1) Mayo cardiac stage IIIB (N-terminal pro–brain natriuretic peptide [NT-proBNP] > 8500 pg/mL, troponin I > 0.1 ng/mL) were excluded from mHDM/SCT at MSKCC, but BMC did not exclude patients solely based on biomarker stage, and (2) all patients with estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 were considered for mHDM/SCT rather than full-intensity HDM/SCT at MSKCC, but there was no strict eGFR criteria for consideration of mHDM/SCT versus full-intensity HDM/SCT at BMC.
Evaluation of Response
Organ involvement was defined according to consensus criteria [12]. Hematologic response was assessed in accordance with the current consensus criteria [13]. Hematologic CR was defined as the absence of monoclonal protein by serum and urine immunofixation electrophoreses and normalization of serum free light chain ratio. Hematologic very good partial response (VGPR) was defined as a reduction of the difference in serum free light chains to less than 40 mg/L, and hematologic partial response (PR) was defined as a greater than 50% reduction in the difference in serum free light chains, only if the initial difference in serum free light chains was greater than 50 mg/L. PR and VGPR were only assessed for patients after serum free light chains testing became available in the year 2003 [13].
Renal response was defined according to the updated 2014 staging system [14]. The 2012 criteria for cardiac response incorporates NT-proBNP, which were not routinely evaluated until 2016 at BMC [15]. However, BNP was available in all our patients, so cardiac response was defined as previously described by a 30% improvement in the BNP [16]. Renal and cardiac responses could only be assessed after the year 2003. eGFR was calculated by the Modification of Diet in Renal Disease Study equation. Complete assessments of hematologic and organ responses were done at 6 and 12 months after SCT and annually thereafter.
Statistical Analysis
Descriptive statistics were used to summarize patient characteristics and to analyze the variables of the study. The actuarial Kaplan-Meier method was used to estimate OS, as measured from the infusion of stem cells (day 0) until death or censor date of February 28, 2018 if alive. EFS was calculated as the time from day 0 to next therapy or date of death, whichever occurred first. Survival measurements were compared using the log-rank test using GraphPad Prism version 7.0c for Mac (GraphPad, La Jolla, CA).
RESULTS
Patients
Patient characteristics are summarized in Table 1. A total of 334 patients were included in this study, of which 216 (65%) were men. The median age was 61 years (range, 28 to 80). Involvement of only 1 organ was present in 99 patients (30%). Distribution of organ involvement was as follows: kidney, 75%; heart, 56%; gastrointestinal, 34%; liver, 23%; nervous system, 27%; and lungs, 11%. A total of 252 patients (75%) had a lambda clonal plasma cell dyscrasia, and the median percentage of plasma cells in the bone marrow was 10% (range, <5% to 53%). Of 334 patients, 25 patients (7%) underwent SCT while on dialysis, 106 patients (32%) were over the age of 65, 9 patients (3%) had left ventricular ejection fraction less than 45%, 44 (13%) had a stem cell collection yield < 2.5 ×· 106 CD34+/kg, and 113 (34%) had eGFR <50 mL/min/1.73 m2. Twenty-seven of 127 patients (21%) with troponin I collected had a troponin I level >.1 ng/mL. The median time from diagnosis of AL amyloidosis to the SCT was 4.8 months (range, 0 to 146). A total of 43 patients (13%) had received treatment before their mHDM/SCT. Planned induction therapy with bortezomib and dexamethasone for 2 to 4 cycles was administered to 15 of 210 patients (7%) at BMC and 21 of 81 patients (26%) at MSKCC who received first-line mHDM/SCT.
Table 1.
Baseline Characteristics (N = 334)
| Characteristic | Value |
|---|---|
| Male | 216 (65) |
| Median age, yr (range) | 61 (28–80) |
| Lambda light chain isotype | 252 (75) |
| Median dFLC, mg/L (range), n = 197 | 45 (.9–2442) |
| Median bone marrow plasma cells, % (range) | 10 (0–53) |
| Median 24-hr urine total protein, g/24 hr (range) | 3.6 (0–58) |
| Median creatinine, mg/dL (range) | 1.1 (.4–12.3) |
| Median eGFR, mL/min/1.73 m2 (range) | 69 (2–239) |
| Median IVSd, mm (range) | 12 (7–23) |
| Median LVEF, % (range) | 61 (30–87) |
| Median B-type natriuretic peptide, pg/mL (range), n = 181 | 185 (7–3200) |
| Median troponin I, ng/mL (range), n = 127 | .06 (0-.5) |
| Median alkaline phosphatase, U/L (range) | 90 (31–1385) |
| Median albumin, g/dL (range) | 3.4 (.9–5.1) |
| Organ involvement | |
| Renal involvement | 252 (75) |
| Cardiac involvement | 188 (56) |
| Gastrointestinal involvement | 114 (34) |
| Hepatic involvement | 77 (23) |
| Peripheral nervous system involvement | 91 (27) |
| Autonomic nervous system involvement | 41 (12) |
| Pulmonary involvement | 36 (11) |
| Single organ involvement | 99 (30) |
Values are n (%) unless otherwise defined. dFLC indicates difference between involved and uninvolved serum free light chain; IVSd, interventricular septal thickness at end diastole; LVEF, left ventricular ejection fraction.
Hematologic Response
After 1 year 71 patients (21%) had died and 11 (3%) did not return for response assessment. Of 252 assessable patients at 1 year after SCT (Table 2), 84 patients (33%) had a hematologic CR, 63 patients (25%) had a PR, and 78 patients (31%) had no response. Twenty-seven of 138 assessable patients (20%) achieved a VGPR. Twenty-seven of 111 patients (24%) with hematologic CR and VGPR at 1 year after SCT required further treatment for recurrence of plasma cell dyscrasia at a median of 4 years (range, 1.1 to 11.1) after SCT.
Table 2.
Hematologic and Organ Responses at 1 Year after mHDM/SCT
| Hematologic Response n/N (%) | Renal Response n/N (%) | Cardiac Response n/N (%) | |
|---|---|---|---|
| Overall | 174/252 (69) | 53/122 (43) | 45/119 (38) |
| Hematologic CR | 84/252 (33) | 20/38 (53) | 17/40 (42) |
| VGPR | 27/138 (20) | 12/24 (50) | 8/19 (42) |
| Partial hematologic response | 63/252 (25) | 18/38 (47) | 18/44 (41) |
| No hematologic response | 78/252 (31) | 2/22 (9) | 2/16 (13) |
Organ Response
Of 119 assessable patients, 45 (38%) had a cardiac response (Table 2). Specifically, cardiac response occurred in 17 of 40 patients (42%) with a hematologic CR, 8 of 19 patients (42%) with a VGPR, 18 of 44 patients (41%) with a PR, and 2 of 16 patients (13%) with no response. Of 122 assessable patients, 53 (43%) had a renal response. Similarly, renal response occurred in 29 of 38 patients (53%) with a hematologic CR, 12 of 24 patients (50%) with VGPR, 18 of 38 patients (47%) with PR, and 2 of 22 patients (9%) with no response.
OS and Mortality
With a median follow-up of 4.4 years, the median OS for all patients from day 0 of SCT was 6.1 years and median EFS 4.3 years (Figure 1). Median OS was 13.4 years for the 84 patients who achieved a hematologic CR, 7 years for the 27 patients who achieved a VGPR, not yet reached for the 63 patients who achieved a PR, and 1.6 years for 155 patients who had no response, including the 71 patients who died within 1 year of treatment (Figure 2). A total of 204 patients (61%) died. Seventy-one patients (21%) died within 1 year and were considered nonassessable in terms of assessment of hematologic and organ response. Among these patients, 33 deaths (10%) were treatment-related (deaths within the first 100 days after HDM/SCT). Since 2003 TRM was lower at 6% (12/199) and even lower since year 2011 with TRM of 3% (2/60).
Figure 1.
(a) Overall survival from D0 of stem cell transplantation. (b) Event-free survival from D0 of stem cell transplantation.
Figure 2.
Overall survival based on hematologic CR, VGPR, PR and No response.
Treatment for Relapse after SCT
Of the 334 patients who underwent mHDM/SCT, 101 (30%) received a second line of treatment for progression of disease at a median of 23.2 months (range, 1.9 to 145.8). Of these, 38 (38%) received proteasome inhibitor–based therapy, 34 (34%) received immunomodulatory therapy, 13 (13%) received HDM/SCT, 7 (7%) received oral melphalan, 5 (5%) received dexamethasone only, 2 (2%) received rituximab, 1 (1%) received daratumumab, and 1 (1%) received bortezomib/lenalidomide/dexamethasone.
DISCUSSION
HDM/SCT have been the cornerstone of treatment for AL amyloidosis for more than 2 decades, with durable responses, prolonged survival, and decreasing TRM [3,4,8,17]. However, for patients who do not qualify for the full conditioning dose of melphalan because of poor functional status and/or advanced amyloid-related organ dysfunction, the question of whether to treat with mHDM with SCT versus a novel therapeutic agent is still unanswered [6–8]. Patients who receive mHDM/SCT have historically had poorer outcomes than those who received the full dose of melphalan with SCT with respect to hematologic response and survival, but it is still unknown whether this difference is solely attributable to differences in baseline characteristics. Although some multivariate analyses have shown a significant effect of melphalan dosing on OS [5,8], others have demonstrated no effect of melphalan dosing on OS [7]. These analyses were all retrospective in nature, however, so further study is still necessary to determine the true efficacy of mHDM/SCT.
Here we present long-term outcomes of 334 patients with AL amyloidosis who received mHDM/SCT from 2 high-volume transplant centers. To our knowledge, this is the largest reported study of AL amyloidosis patients treated with mHDM/SCT. Our results show that median OS in these patients is still considerable at 6.1 years, with median EFS of 4.3 years. Furthermore, for patients who achieved a CR, median OS was even longer at 13.4 years. In comparison, our prior report of 629 AL amyloidosis patients who received HDM/SCT demonstrated a median OS of 7.6 years [4]. For the subset of 350 patients who received full-intensity HDM/SCT, the median OS was 10.5 years [4].
Although indeed OS is better in patients who receive full-intensity HDM/SCT, perhaps it would be more appropriate to compare with the long-term outcomes of patients who received nontransplant therapy upfront, because patients who are eligible for full-intensity HDM/SCT represent a healthier, more robust population. One study of upfront bortezomib or lenalidomide in 85 patients with AL amyloidosis showed a median OS of 3.9 years [18]. Another study of cyclophosphamide, bortezomib, and dexamethasone upfront in 230 patients with AL amyloidosis who were ineligible for SCT demonstrated that 55% of patients were projected to survive 5 years and median time to second-line therapy or death was 13 months [19]. First-line melphalan and dexamethasone were also studied in a cohort of 140 patients with advanced cardiac disease and reported a median OS of 20 months [20]. Thus, compared with nontransplant therapies, patients in our cohort who received mHDM/SCT had substantially longer median OS and EFS.
Overall, a high proportion of patients (69%) in our cohort responded to therapy, including CR, VGPR, and PR. Our study confirms that patients with a hematologic response had improved OS. Similar to prior reports [8,9], TRM has improved over time, with 10% TRM overall, 6% since 2003, and only 3% since 2011. Thus, it should be appreciated that despite the risk associated with mHDM/SCT, it has decreased even in an older or more compromised population and is associated with excellent outcomes. Another consideration is the cost-effectiveness of SCT compared with nontransplant therapies. Although the upfront cost is higher for SCT, remission is more durable, and the EFS was 4 years in our study. In contrast, patients treated with nontransplant therapies, such as proteasome inhibitors and immunomodulatory drugs, incurred costs of approximately 15,000 to 50,000 euros per line of treatment in a 2011 French study [21]. Another study of patients with multiple myeloma also showed that SCT was more cost-effective given the prolonged survival, even in patients over the age of 65 [22]. The study was based on data from the Surveillance, Epidemiology, and End Results–Medicare database and showed a median cost for the first 100 days after transplantation of $60,000 (range, $37,000 to $85,000).
In our study hematologic response was also durable, with only 24% of patients with hematologic CR and VGPR requiring further treatment at a median of 4 years after SCT. This is similar to a previous report from the Mayo Clinic of 410 patients with AL amyloidosis who received HDM/SCT, at both 200 mg/m2 and lower doses, which showed a 36% rate of relapse or progression at a median of 1.97 years [23]. Previously, we had also reported on the overall rate of hematologic relapse for all patients at BMC who received HDM/SCT at both full intensity and modified doses. Of 647 patients, 38.5% of patients relapsed after a hematologic CR. Of these patients, 71% had received the full-intensity melphalan dosing and 29% received mHDM. For the former group median time to relapse was 4 years, and for the mHDM group median time to relapse was 4.75 years [24].
The major limitation of this study is its retrospective design. Although a randomized clinical trial comparing mHDM/SCT and nontransplant therapies would be ideal to determine superiority, it might never be feasible to conduct such a study given the prolonged survival seen with mHDM/SCT already. Another limitation is the inability to accurately qualify hematologic and organ response before 2003 because of missing data, lack of availability of the serum free light chain assay, and absence of standardized definitions of organ response. Additionally, NT-proBNP was not available at our institutions until very recently, so Mayo Biomarker Stage could not be assessed.
In conclusion, mHDM/SCT for patients with AL amyloidosis ineligible to receive full-dose melphalan conditioning is still an effective treatment option associated with low TRM and prolonged survival, especially in patients who achieve a hematologic CR. This treatment should be considered in select patients, because the outcomes compare favorably with previously reported outcomes of other nontransplant treatment options available for these patients.
ACKNOWLEDGMENTS
The authors thank the current and past members of the Amyloidosis Center, Cancer Clinical Trials of Office, Stem Cell Transplant Program, and Center for Cancer and Blood Disorders at Boston University School of Medicine and BMC.
Footnotes
Financial disclosure: The authors have nothing to disclose.
Conflict of interest statement: There are no conflicts of interest to report.
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