Autografting

Refinement in patient selection to reduce treatment-related mortality from autologous stem cell transplantation in amyloidosis

Abstract

This study sought to develop selection guidelines to determine the eligibility for SCT of patients with light-chain amyloidosis. Patients with biopsy-confirmed lightchain amyloidosis who underwent SCT between 8 March 1996 and 31 December 2011 were reviewed in two cohorts by date of transplantation: between 8 March 1996 and 30 June 2009 (n=410) and between 1 July 2009 and 31 December 2011 (n=89). Also evaluated were patients who died before post-transplant day 100 to determine the features predictive of early death. After 1 July 2009, fewer transplant recipients had Mayo stage III cardiac involvement. Mortality before post-transplant day 100 was 10.5% (43/410) in the earlier group and 1.1% (1/89) in the later group. In the earlier group, one-quarter of transplant recipients with N-terminal pro-brain natriuretic peptide (NT-proBNP) >5000 pg/mL died by 10.3 months. When serum troponin T was >0.06 ng/mL, 25% died at 3.7 months. The Mayo staging system is predictive for OS but not useful for selecting transplant recipients. Patients with serum troponin T >0.06 ng/mL or NT-proBNP >5000 pg/mL (not on dialysis) should not be considered candidates for SCT because of early mortality.

Introduction

Ig light-chain amyloidosis (also called primary systemic amyloidosis or amyloid light chain amyloidosis) results from the deposition of Ig fragments in visceral organs. The deposition of amyloid fibrils leads to dysfunction of the organs and death of the patients.1 Although patient survival has improved over the past 15 years,2 their prognosis remains serious. When SCT was introduced, few effective alternative treatments were available.3 At that time, combination therapy with melphalan and prednisone was the primary nontransplant option, with a median survival of only 18 months. Since that time, the introduction of melphalan and dexamethasone has seriously challenged the concept of high-dose therapy for amyloidosis.4 In a single, prospective randomized study, SCT was found not superior to conventional therapy with melphalan and dexamethasone.5 However, this study had serious patient selection issues insofar as the treatment-related mortality associated with transplant was 24%, making it nearly impossible to show any benefit from the technique. The acceptable treatment-related mortality for transplant at one point was 10–15%,6 although studies have shown mortality rates of 40%.7 A high mortality rate with SCT is no longer acceptable because lower-risk alternatives, including lenalidomide-based8, 9 and bortezomib-based10 therapies, have been introduced, with much lower immediate risk to patients. Any attempt to advance the field of SCT requires highly refined patient selection criteria so that patients can be offered SCT safely. As a consequence of this reduced acceptability of transplant-related mortality in the era of novel agent alternatives, we narrowed our criteria for transplant eligibility at the end of 2008. In this retrospective study, we reviewed the outcomes to determine whether fixed cutoffs could be recommended for eligibility. The purpose of this study was to determine the appropriate criteria for transplant centers that see small numbers of these patients to identify those patients who can receive transplants without excessive risk.

Patients and methods

This study was approved by the Mayo Clinic Institutional Review Board. In addition, in accordance with Minnesota state law, each patient considered in this study must have given written consent for medical record review. We reviewed patients with biopsy-confirmed Ig light-chain amyloidosis who underwent SCT between 8 March 1996 and 31 December 2011.

The study performed two patient comparisons. In the first, all patients who received transplants between 8 March 1996 and 30 June 2009 were compared with those who received transplants between 1 July 2009 and 31 December 2011 to determine differences between the two groups. The second study compared all transplant recipients who died from any cause before post-transplant day 100 with those who survived beyond day 100 to determine features predictive of early death.

All patients had amyloidosis confirmed histologically with Congo red tissue biopsy specimen.11 In the past 5 years of the study interval (2007–2011), every patient had mass spectroscopic analysis on the amyloid tissues to validate whether the protein subunit was Ig light chain or heavy chain.12 Before that time, the diagnosis required a serum or urine monoclonal protein in the serum or urine or clonal plasma cells in the BM, negative results from transthyretin screening of amplified DNA, and no evidence of fibrinogen amyloidosis on a renal biopsy specimen.13 No patients with light-chain amyloidosis localized to a nonvital organ, such as the skin or carpal ligament, were included for SCT.

The standard baseline evaluation of patients included immunofixation of serum and urine. An echocardiogram was performed in all patients. In 2004, Ig-free light-chain assays were introduced. PCR analysis was introduced in 1996,14 but transthyretin screening was not clinically introduced into routine clinical care at Mayo Clinic until 2005. Troponin T and N-terminal pro-brain natriuretic peptide (NT-proBNP) screening began in 2006.

All transplant recipients received at least 1.98 × 106 CD34+cells/kg. Apheresis was performed by standard techniques, processing 11–14 L of blood in a 4-h period.15 Patients were conditioned, infused and monitored on an outpatient basis, as previously reported.16 Hospitalization occurred only in the event of a fever that could not be controlled with outpatient antibiotics, mucositis or dehydration.17 Supportive care was standard for transplant after myeloablative chemotherapy and included a prophylactic fluoroquinolone antibiotic, fluconazole, acyclovir and penicillin. Growth factors were not administered after stem cell infusion.

The criteria for hematological and organ responses have been previously published.18 NT-proBNP and troponin levels were incorporated into organ response criteria, as defined by consensus,19 for patients for whom these values were available.

Patient data were entered into a continuously updated database (JMP version 9.0.1, SAS Institute, Inc., Cary, NC, USA). Differences between groups were analyzed using the Kruskal–Wallis rank sum test for continuous variables and the Fisher’s exact test for discrete variables. All probabilities reported are two-tailed. Significance was defined as P<0.05. Survival was based on the Kaplan–Meier method.

Results

Of the 499 patients identified, none was lost to follow-up, and survival data were complete. Before 1 July 2009, 410 patients underwent auto-SCT. Forty-three of these patients died before post-transplant day 100 (10.5%). From that date onward, 89 patients underwent transplantation, with 1 death before post-transplant day 100 (1.1%). The goal sought by our transplant group was to try to create selection criteria that could make transplantation for amyloidosis as safe as it is for multiple myeloma. We set our criteria at an all-cause d+100 mortality of 2%. A logistic fit of therapy-related mortality by NT-proBNP level was performed and a receiver operating characteristic curve was generated. The 2% probability of early death fell at NT-proBNP between 4700 and 5400, and hence 5000 was selected as the cutoff for analysis. Table 1 lists the characteristics of those patients selected for transplantation in the two time periods. After 1 July 2009, there was a significant reduction in patients with Mayo stage III cardiac involvement, a slightly lower serum creatinine level, and a slightly lower pretreatment-involved free light-chain level. In the earlier group, the NT-proBNP level in the highest decile was >6537 pg/mL, whereas in the later group, the highest decile had an NT-proBNP level >4023 pg/mL, reflecting the increased reluctance of our group to perform transplants on patients with extreme elevations of NT-proBNP.

Table 1 Comparison of patients receiving transplants before and after 1 July 2009

The one patient in the later group who died before post-transplant day 100 was a 54-year-old man with λ light-chain amyloid and a pretransplant-free light chain level of 63.4 mg/dL, with renal and cardiac amyloid, a pretransplant NT-proBNP level of 5408 pg/mL, and a serum troponin T level of 0.02 ng/mL. He was conditioned with melphalan 140 mg/m2, and died on post-transplant day 36 of sudden cardiac arrest, having achieved full engraftment of neutrophils 24 days before death and full engraftment of platelets (>50 × 109/L) 21 days before his death. The cardiac arrest occurred 2 weeks after hospital discharge. An autopsy was not performed.

During this 30-month period, six patients with an NT-proBNP level >5000 pg/mL received transplants. Two of these patients, however, were on dialysis, which can have a profound effect on the level of NT-proBNP,20 and one of these two was not believed to have cardiac amyloidosis. Four of the six are alive, one having died 9.6 months after transplant, from a severe upper gastrointestinal tract hemorrhage following dialysis, possibly related to heparin administration.

Table 2 provides the characteristics of the 43 patients who received their transplants before 1 July 2009 and who died before post-transplant day 100. These patients were compared with longer-term survivors who received transplants during the same period. The comparison revealed significant differences between the two groups in Mayo stage, clinically defined cardiac involvement, septal thickness, and levels of creatinine, troponin T, free light chain, albumin and BNP. The NT-proBNP level was >5000 pg/mL in 41 patients. Of the 41 patients, 7 had a serum creatinine level >1.8 mg/dL. Two had serum creatinine levels of 2.0 and 2.2 mg/dL, respectively. Five were transplanted on stable dialysis with creatinine levels of 5.9, 8.0, 10.1, 12.0, and 12.4 mg/dL, respectively. All seven survived >9 months post SCT. The median survival of the 41 patients was 27 months, but 10 (25%) of them had died by 10.3 months (Figure 1).

Table 2 Survival (before/after post-transplant day 100) in 410 patients who received transplants before 1 July 2009
Figure 1
figure1

Survival of BM transplant recipients with an N-terminal pro-brain natriuretic peptide level higher than (N=41, bold) and lower than (N=327, narrow) 5000 pg/mL. P=0.0003.

We reviewed the transplant recipients whose serum creatinine level was >1.8 mg/dL and who were not on chronic stable dialysis at the time of transplantation. Thirty-four patients were identified, five of whom died before post-transplant day 100. However, 21 of these patients are still alive. The median survival for the entire group has not been reached, and 60% were alive at 72 months, the longest survivor now at 170 months.

Thirty-seven patients had troponin T levels >0.06 ng/mL. Nine of these patients (25%) had died at 3.7 months, and at the time of this writing 24 of 37 patients have died. The median survival of these patients with high troponin levels was 26.1 months (Figure 2). We identified 72 Mayo stage III patients in this study, and 31 (43%) survive at 5 years (Figure 3). Of the 72, 27 had an NT proBNP >5000 pg/mL (38%). The d+100 all-cause mortality of these 27 patients, who would have been excluded from SCT using the proposed new criteria, was 4/27 (15%), considered unacceptable. Conversely, there were 24 stage III Mayo patients with both troponin level <0.06 ng/mL and NT-proBNP level <5000 pg/mL. The median survival of this cohort is 66.1 months, with 15 of the 24 alive with a median follow-up of the survivors of 39.1 months. There were 71 patients transplanted having either a troponin T >0.06 ng/mL or NT-proBNP >5000 pg/mL. Twelve died before day 100, with an all-cause mortality of 17%. Median survival of the 71 patients was 27.9 months.

Figure 2
figure2

OS of transplant recipients with troponin T level higher than (N=49, bold) and lower than (N=396, narrow) 0.06 ng/mL. P<0.0001.

Figure 3
figure3

Survival of Mayo stage III (N=72, bold) transplant recipients compared with stage I and II (N=294, narrow). P<0.0001.

Discussion

The value of SCT in the treatment of amyloidosis remains controversial. Its use is more common in the United States than in Great Britain, where only 1% of amyloidosis patients receive transplants, and it is not widely used in other European countries.21 SCT in the era of novel agents, with proven high response rates, cannot be justified until the post-transplant mortality rate is reduced to levels seen in multiple myeloma patients who receive transplants.22 Investigators at Boston University23 reviewed 421 patients and demonstrated a significant decline in treatment-related mortality over time (same definition of treatment-related mortality as ours, post-transplant day 100). The mortality among 297 patients who received transplants between 1994 and 2003 was 13.8%. A similar group of 124 patients who received transplants from 2004 through 2008 had a treatment-related mortality of 5.6%. This declining mortality is in accord with what we are currently seeing, with improved supportive care and refined patient selection. They also noted that in patients who were on dialysis the treatment-related mortality was 8%, and that in patients with cardiac involvement BNP levels were predictive of mortality at 100 days.23 Combination treatment with melphalan and dexamethasone has been reported to be highly effective, with the median survival in the 5-year range and low treatment-related mortality. However, others have not had good results, with a median survival of 1 year, presumably related to the higher proportion of cardiac amyloidosis.24, 25 In the former of these two studies, patients had advanced cardiac amyloidosis as defined by NYHA class greater than stage II, systolic blood pressure <90 mm Hg or symptomatic pleural effusion.

To justify SCT, criteria need to be established so that centers that see only a few of these patients annually can select those who can receive transplants safely and then be considered for post-transplant consolidation therapy to achieve the desired state of very good PR or CR.26, 27 We believe that the criterion that would lead to exclusion of patients destined not to tolerate high-dose therapy is a serum troponin T level >0.06 ng/mL, which has been previously reported.28 However, we now add the criterion of an NT-proBNP level >5000 pg/mL. We believe the mortality rates seen with an NT-proBNP level >5000 pg/mL make SCT an unacceptable alternative unless preinduction chemotherapy were to reduce this cardiac biomarker to levels that would render transplantation a safer procedure.29 We do not believe the serum creatinine is a clear criterion for exclusion, although the risk of acute renal injury and the need for dialysis support during transplantation is sharply increased by high levels of proteinuria or elevations in serum creatinine.30, 31 We became more restrictive in 2008, selecting patients eligible for transplantation based on our analysis of predictors of early mortality. By restricting transplantation to patients with NT-pro BNP <5000, we automatically saw a population with less cardiac involvement. Moreover, as NT-proBNP is renally excreted, some patients would have an elevated NT-pro BNP owing to renal failure. There were seven such patients whose cardiac biomarkers may be directly related to renal insufficiency.

We have previously reported the number of involved organs as being a critical criterion for high risk after transplant, but we increasingly have come to believe that this criterion is unreliable.32 We believe that concordance in counting organs is poor among various medical centers. Moreover, there are those patients who have proven organ involvement but minimal organ dysfunction, which is quite different from patients who have organ involvement and advanced dysfunction. Organ counting is a somewhat subjective criterion, and the inability to distinguish mild from advanced organ involvement is a barrier to its optimal use. Patients with soft-tissue involvement, including the tongue, periarticular amyloid or claudication, are difficult to integrate into an organ-counting scheme. Therefore, we believe that use of cardiac biomarkers is a better and more reproducible method to ensure safe outcomes.

The Mayo staging system has been validated to be useful in predicting survival both in patients who receive high-dose therapy as well as in those who receive standard-dose therapy at the time of diagnosis.33, 34 However, the cutoffs for the stages are serum troponin <0.035 ng/mL and NT-proBNP <332 pg/mL. Although these criteria clearly separate patients into three groups with very significant differences in OS, this does not necessarily mean that the Mayo amyloidosis staging system is a useful tool to select patients for SCT.35 Patients with advanced cardiac amyloidosis are destined to do poorly irrespective of whether they are treated with novel agents or SCT. In fact, the early mortality rate for patients with amyloidosis seen at Mayo Clinic has not improved in nearly 40 years.2 Simply excluding patients with Mayo stage III from participation in clinical trial protocols or SCT appears to be too stringent, and many patients who have moderate cardiac involvement may benefit from high-dose therapy and SCT. In this study, we identified 72 Mayo stage III patients, and 31 (43%) survive at 5 years. Clearly, the majority of patients that we would exclude from transplant selection would be Mayo stage III, but the converse is not true. The majority of patients with Mayo stage III disease can have a very good outcome after SCT. Ten patients (11%) with Mayo stage III disease received transplants after 1 July 2009. Although the follow-up is short, the 1-year survival is 80% (8/10). In the 30 months since the changes were instituted, our transplant volumes were 2.97 transplants a month. For the 42 months before the change, we were transplanting 3.45 each month. The new criteria reduced our transplant volume by 14%, but resulted in fewer therapy-related deaths. Nonetheless, this represents a retrospective analysis of data with all the inherent biases. We believe these criteria would still be useful for transplant centers that are asked to consider intervention in amyloidosis patients if seen infrequently.

In conclusion, we believe the most rational approach is to exclude patients from transplantation based on their cardiac biomarker status, eliminating those patients whose troponin T is >0.06 ng/mL, based on our previously published criteria but validated in this larger cohort by adding NT-proBNP level >5000 pg/mL as an exclusion criterion as well. These patients should be considered for less toxic therapy, including novel agent-based treatment, alkylator-based treatment or participation in clinical trials.

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Correspondence to M A Gertz.

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The authors declare no conflict of interest.

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Author Contributions

All authors were involved in study conception, data analysis and acquisition.

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Keywords

  • amyloidosis
  • diastolic heart failure
  • multiple myeloma
  • nephrotic syndrome
  • SCT

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