Autologous stem cell transplantation has been an essential part of the treatment armamentarium in light chain amyloidosis for several decades. This review provides a comprehensive assessment of eligibility criteria for ASCT in AL amyloidosis, conditioning dosing, efficacy in terms of hematologic and organ response, and future areas of research.
Autologous stem cell transplantation (ASCT) has been an essential part of the treatment armamentarium in light chain (AL) amyloidosis for several decades. Patients who achieve a complete hematologic response following ASCT have a long overall survival. However, only 1 randomized controlled trial compared ASCT with the standard of care used at the time, which was melphalan and dexamethasone, and the results did not support the use of ASCT in AL amyloidosis. These results are of limited significance due to the unexpected high transplant-related mortality (TRM) (24%). TRM is a major concern in AL amyloidosis, but its incidence can be lessened by better patient selection and by patients receiving ASCT in specialized centers. ASCT in AL amyloidosis is performed only in selected patients; approximately 20% of patients with AL amyloidosis are transplant eligible up front or after bortezomib (Velcade) based conditioning. The introduction of newer agents such as bortezomib and daratumumab (Darzalex), which lead to deep responses and have good safety profiles, encourage revisiting the benefit and timing of ASCT in the modern era.
This review provides a comprehensive assessment of eligibility criteria for ASCT in AL amyloidosis, conditioning dosing, efficacy in terms of hematologic and organ response, and future areas of research.
In immunoglobulin light chain (AL) amyloidosis, clonal plasma cells in the bone marrow produce light chains that misfold and deposit in various organs.1 These depositions interfere with organs’ function,2 which reduces quality of life (QOL) and shortens survival. The treatment of AL amyloidosis is aimed at quickly clearing the amyloidogenic light chain burden by eliminating the plasma cell clone that produces it.2
The key concepts of effectively treating AL amyloidosis are (1) early diagnosis; (2) accurate typing; (3) a multidisciplinary approach to management; and (4) tailored treatment to tolerance (choosing the safest therapy based on organ involvement and comorbidities). The extent of cardiac involvement drives therapy and outcomes, because patients with advanced cardiac involvement are at increased risk of early death from arrhythmias and progressive heart failure.3 The goal of treatment in AL amyloidosis is for the patient to achieve a response as deep as possible, as quickly as possible.4,5
ASCT has been an essential part of the treatment armamentarium in light chain (AL) amyloidosis for several decades because of high response rates and prolonged responses. However, in the past 2 decades, treatment options for AL amyloidosis patients have expanded to include proteosome inhibitors,6-10 immunomodulatory drugs,11-15 alkylators,8,10,16 and monoclonal antibodies.17-20 Currently, more than 50% of patients with AL amyloidosis achieve a very good partial response or better (≥VGPR)21-24 to frontline treatments, making the role and the optimal timing of ASCT an area of debate. Moreover, the impact of ASCT on high-risk cytogenetics is unclear.25
The role of induction therapy prior to ASCT is evolving. Historically, the norm had been no induction prior to ASCT based on 2 justifications. First, a majority of patients with AL amyloidosis had low plasma cell burden, making “debulking” prior to ASCT seemingly unnecessary. Second, induction could render patients who were previously eligible for ASCT ineligible, due to toxicity. Prospective data are quite limited.
In a small trial from China, 56 patients were randomized to receive either 2 cycles of bortezomib and dexamethasone (BD) prior to ASCT, or to move directly to ASCT (Table).26 No attrition occurred in the BD arm prior to ASCT, and 2-year progression-free survival (PFS) was 81% and 50%, respectively, favoring BD induction. Two-year overall survival (OS) was 95% and 69%, respectively. Although the anticipated complete response (CR) rate (defined as normalization of the free light chain level and ratio, negative serum and urine immunofixation) for the noninduced patients was of no surprise, the 2-year OS was much lower than expected, because, based on results of previous larger studies, the anticipated 5-year OS post ASCT is 65% to 75%.
In contrast, the prospective phase 2 study by Minnema et al included 50 patients who were treated with 4 cycles of BD before ASCT.24 The overall hematologic response after induction treatment was 80% (CR, 20%; VGPR, 38%). Fifteen patients (30%) did not proceed to ASCT, mainly due to toxicity induced by the BD treatment; therefore, the primary end point of the study was not met. Treatment-related mortality (TRM) was 0%. In the patients who proceeded to ASCT, overall hematologic responses improved at 6 months after transplant to 86% (CR, 46%; VGPR, 26%).
Two other prospective studies have incorporated BD prior to ASCT; both were single-arm trials27,28 and used bortezomib along with melphalan conditioning, and one of them used bortezomib as consolidation as shown in the Table. Each of these strategies yielded higher-than-expected CR rates, but at the cost of patient attrition prior to ASCT. Moreover, the role of induction cannot be separated from the novel conditioning27,28 and consolidation.27 A similar pattern of patient attrition that occurred when induction was given prior to ASCT was seen in a prospective study published in 2004 that randomized 100 patients newly diagnosed with AL amyloidosis to ASCT up front vs 2 cycles of induction with melphalan and prednisone prior to ASCT. There were no differences in OS, hematologic response, or organ response between the 2 arms, but 16 patients randomized to the induction arm became ineligible for subsequent ASCT.29
A number of retrospective studies suggest that induction, especially bortezomib induction, yields better outcomes. A major problem with these retrospective studies is that they are not designed as intention-to-treat trials, which makes it impossible to know if sicker patients were weeded out and never made it to ASCT; this would leave the noninduction comparator group as a population of higher-risk patients more likely to have higher TRM, which in turn reduces both survival and evaluability for response.
One such retrospective study evaluated 128 patients with AL amyloidosis who were divided into 3 groups: no induction (15.5%), induction with melphalan and prednisone (MP; 19.5%), and induction with novel agents (65%). At day 100 post ASCT, overall hematologic response rates (and CR rates) were 60% (10%), 62% (25%), and 87% (19%) in the no-induction group, MP group, and novel-agents group, respectively.30 Induction with novel agents was predictive of OS in a multivariate analysis. Most of the OS benefit in the novel-agents group occurred in the first 12 months, suggesting a potential weeding-out of sicker patients in the induction group.
Another retrospective study reported outcomes of 63 patients: 34 received bortezomib-based therapy before ASCT, and 29 patients either did not receive induction prior to ASCT or received induction therapy that was not bortezomib based.31 At diagnosis, the bortezomib-treated patients had been more likely to have cardiac involvement and gastrointestinal involvement. Time to transplant was longer in the bortezomib-treated group (median, 226 days vs 150 days). Inexplicably, time from diagnosis to ASCT in the nonbortezomib group was quite long at 5 months. The patients who received bortezomib induction were more likely to receive melphalan 200 mg/m2 (62% vs 45%, respectively), and in these patients, there was a trend toward better CR at 3 months (26% vs 12% respectively). The median OS and the organ responses were also higher in the bortezomib induction group. By 24 months, approximately one-third of the nonbortezomib patients had died in contrast to 6% of the bortezomib-induced group.
The thought process around tumor bulk (≤10% bone marrow plasma cells [BMPC] at presentation) was in part supported by a retrospective publication from the Mayo Clinic in which patients with Mayo 2012 stage I/II disease and BMPC ≤10% did well (5-year OS above 80%), regardless of whether or not they received induction therapy prior to ASCT.32 These findings have been challenged by recent studies. In a retrospective study of 227 patients with <10% BMPC, 124 patients received bortezomib-based induction prior to ASCT, 68 did not receive induction, and 35 patients received other chemotherapeutic induction.33 OS, PFS, overall hematologic response rates, CR rates, and cardiac and renal responses were all higher in patients who received bortezomib-based induction prior to ASCT. Once again, the 2-year mortality was markedly different between the bortezomib induction group vs the patients who received no induction or nonbortezomib induction: 0% vs almost 25%, respectively. On multivariate analysis, only the difference between the involved and uninvolved serum free light chain (dFLC) >50 mg/l and bortezomib induction predicted for OS. Another retrospective study of 45 patients that evaluated induction regimens with novel agents showed a 3-year PFS benefit for patients treated with novel-agent induction vs conventional chemotherapy (79% vs 53%, respectively; P = .05), but no significant OS benefit (95% vs 71%).34
To conclude, most studies support the use of bortezomib-based induction therapy prior to ASCT, even for patients with low disease burden (Figure).
Deep responses have been reported with daratumumab therapy in AL amyloidosis; daratumumab is the first FDA approved drug for AL amyloidosis based on the phase 3 ANDROMEDA trial (NCT03201965) that compared daratumumab plus bortezomib, cyclophosphamide, and dexamethasone (VCd) with VCd alone in newly diagnosed patients.17,35 The addition of daratumumab to VCd resulted in a significant improvement in the overall hematologic response (92% vs 77%, respectively), as well as a significant improvement in the rate of complete hematologic response (50% vs 14%). Although ASCT was not a planned part of the trial, 13 patients in the daratumumab + VCd arm and 20 patients in the VCd-alone arm proceeded to ASCT. In the safety run-in report (only of the daratumumab + VCd arm), 5 patients died, including 3 who underwent ASCT.17 The quadruplet resulted in shorter time to response and improved organ response. Because of the deep responses to daratumumab + VCd,35 we recommend using the quadruplet as first-line treatment, if possible (Figure).
If daratumumab/VCd is not available, we recommend using VCd prior to ASCT. A prospective study investigated VCd in 230 newly diagnosed with AL amyloidosis; the overall hematological response rate was 60%, with a VGPR or better in 43%.8 Only 17 patients underwent ASCT, all as part of second-line therapy. The first report to describe the use of VCd in AL amyloidosis was a retrospective study that evaluated VCd as used in 17 patients with AL amyloidosis (bortezomib was given at 1.5 mg/m2 once weekly).36 The overall hematological response rate was 94%, with a CR rate of 71%. The median time to response was 2 months. Five of those patients proceeded to ASCT; 3 of them had initially been considered transplant ineligible and became eligible only after therapy.
It is well recognized that, in general, depth of response is prognostic in AL amyloidosis,1 but a retrospective study has demonstrated that response to induction pre-ASCT is also predictive of OS.36 Bortezomib, lenalidomide, and dexamethasone (VRd) is commonly used in patients with multiple myeloma, given the higher response rate they experience compared with lenalidomide and dexamethasone; however, generally, patients with AL amyloidosis have a lower tolerance of lenalidomide, with lenalidomide not infrequently causing hypotension and cardiac decompensation in more fragile patients with AL amyloidosis. We consider using VRd only in patients who do not have cardiac involvement or autonomic dysfunction. Bortezomib with dexamethasone is also an induction option.25,30
Organ compromise can lead to significant complications and early mortality, mandating careful patient selection. Carefully selecting who can or cannot receive ASCT heavily influences patients’ outcomes. Selection criteria are not uniform among the specialized centers, but generally, only 20% to 30% of patients with AL amyloidosis are deemed eligible for ASCT.
The early reports of ASCT use in patients with AL amyloidosis elicited important safety issues, with TRM ranging from 13% to 43%.37,38 To lower TRM, clinicians developed risk-adapted approaches that included patient-related factors, such as performance status, and disease-related factors, most importantly the extent of cardiac involvement. Some centers use a more liberal approach to patient selection and use attenuated doses of melphalan conditioning, while others have more strict eligibility criteria aiming to use full-dose melphalan.
At Mayo Clinic, the current consensus criteria for ASCT eligibility of patients with AL amyloidosis include physiologic; age 70 years or younger (determined clinically); performance score of 2 or less; systolic blood pressure 90 mm Hg or greater; troponin T (TnT) lower than 0.06 ng/ml (or high sensitivity -TnT <75 ng/ml); creatinine clearance (CrCl) 30 ml/min or greater (unless on chronic dialysis); and categorized as New York Heart Association Class I/II. Elevated cardiac biomarkers are associated with high rates of early mortality39 and therefore are included in our eligibility criteria. Some centers use less stringent selection criteria for ASCT, ie, they do not include cardiac biomarkers as a tool to exclude patients from ASCT. At Mayo Clinic, dialysis is not considered to be an exclusion criterion if all other eligibility criteria are met.40
ASCT is safe for selected patients with AL amyloidosis 70 years or older as long as they meet the other criteria listed above. In a retrospective report of 34 patients, TRM was 3% (1 patient died) and 35% completed the entire transplant course outpatient.41
Mobilization and collection may also jeopardize patients with AL amyloidosis. In one report of 629 patients, 11 patients died during mobilization and collection42; a retrospective study that included 101 patients reported 4 deaths during mobilization.43 Other adverse effects of stem cell mobilization and collection can include volume overload, thromboembolic events, and bleeding. The susceptible population is mainly patients with cardiac involvement. Plerixafor used to enhance stem cell yield is safe and well tolerated in AL amyloidosis.44,45
Conditioning in amyloidosis can be performed with full-intensity melphalan (200 mg/m2) or with reduced melphalan doses (100-140 mg/m2). Dose-reduced melphalan has made ASCT possible for sicker AL amyloidosis patients without excessive TRM. Lower doses of melphalan, however, result in lower CR rates, which translate into lower PFS and OS rates. Given the option of novel agent based therapies6,17 that give CR rates higher than those generally attained with attenuated dose melphalan conditioning, it is our practice at the Mayo Clinic to carefully select patients to whom we can administer full-dose melphalan. Therefore, for patients that are assessed as unable to receive full-dose melphalan, we choose to offer other novel agents based therapies.
The concept of using attenuated melphalan conditioning to transplant sicker patients was introduced at Boston University.46 Although TRM was shown to be reduced, it has since been repeatedly demonstrated that response rate is sacrificed with this maneuver. In a report of 629 patients transplanted at Boston University, hematologic CR was higher in patients receiving 200 mg/m2 than in those receiving 100 to 140 mg/m2 (45% vs 34%, respectively; P = .0091).42 Fifty-six percent of the cohort received melphalan 200 mg/m2, whereas 44% received melphalan 100 to 140 mg/m2; the latter group included patient 65 years or older and those with poor performance status, left ventricular ejection fraction 40% to 45%, or low yield stem cell collection. The reported overall TRM was 7.5% (3.4% after 2005). Hematologic CR rates were higher in patients that received melphalan 200 mg/m2 (45% versus 34%, respectively; P = .0091). The median OS was higher for patients treated with 200 mg/m2 (10.5 vs 5.2 years, respectively; P = .0001). Similar results have been shown at the large amyloidosis transplant centers,47,48 including the Mayo Clinic and Memorial Sloan Kettering. A Center for International Blood and Marrow Transplant Research report, which included 1536 patients with AL amyloidosis undergoing ASCT, demonstrated similar findings; it also showed lower relapse risk with full-dose melphalan (HR, 0.237; 95% CI, 0.118-0.474; P = .001).49
In an effort to include sicker patients as ASCT candidates, but to compensate for lower CR rates, an approach has been to use attenuated melphalan doses followed by consolidative chemotherapy post ASCT for those not achieving a deep response50 (see section below on consolidation and maintenance). In a report of 334 patients who received modified conditioning, the overall hematologic response was 69%, with TRM of 3% after 2010. The median OS was 6.1 years for the entire study population and 13.4 years for the subgroup who achieved hematologic CR.51
As shown in the Table, bortezomib has also been evaluated as part of the conditioning regimen along with high-dose melphalan. Given the small sample size, there is no way to properly judge whether there is any benefit to this approach.32,40
TRM has declined over the years, due to the refinement of eligibility criteria and
better supportive care.48,49 Specialized centers have superior survival outcomes,49 with TRM less than 5%.48 However, ASCT is associated with many other important potential complications, mainly renal impairment,52,53 fluid accumulation, cardiac arrhythmia, gastrointestinal toxicity,54 and infections.
Progressive renal impairment occurring during ASCT can increase TRM, have a crucial impact on the future choice of therapies, and negatively influence QOL. In a retrospective report of 655 patients,52 a subgroup of 87 patients had an estimated glomerular filtration rate (eGFR) of less than 45, and of this subgroup, 16% required dialysis within 100 days of ASCT. Among patients with eGFR of ≥45, 6% required dialysis within 100 days of ASCT. In another retrospective report of 173 patients with AL
amyloidosis who underwent ASCT, 21% developed acute kidney injury (AKI) during ASCT and 5% required dialysis. The risk factors for AKI were low creatinine clearance, high urinary protein, cardiac involvement, and bacteremia during the ASCT course.53 Therefore, at Mayo, we generally refrain from transplanting patients with CrCl ≤30 ml/min (unless they are on chronic dialysis).
Gastrointestinal toxicity may include diarrhea that can increase the length of hospitalization, worsen preexisting hypoalbuminemia, and result in higher use of antibiotics. Age and impaired kidney function are risk factors for severe
diarrhea.54 Cardiac decompensation may result from excessive fluid administration.
The timing of transplant, upfront or at relapse, remains a debatable issue, with limited published data and no prospective trials. Some centers use ASCT only in patients who fail to achieve deep responses to induction,55 while other centers transplant all eligible patients up front. Patients who are not transplant eligible at diagnosis may become eligible if they attain organ response after up-front therapy.
In an attempt to address “intention to treat” in the context of “early and delayed transplant”, all 651 patients with AL amyloidosis whose stem cells were collected at the Mayo Clinic between 2004 and 2018 were included in a retrospective analysis. Patients were divided into 2 groups: those transplanted early (ASCT within 90 days of stem cell collection) and those who had ASCT later. There was no OS difference between early and delayed ASCT.56 In the subgroup that achieved VGPR or better prior to stem cell collection, there was a trend towards superior OS in the early transplant cohort, but the difference was minor (median OS, 14 vs 13 years, respectively). Similar results were reported in a retrospective United Kingdom (UK) study.57
The Amyloidosis Group from Pavia, Italy, has proposed a sequential response-driven approach. The authors reported the outcomes of 139 newly diagnosed patients who were treated with VCd induction. Only those patients who achieved less than a VGPR were given an ASCT.55 The hematologic response to VCd was 68%, with 51% achieving ≥VGPR. Forty percent of the cohort underwent ASCT, and their overall hematologic response rate was 80%, with 65% achieving VGPR or better. There was no OS difference (5-year OS, 86% vs 84%, respectively) nor a significant difference in the duration of response between the 2 groups (60 vs 49 months). Of note, 21 patients (15%) did not achieve VGPR or better but did not undergo ASCT because of refusal or ineligibility. With rescue chemotherapy, they had a 5-year OS of 51%. An interesting UK study reported the outcomes of 22 AL amyloidosis patients who were initially transplant ineligible but became transplant eligible after bortezomib-based therapy. There was no TRM, and 77% achieved VGPR or better and 86% achieved cardiac response.58
As induction is used more and more, some patients come to stem cell collection in complete response—fewer, but some, are even minimal residual disease
(MRD) negative.59-61 With VCd, nearly 20% of patients may achieve CR; in
contrast, more than 50% of patients receiving daratumumab + VCd achieve CR. No good guidance exists regarding what to do in these instances. Does one collect and store stem cells? Does one consolidate with transplant? It is known that post ASCT, 34% to 40% of patients achieve CR, and patients achieving CR have a 10-year OS of 75%.62,63 In a retrospective study that explored the characteristics of 186 patients with AL amyloidosis who survived more than 10 years, achieving complete hematologic response was predictive of treatment-free survival, whereas ASCT was not predictive in the multivariate analysis.64
Consolidation post ASCT is an appealing intervention for those patients who do not achieve deep hematological responses, but prospective data on this topic are in short supply. Using a risk-adapted conditioning approach in 83 patients—post-ASCT thalidomide or bortezomib consolidation—CR rates increased from 24% at day 100 to 48% at 12 months.50
Patients consolidated with bortezomib achieved outstanding CR rates (62%). Patients who achieved CR via ASCT had comparable event-free survival and OS with patients who achieved CR via ASCT and consolidation. In a retrospective series of 471 patients who underwent ASCT at our institution, 15% received consolidation.65 Comparing the patients who received consolidation with those who did not, the no-consolidation patients had inferior PFS and OS; however, focusing on the subset of 91 patients who did not achieve VGPR or better post ASCT, those receiving consolidation had a superior PFS compared with those who did not receive consolidation (22 months vs 9 months, respectively; P <.001). OS was not different between these 2 groups. When the OS analysis was limited to those patients who received consolidation and upgraded their response, this subgroup had better survival compared with those with inadequate response who did not receive consolidation (5-year OS, 79% vs 52%; P = .07). At the Mayo Clinic, we consider patients who have not achieved at least a VGPR as refractory, and we treat them with second-line therapy (Figure).
Maintenance after ASCT has not been prospectively evaluated, and a trial evaluating ixazomib (Ninlaro) as maintenance therapy post ASCT is ongoing. In a retrospective study, 25 patients received maintenance and 25 didn’t, and maintenance did not impact OS or PFS.66 At the Mayo Clinic, we use maintenance for patients with overt multiple myeloma (patients who fulfilled CRAB criteria at diagnosis) and consider it for patients with >20% BMPC and high-risk genetics.
ASCT leads to deep and durable responses57 in a disease where the depth of clonal control directly influences long-term organ function and survival. The first report of outcomes of ASCT in 5 AL amyloidosis was published in 1996,67 and ever since several centers gained long-term experience with ASCT in AL patients.42,47 Over the years, results of transplanted patients have become more and more favorable, with complete response (CR) rates as high as 40% and low relapse rates,42 with a good prognosis for long-term long survival among patients who achieve deep response.48,56
A matched case-control study that compared outcomes of 63 patients with AL amyloidosis who underwent ASCT with those of 63 similar patients who were not transplanted showed better OS in the ASCT cohort (71% vs 41%, respectively).68 However, these results were contradicted by those of the only prospective randomized controlled trial that compared ASCT with no ASCT (oral melphalan and dexamethasone) in AL amyloidosis. This study reported inferior survival in the ASCT arm (median OS, 22.2 vs 56.9 months).69 The inferior outcomes were considered by many to be related to the exceptionally high TRM (24%) in the ASCT group. The highest mortality rates occurred at transplant sites that had less experience transplanting patients with AL amyloidosis.70 A prospective study published by our group evaluated ASCT vs chemotherapy based on patient selection. The 3-year PFS (29.1% vs 51.7%) and OS (58.8% vs 83.6%) rates were higher in the ASCT arm, while the hematologic response rates were similar. However, this study did not meet its accrual goal and therefore was underpowered to determine differences in outcomes between the ASCT arm and the non-ASCT arm.71
In the era of novel agents, a retrospective study of 72 patients showed superiority of ASCT. Patients receiving ASCT were more likely to achieve deep responses (≥VGPR) and had higher PFS (not reached vs 9 months), OS (74 vs 9 months), and duration of response (DOR; 31 months vs 7 months).72 A systematic review and meta-analysis published in 2009 failed to show that ASCT improves outcomes vs conventional chemotherapy,73 but the quality of the evidence was low. A recently published retrospective case-matched study compared ASCT with bortezomib and showed no significant difference in any of the following: OS at 2 years, median PFS, time to next treatment, overall hematological responses at 6 months, or organ responses at 12 months.23
Long-term survival data coming from several centers are encouraging. In a long-term report of 159 patients with AL amyloidosis who were transplanted at Mayo Clinic, 47 patients (30%) survived more than 15 years.47 Survival was longer in patients without cardiac involvement, in those who achieved hematological CR, and in patients who received full-dose melphalan. In a report from the UK group, 33% of 264 patients survived at 20 years, and the median OS was 7.2 years.74
In a report from the Boston University group, of 692 patients with AL amyloidosis who underwent ASCT between 1994 and 2014, the median OS was 7.6 years and hematologic CR was achieved in 40% of evaluable patients.42 Thirty percent of the cohort survived more than 20 years. Hematologic relapse occurred in 32% of patients who had achieved CR at a median of 4.3 years, with a median OS in those patients of 8.5 years.75
Several open questions remain, and they can be answered only by further clinical trials. Daratumumab therapy has changed the landscape of treatment of AL amyloidosis, generating deep and durable responses and having a very good safety profile. Venetoclax (Venclexta), a well-established therapy for multiple myeloma, is also an appealing treatment option for AL amyloidosis since 50% of this population harbors translocation t(11;14). The question of whether ASCT is superior to the current standard of care remains open, and a prospective randomized controlled trial clarifying this issue in AL amyloidosis is critically needed. Should ASCT be done in patients who achieve MRD negativity after induction, or even CR? Prospective clinical trials that incorporate updated measures of outcome are necessary to evaluate the long-term outcomes of different groups—patients who achieve deep responses prior to transplant vs patients who achieve deep responses after transplant vs patients who do not undergo ASCT—are warranted. Despite these unprecedented advances in treating AL amyloidosis, we still believe ASCT is important in its treatment paradigm.
Financial Disclosure: AD serves on the advisory board and independent review committee for Janssen and data monitoring safety committees for Oncopeptides and Sorrento and receives research funding from Alynlam, Pfizer, Takeda, and Bristol Myers Squibb.
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