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Stem Cell Transplantation for Light Chain Amyloidosis: Decreased Early Mortality Over Time

Publication: Journal of Clinical Oncology

Abstract

Purpose

Autologous stem-cell transplantation (ASCT) has been used in patients with immunoglobulin light chain (AL) amyloidosis for more than two decades. Early experience raised concerns regarding safety with high early-mortality rates.

Patients and Methods

We report 20 years of experience with ASCT for AL amyloidosis at the Mayo Clinic Rochester. In all, 672 consecutive patients receiving ASCT for AL amyloidosis were divided into three cohorts on the basis of date of transplantation (cohort 1, 1996-2002 [n = 124]; cohort 2, 2003-2009 [n = 302]; and cohort 3, 2010-2016 [n = 246]).

Results

The median age for the entire cohort was 59 years, with patients in cohort 3 being slightly older than those in the other two cohorts (60 v 58 v 54 years for cohorts 3, 2, and 1, respectively; P < .001). Fewer patients in cohort 3 had more than two organs involved (9% v 18% v 19% for cohorts 3, 2, and 1, respectively; P < .001). More patients received pretransplantation therapy in cohort 3 compared with earlier time periods (49% v 38% v 42% for cohorts 3, 2, and 1, respectively; P = .02). Hematologic response was higher in cohort 3 (84% v 79% v 69% for cohorts 3, 2, and 1, respectively; P = .002). Median overall survival for the entire cohort was 122 months and improved over time (not reached v 120 months v 75 months for cohorts 3, 2, and 1, respectively; P < .001). Treatment-related mortality declined over time (2.4% v 8.6% v 14.5% for cohorts 3, 2, and 1, respectively; P < .001). On multivariable analysis, conditioning dose, Mayo stage 2012, and hematologic response were independent predictors of survival.

Conclusion

ASCT is a highly effective therapy for AL amyloidosis. The improved survival and markedly reduced treatment-related mortality in eligible patients indicate that this will remain an important first-line option even in the era of treatment approaches that use novel agents.

Introduction

Immunoglobulin light chain (AL) amyloidosis is a multisystem disorder characterized by a plasma-cell or B-cell clone producing misfolded light chain proteins that deposit in tissues and cause tissue damage and organ dysfunction.1,2 The treatment of AL amyloidosis has traditionally focused on elimination of the plasma-cell clone responsible for the production of the amyloidogenic protein, and treatment regimens have largely been derived from those used in multiple myeloma (MM). The success of autologous stem-cell transplantation (ASCT) in MM led to investigation of this approach in AL amyloidosis. Early experience and clinical trials with this approach highlighted significant safety concerns with reports of treatment-related mortality (TRM) ranging from 13% to 43%.3-5 Several patient- and disease-related factors were identified as predictive of a high TRM, particularly cardiac involvement, which led to the development of risk-adapted approaches for the use of ASCT in AL amyloidosis that showed a reduction in TRM over time.6-9
The introduction of novel agents for treating MM provided several alternative therapies directed against the plasma-cell clone in patients with systemic amyloidosis. Immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies have been studied in numerous clinical trials in newly diagnosed and relapsed or refractory patients with AL amyloidosis, with promising results in terms of both hematologic and organ response.10-15 In addition, newer agents aimed at clearing amyloid light chain that has already deposited in organs are currently being investigated.16 We reviewed the Mayo Clinic experience of ASCT in AL amyloidosis to assess trends in safety and efficacy over time during the era of novel therapies, and we report extended outcomes with monitoring over a period of 20 years.

Patients and Methods

We retrospectively reviewed data on all patients with biopsy-proven systemic AL amyloidosis who underwent ASCT between March 8, 1996, and August 31, 2016. The study was approved by the Mayo Clinic Institutional Review Board.
Patients were divided into three study cohorts of approximately equal time span on the basis of date of stem cell transplantation (ASCT): cohort 1 (1996-2002), cohort 2 (2003-2009), and cohort 3 (2010-2016). The time periods were chosen to allow for assessment of changes in patient characteristics, treatment practices, and outcomes over time.
Organ involvement was defined according to consensus criteria.17 To identify the number of organs involved, heart, kidney, liver, peripheral or autonomic nerves, and other organs (soft tissue and GI tract) were included as involved or not involved. For bone marrow plasma cells, the highest estimate on the aspiration and biopsy was used. Risk stratification was according to the 2004 Mayo and 2012 revised Mayo staging systems.18,19
Selection criteria for ASCT in AL amyloidosis have undergone significant modification over the time period of the study and warrant further clarification. Two major advances over the years in treatment of AL amyloidosis have had a significant effect on our institution’s selection criteria for ASCT for patients with AL amyloidosis. First, the availability of novel agents, particularly the introduction of bortezomib in 2005 as a therapeutic option for AL amyloidosis, had a profound effect on our willingness to provide transplantation for higher-risk patients. In addition, the availability of these agents before transplant may have helped improve organ function to reduce toxicity from ASCT. Second, our understanding of high-risk disease features in AL amyloidosis has significantly improved over time. Our criteria for eligibility for ASCT in the early time period focused on performance status, serum creatinine, and alkaline phosphatase.20 However, these criteria evolved over the years. We added troponin, severe autonomic failure, N-terminal prohormone brain natriuretic peptide (temporarily), and systolic blood pressure to our selection criteria in a sequential manner as data emerged showing the prognostic effect of these factors on ASCT outcomes.21-24 These data have helped shape our current consensus guidelines on selection criteria for patients with AL amyloidosis undergoing ASCT, which include age 70 years or younger, Eastern Cooperative Oncology Group performance score ≤ 2, systolic blood pressure ≥ 90 mmHg, troponin T ≤ 0.06 ng/mL, creatinine clearance ≥ 30 mL/min, New York Health Association functional class I or II, and no more than two organs significantly involved. Our institutional policy was strict adherence to the selection criteria available at the time of transplantation. However, individual physician assessment was an important factor in selecting patients, and the variable most dependent on this was assessment of physiological age.
Patients were mobilized and conditioned and received transplantation according to previously published institutional protocols.25 Response was measured at approximately 100 days after ASCT according to updated consensus criteria.26 Data regarding immunoglobulin free light chains were limited before 2003, and response assessment for cohort 1 was based on criteria that were accepted before the assay was available.17
Statistical analysis was performed by using JMP software (SAS Institute, Cary, NC). Patient- and disease-related factors were compared by using the χ2 test for categorical variables and the Wilcoxon signed rank test for continuous variables. Survival analysis was performed by using the Kaplan-Meier method. Overall survival (OS) was calculated from day zero of bone marrow transplantation to death as a result of any cause. TRM was defined as death as a result of any cause within 100 days of ASCT. The Cox proportional hazards model was used to assess for predictors of OS. The variables included in the univariable analysis were time period, age, sex, number of organs involved, bone marrow plasma cells, Mayo stage 2012, conditioning dose, pretransplantation chemotherapy, and hematologic response. Variables reaching a P value < .1 were included in the multivariable analysis.

Results

The bone marrow transplantation program for AL amyloidosis at the Mayo Clinic began in 1996, and between March 8, 1996, and August 31, 2016, a total of 672 patients underwent ASCT for systemic AL amyloidosis. The proportion of new referrals seen for AL amyloidosis at our institution who received an ASCT in each time period was 21% in cohort 3, 22.6% in cohort 2, and 12.9% in cohort 1. Table 1 lists the baseline characteristics for the entire cohort by time period of transplantation. The median age for the entire cohort was 59 years, with patients in the most recent time period (cohort 3) being slightly older (60 v 58 v 54 years for cohorts 3, 2, and 1, respectively; P < .001). There was a higher proportion of men in each cohort, consistent with earlier reports of the higher prevalence of systemic amyloidosis in men.27 The rates of cardiac and neurologic involvement were not significantly different across time periods. The median N-terminal prohormone brain natriuretic peptide was 490 pg/mL in cohort 1 (n = 61), 657 pg/mL in cohort 2, and 453 pg/mL in cohort 3 (P = .21). Fewer patients presented with renal or hepatic involvement in cohort 3 compared with cohorts 2 and 1 (60% v 70% v 68% for renal involvement in cohorts 3, 2, and 1, respectively; P = .03; 7% v 13% v 17% for hepatic involvement in cohorts 3, 2, and 1, respectively; P = .02). In addition, fewer patients in cohort 3 had extensive organ involvement (defined as more than two organs involved) than the earlier cohorts (9% v 18% v 19% for cohorts 3, 2, and 1, respectively; P = < .001).
Table 1. Baseline Characteristics
The majority of patients had a plasma-cell clone with lambda light chain restriction in each cohort (67% v 77% v 73%). The fraction of patients with more than 10% bone marrow plasma cells was lower in cohorts 3 and 2 compared with cohort 1 (41% v 39% v 53% for cohorts 3, 2, and 1, respectively; P = .03). Mayo stage was available for 537 patients by 2004 criteria and 491 patients by 2012 criteria (Table 1).
Conditioning was performed with full-intensity melphalan 200 mg/m2 in 69% of patients and with reduced-intensity melphalan < 200 mg/m2 in 30% of patients (87% received melphalan 140 mg/m2). Six patients (1%), all in cohort 3, received conditioning with carmustine, etoposide, cytarabine, and melphalan (BEAM). The number of patients receiving full-intensity conditioning was greater in cohort 3 compared with cohorts 2 and 1 (76% v 66% v 65% for cohorts 3, 2, and 1, respectively; P = .001). Pretransplanation chemotherapy was given in 43% of patients. The number of patients receiving therapy before transplantation was greater in cohort 3 compared with earlier time periods (49% v 38% v 42% for cohorts 3, 2, and 1, respectively; P = .02). Predictably, the number of patients receiving corticosteroid alone before transplantation decreased over time, and the use of novel agents increased. Within cohort 3, 38% of patients received a bortezomib-containing regimen before transplantation. The majority of patients (69%) received a transplantation within 6 months of diagnosis of amyloidosis. The number of patients transplanted within 6 months of diagnosis was lower in cohort 3 compared with cohorts 2 and 1 (64% v 76% v 61% for cohorts 3, 2, and 1, respectively; P = .004). This is mainly a result of the increased use of pretransplantation induction chemotherapy.

Hematologic Response

Data regarding response was available in 95% of patients. Response assessment did not include light chain assessment for patients in cohort 1 (a requirement for the grade very good partial response [VGPR]). Overall response (complete response [CR], VGPR, or partial response) was higher in cohort 3 than cohorts 2 and 1 (84% v 79% v 69% for cohorts 3, 2, and 1, respectively; P = .002). The rates of CR were similar across the three time periods (39% v 43% v 32% for cohorts 3, 2, and 1, respectively; P = .1). Figure 1 summarizes the response data for the entire cohort by time period.
Fig 1. Response rates for the entire cohort and by time period. CR, complete response; NA, not available; NR, no response; PR, partial response; VGPR, very good partial response.

Survival

Median follow-up of survivors was 78 months (interquartile range, 43 to 127 months). Median OS for the entire cohort was 122 months. Median OS improved over time (not reached v 120 months v 75 months for cohorts 3, 2, and 1, respectively; P < .001; Fig 2A). Hematologic response has been shown to be a strong predictor of outcome in patients with amyloidosis.26 Median OS was 187 months for patients achieving a CR, 105 months for VGPR, 74 months for partial response, and 16 months for NR (P < .001; Fig 2B). Median OS by Mayo stage 2012 was 187 months for stage I, 161 months for stage II, 65 months for stage III, and 100 months for stage IV (P < .001; Fig 2C). Patients receiving full-intensity melphalan had a longer median OS compared with patients who received reduced-intensity conditioning (169 v 54 months, respectively; P < .001; Fig 2D).
Fig 2. Overall survival (A) by time period of stem cell transplantation, (B) according to hematologic response, (C) by Mayo stage 2012, and (D) by melphalan conditioning dose. CR, complete response; NR, no response; OS, overall survival; PR, partial response; VGPR, very good partial response.
There was no significant difference in OS on the basis of time from diagnosis to transplantation. Median OS was 131 v 121 v 97 months for time to transplantation of < 6, 6 to 12, and > 12 months, respectively (P = .65). Patients who received pretransplantation chemotherapy had an OS similar to that of patients who did not (median OS, 121 v 132 months; P = .46).
All-cause mortality through 100 days after transplantation for the entire cohort was 7.4%. Rates improved over time (2.4% v 8.6% v 14.5% for cohorts 3, 2, and 1, respectively; P < .001; Fig 3). Causes of death are listed in Table 2. Sepsis and cardiovascular events (including sudden cardiac arrest, arrhythmia, or pulmonary embolism) accounted for the majority (68%) of deaths for the entire cohort. Sepsis was the most common cause of death in cohort 3. The rates of cardiovascular events as the cause of death seemed to decrease over time (17% v 46% v 33% for cohorts 3, 2, and 1, respectively; P = .13); however, given the small number of events, this was not statistically significant.
Fig 3. Rates of all-cause mortality at day 100 after stem cell transplantation by time period.
Table 2. 100-Day All-Cause Mortality and Cause of Death

Univariable and Multivariable Analyses

Table 3 shows the results of the univariable and multivariable models for predictors of OS. Factors that predicted survival on univariable analysis included time period, age 65 years or older, bone marrow plasma cells ≥ 10%, Mayo stage, conditioning dose, and hematologic response. Independent predictors of OS on multivariable analysis were hematologic response, Mayo stage 2012, and conditioning dose.
Table 3. Univariable and Multivariable Analysis for Overall Survival

Discussion

Stem cell transplantation has been the standard for treating MM for more than 25 years and has been used as a treatment modality in AL amyloidosis for more than two decades.28 The rationale for using ASCT to treat amyloidosis is far better than that for myeloma. Unlike patients with MM, patients with amyloidosis tend to have a much lower tumor burden and less proliferative disease. At the time of transplantation, the majority of patients with amyloidosis, even without induction chemotherapy, have < 10% plasma cells in the bone marrow. In addition, unfavorable cytogenetics (as seen in nearly 25% of patients with MM) occurs in less than 5% of patients with amyloidosis.29,30 The most common genetic abnormality in amyloidosis is t(11;14), which predicts for resistance to bortezomib but has no effect on the outcome of ASCT. Deletion of 17p and t(4:14) is uncommon.31 Patients with MM frequently have a high proliferative rate in the bone marrow, which is seen in only a small fraction of patients with amyloidosis. In effect, transplantation for a patient with amyloidosis is akin to transplantation for a patient with monoclonal gammopathy of undetermined significance (low tumor burden, low proliferative rate, and favorable genetics), and the theoretical underpinning for transplantation favors its application in amyloidosis far more than in myeloma. Nevertheless, its effectiveness has remained controversial, and the only randomized controlled trial comparing it to chemotherapy showed no benefit and a high TRM (24%).5 A more recent nonrandomized prospective study conducted at our institution comparing chemotherapy to ASCT in patients who were eligible for transplantation, with treatment on the basis of patient preference, revealed similar response rates; improved 3-year progression-free survival and OS were seen in the ASCT arm.32
We report outcomes over a period of 20 years at our institution with positive results in terms of both safety and efficacy. The overall TRM of 7.4% is far lower than that reported in the randomized trial, and to the best of our knowledge, the TRM of 2.4% in the most recent time period represents the lowest reported 100-day all-cause mortality in a cohort of this size undergoing ASCT for AL amyloidosis. The response rate of 84% (CR, 39%) and 5-year OS of 84% in the most recent time period highlights the utility of ASCT in AL amyloidosis. In addition, the TRM is approaching that reported in myeloma in a recent nationwide study from the Danish Multiple Myeloma Registry, which reported a TRM of 2.1% for patients with MM receiving an ASCT.33 Supportive care for ASCT has not dramatically changed over time; however; eligibility for ASCT has undergone significant refinement over the years, and we believe the improvement in TRM largely reflects better patient selection on the basis of published data regarding high-risk features.24,34-36
The number of transplantations per year increased initially; however, it has fallen in the most recent time period (35 v 43 v 17 per year in cohorts 3, 2, and 1, respectively). This likely reflects the introduction of novel agents as alternative therapeutic options for patients with AL amyloidosis and the exclusion of higher-risk patients from ASCT.
Our study confirms the importance of hematologic response as a predictor of OS. Over time, the overall response rate improved; however, it must be noted that the number of patients receiving chemotherapy before transplantation was also greater in the most recent time period (49% v 38% v 42% for cohorts 3, 2, and 1, respectively; P = .02). The role of induction therapy before transplantation remains unclear; to date, results in clinical trials are mixed.37-39 Consolidation after transplantation remains an option for patients who did not achieve VGPR or better and has been shown to deepen the response achieved after ASCT. Conditioning dose of melphalan remained an important prognostic factor in our analysis. This may reflect in part the performance status and degree of organ involvement in patients who received reduced-intensity conditioning; however, given its independent effect on survival in our multivariable model, any reduction in melphalan conditioning dose needs to be carefully considered.
Our study was a single-center, retrospective study that took place over a long period of time; consequently, it has a number of limitations. Criteria for response assessment have evolved, and the immunoglobulin free light chain assay has become critical for response categorization. The assay was not available before 2003, so the VGPR category is not present in cohort 1. In addition, response assessment was based on data at approximately 100 days after ASCT, and response in patients who showed improvement in free light chains after this time point may be under-reported in patients who did not return to our center. The Mayo staging system was introduced in 2004 with assessment of cardiac biomarkers and refined in 2012 with the addition of the immunoglobulin free light chain assay. There were increased numbers of patients without data for accurate staging in cohorts 1 and 2. Both hematologic response and Mayo stage were strong predictors of survival on multivariable analysis, and the missing data may have affected our results. Selection criteria for ASCT in AL amyloidosis changed over time with improved understanding of high-risk disease features. Although this may be viewed as a limitation, our retrospective analysis has provided us with an opportunity to highlight the importance of patient selection in improving the safety of this therapy for amyloidosis.
In summary, our data show excellent results with ASCT for patients with AL amyloidosis and a marked reduction in toxicity over time. Our results contrast with those of the only randomized trial of ASCT in AL amyloidosis published a decade ago.5 Judicious patient selection is critical in ensuring that this treatment is delivered safely. The need to reassess ASCT in a controlled trial remains, particularly with the increasing availability of novel therapies. However, given the markedly improved safety and encouraging response rates with ASCT in eligible patients, careful consideration must be given to inclusion criteria for any such trial. Transplantation is associated with many patients who have survived for more than 15 years with many of them in continued response; no such data exist for patients treated with novel agents.

Authors' Disclosures of Potential Conflicts of Interest

Stem Cell Transplantation for Light Chain Amyloidosis: Decreased Early Mortality Over Time

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

M Hasib Sidiqi

Travel, Accommodations, Expenses: Amgen, Bristol-Myers Squibb, Novartis

Mohammed A. Aljama

No relationship to disclose

Francis K. Buadi

No relationship to disclose

Rahma M. Warsame

No relationship to disclose

Martha Q. Lacy

No relationship to disclose

Angela Dispenzieri

Consulting or Advisory Role: Prothena (Inst), GlaxoSmithKline (Inst)
Research Funding: Celgene (Inst), Janssen Oncology (Inst), Pfizer (Inst), Takeda (Inst), Alnylam Pharmaceuticals (Inst)
Travel, Accommodations, Expenses: Pfizer, Janssen Oncology, Prothena

David Dingli

No relationship to disclose

Wilson I. Gonsalves

Consulting or Advisory Role: Amgen (Inst)

Shaji Kumar

Consulting or Advisory Role: Takeda (Inst), Janssen Oncology (Inst), Amgen (Inst), Celgene (Inst), AbbVie (Inst), Merck (Inst), Kite Pharma (Inst), Oncopeptides
Research Funding: Celgene (Inst), Takeda (Inst), AbbVie (Inst), Novartis (Inst), Sanofi (Inst), Janssen Oncology (Inst), Merck
(Inst), Genentech (Inst), Kite Pharma (Inst)

Prashant Kapoor

Consulting or Advisory Role: Celgene, Sanofi
Research Funding: Takeda, Amgen, Celgene

Taxiarchis Kourelis

No relationship to disclose

William J. Hogan

No relationship to disclose

Morie A. Gertz

No relationship to disclose

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Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 1323 - 1329
PubMed: 29558277

History

Published online: March 20, 2018
Published in print: May 01, 2018

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Authors

Affiliations

M Hasib Sidiqi
All authors: Mayo Clinic Rochester, Rochester, MN
Mohammed A. Aljama
All authors: Mayo Clinic Rochester, Rochester, MN
Francis K. Buadi
All authors: Mayo Clinic Rochester, Rochester, MN
Rahma M. Warsame
All authors: Mayo Clinic Rochester, Rochester, MN
Martha Q. Lacy
All authors: Mayo Clinic Rochester, Rochester, MN
Angela Dispenzieri
All authors: Mayo Clinic Rochester, Rochester, MN
David Dingli
All authors: Mayo Clinic Rochester, Rochester, MN
Wilson I. Gonsalves
All authors: Mayo Clinic Rochester, Rochester, MN
Shaji Kumar
All authors: Mayo Clinic Rochester, Rochester, MN
Prashant Kapoor
All authors: Mayo Clinic Rochester, Rochester, MN
Taxiarchis Kourelis
All authors: Mayo Clinic Rochester, Rochester, MN
William J. Hogan
All authors: Mayo Clinic Rochester, Rochester, MN
Morie A. Gertz [email protected]
All authors: Mayo Clinic Rochester, Rochester, MN

Notes

Corresponding author: Morie A. Gertz, MD, MACP, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: [email protected].

Author Contributions

Conception and design: M Hasib Sidiqi, Mohammed A. Aljama, Francis K. Buadi, Rahma M. Warsame, Martha Q. Lacy, Angela Dispenzieri, David Dingli, Wilson I. Gonsalves, Shaji Kumar, Prashant Kapoor, William J. Hogan, Morie A. Gertz
Collection and assembly of data: M Hasib Sidiqi, Mohammed A. Aljama, Taxiarchis Kourelis, Morie A. Gertz
Data analysis and interpretation: M Hasib Sidiqi, Mohammed A. Aljama, Morie A. Gertz
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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M Hasib Sidiqi, Mohammed A. Aljama, Francis K. Buadi, Rahma M. Warsame, Martha Q. Lacy, Angela Dispenzieri, David Dingli, Wilson I. Gonsalves, Shaji Kumar, Prashant Kapoor, Taxiarchis Kourelis, William J. Hogan, Morie A. Gertz
Journal of Clinical Oncology 2018 36:13, 1323-1329

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