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1.
Risk factors, treatments and outcomes of patients with light chain amyloidosis who relapse after autologous stem cell transplantation
Zhang, Y., Guo, J., Chen, W., Zhao, L., Huang, X.
Bone marrow transplantation. 2023
Abstract
Relapse after ASCT is an important factor affecting the long-term prognosis of patients with AL amyloidosis. However, the risk factors of relapse are unknown and there are limited studies on treatment outcomes of these patients. We retrospectively reviewed 170 patients with AL amyloidosis who underwent ASCT between 2010 and 2021. Seventy-six patients confirmed as relapse and the median time from ASCT to relapse was 39 months. On multivariate analysis of variables before and after ASCT, lambda restricted, dFLC >30 mg/L pre ASCT, reduced dose melphalan and dFLC >10 mg/L at 6 months after ASCT were independent risk factors for relapse, and achieving CR after induction therapy and renal response after ASCT were protective factors. Most relapsed patients were treated with bortezomib-based regimens (50%) followed by daratumumab-based regimens (22.2%) and other chemotherapy regimens (13.9%). The overall hematological response in evaluable patients was 68.2% with 56.8% achieving CR/VGPR. The median PFS and OS from post-transplant relapse were 25 months and 81 months, respectively. Patients receiving bortezomib or daratumumab showed a better survival compared to other chemotherapy regimens. In conclusion, this study identified independent risk factors of post-transplant relapse and demonstrated the superiority of bortezomib or daratumumab treatment for these patients. CLINICAL TRIAL REGISTRATION NCT04210791.
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Predictors of hematologic response and survival with stem cell transplantation in AL amyloidosis: a 25-year longitudinal study
Gustine, J. N., Staron, A., Szalat, R., Mendelson, L., Joshi, T., Ruberg, F. L., Siddiqi, O., Gopal, D. M., Edwards, C. V., Havasi, A., et al
American journal of hematology. 2022
Abstract
High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I >0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p<0.001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis. This article is protected by copyright. All rights reserved.
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Predictors and outcomes of acute kidney injury during autologous stem cell transplantation in AL amyloidosis
Nader, R., Zhen, A., Angel-Korman, A., Pavlovich, S. S., Pogrebinsky, A., Doros, G., Menn-Josephy, H., Stern, L., Sanchorawala, V., Havasi, A.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2021
Abstract
BACKGROUND Acute kidney injury (AKI) is a common complication after high dose melphalan and autologous stem cell transplantation (HDM/SCT) in patients with AL amyloidosis. However, its incidence, predictors and outcomes are not well known. METHODS This observational study included 223 patients with AL amyloidosis who underwent HDM/SCT. AKI was defined as an increase in serum creatinine to?=?1.5 times the baseline occurring within the first 30 days of HDM/SCT. RESULTS The median age was 58 years (range: 30-77). Kidney and cardiac involvement were present in 86.1% and 56.8%, respectively. The median eGFR was 83.5?mL/min/1.73m2 (range: 9-213) and proteinuria was 2,899?mg/24?h (range: 0-19,966). AKI occurred in 29.1% of patients. Dialysis was initiated in 15 patients (6.7%) and of these 12 (80%) were able to discontinue dialysis. Most of the episodes of AKI occurred within the first 2 weeks. With a median follow-up of 4.5 years (range: 0.1-16.5), AKI was associated with increased overall mortality, HR 4.53 (95%CI [2-10.23]). The 10-year overall survival (OS) was 87.1% without AKI, versus 56.9% with AKI. AKI was also associated with an increased risk for end stage kidney disease (ESKD), HR 4.6 (95%CI [1.44-14.38]). The risk of developing ESKD at 10-year was 18.9% with AKI, versus 8.1% without AKI. Several risk factors were found and using multivariate logistic regression, a prediction model was developed which included 3 readily available variables: eGFR<60?mL/min/1.73m2, IVSd>12mm, and albumin<3?g/dL. This model was able to predict AKI development with an AUC of 0.8. CONCLUSIONS AKI is common in the post-HDM/SCT period and it leads to increased risk for ESKD and death. Our prediction model is an easily deployable tool in clinical settings as part of the discussion with patients who are being prepared for HDM/SCT.
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4.
Impact of renal impairment on light chain amyloidosis outcomes after autologous hematopoietic stem cell transplantation
Srour, S. A., Qazilbash, M. H.
Annals of translational medicine. 2020;8(7):509
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5.
Prognostic value of NT-ProBNP and troponin T in patients with light chain amyloidosis and kidney dysfunction undergoing autologous stem cell transplantation
Al Saleh, A. S., Parmar, H. V., Vaxman, I., Visram, A., Hasib Sidiqi, M., Muchtar, E., Buadi, F. K., Dispenzieri, A., Warsame, R., Lacy, M. Q., et al
Bone marrow transplantation. 2020
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6.
Depth of response prior to autologous stem cell transplantation predicts survival in light chain amyloidosis
Vaxman, I., Sidiqi, M. H., Al Saleh, A. S., Kumar, S., Muchtar, E., Dispenzieri, A., Buadi, F., Dingli, D., Lacy, M., Hayman, S., et al
Bone marrow transplantation. 2020
Abstract
The goal of therapy in AL amyloidosis is to inhibit further production of the amyloidogenic light chains, thereby allowing organ recovery and improving survival. We aimed to assess the impact of depth of hematologic response prior to ASCT on survival. We conducted a retrospective study of 128 newly diagnosed AL amyloidosis patients who received induction prior to ASCT between January 2007 and August 2017 at Mayo Clinic. The overall response rate to induction was 86% (CR 18%, VGPR 31% and PR 38%). With a median follow up of 52 months, the median PFS and OS was 48.5 months and not reached, respectively. Response depth to induction therapy was associated with improved PFS and OS. The median PFS was not reached for patients achieving =VGPR prior to ASCT and 34.1 months for patients achieving PR or less (P?=?0.0009). The median OS was longer in patients with deeper responses (not reached for =VGPR vs. 128 months for PR or less (P?=?0.02)). On multivariable analysis, independent predictors of OS were melphalan conditioning dose (RR?=?0.42; P?=?0.036) and depth of response prior to transplant (RR 0.37; P?=?0.0295). Hematologic response prior to transplant predicts improved post transplant outcomes in AL amyloidosis.
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7.
Left Atrial Mechanics Associates With Paroxysmal Atrial Fibrillation in Light-Chain Amyloidosis Following Stem Cell Transplantation
Lohrmann, G., Patel, M. A., Brauneis, D., Sanchorawala, V., Sarosiek, S., Vellanki, N., Siddiqi, O. K., Ruberg, F. L., Gopal, D. M.
JACC. CardioOncology. 2020;2(5):721-731
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Abstract
BACKGROUND Atrial fibrillation (AF) during high-dose melphalan and autologous stem-cell transplantation (HDM/SCT) for light-chain (AL) amyloidosis confers significant morbidity. Traditional risk factors provide limited prediction for development of paroxysmal AF during this vulnerable period. OBJECTIVES We sought to assess the association of clinical and echocardiographic parameters, including left atrial (LA) mechanics and development of AF in patients undergoing HDM/SCT therapy. METHODS Baseline echocardiograms, electrocardiograms, and electronic medical records were retrospectively assessed among patients with AL amyloidosis before HDM/SCT (n = 91). LA function analysis was performed using speckle-tracking echocardiography. RESULTS In this study, 42 patients (46%) had cardiac involvement; in the peri-transplant period, 12 (13%) developed AF (7 with cardiac involvement). No significant differences in age, sex, cardiac biomarkers, or cardiac risk factors were seen between patients with and without development of AF; one-third of patients with AF peri-transplant had previous AF. Although LA reservoir strain was reduced in patients with development of AF, time to peak strain rate indexed to R-R interval (TPSRI) (p = 0.001) was prolonged in patients with development of AF compared with sinus rhythm patients in the total cohort but also in subgroups with and without cardiac involvement. CONCLUSIONS TPSRI, a parameter of mechanical dispersion in the early reservoir phase of LA function, is associated with development of AF among patients undergoing HDM/SCT for AL amyloidosis. These findings require validation in larger prospective cohorts.
Clinical Commentary
What is known?
NIHMS1657053
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What are the implications for practice and for future work?
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8.
Prognostic and Added Value of Two-Dimensional Global Longitudinal Strain for Prediction of Survival in Patients with Light Chain Amyloidosis Undergoing Autologous Hematopoietic Cell Transplantation
Pun, S. C., Landau, H. J., Riedel, E. R., Jordan, J., Yu, A. F., Hassoun, H., Chen, C. L., Steingart, R. M., Liu, J. E.
Journal of the American Society of Echocardiography. 2018;31(1):64-70
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Abstract
BACKGROUND Autologous hematopoietic cell transplantation (HCT) is a first-line therapy for prolonging survival in patients with light-chain (AL) amyloidosis. Cardiac involvement is the most important determinant of survival. However, patients with advanced cardiac involvement have often been excluded from HCT because of high risk for transplantation-related mortality and poor overall survival. Whether baseline left ventricular global longitudinal strain (GLS) can provide additional risk stratification and predict survival after HCT in this high-risk population remains unclear. The aim of this study was to evaluate the prognostic implication of baseline GLS and the added value of GLS beyond circulating cardiac biomarkers for risk stratification in patients with AL amyloidosis undergoing HCT. METHODS Eighty-two patients with newly diagnosed AL amyloidosis who underwent upfront HCT between January 2007 and April 2014 were included in the study. Clinical, echocardiographic, and serum cardiac biomarker data were collected at baseline and 12 months following HCT. GLS measurements were performed using a vendor-independent offline system. The median follow-up time for survivors was 58 months. RESULTS Sixty-four percent of patients were in biomarker-based Mayo stage II or III. GLS, brain natriuretic peptide, troponin, and mitral E/A ratio were identified as the strongest predictors of survival (P < .0001). Other predictors included sex, creatinine, free AL, wall thickness, and ejection fraction. Mayo stage was significantly associated with outcome, with 5-year survival of 93%, 72% and 31% in stage I, II, and III patients, respectively. GLS of 17% was identified as the value that best discriminated survivors from nonsurvivors, and the application of this cutoff value provided further mortality risk stratification within each Mayo stage. CONCLUSIONS GLS is a strong predictor of survival in patients with AL amyloidosis undergoing HCT, potentially providing incremental value over serum cardiac biomarkers for risk stratification. GLS should be considered as a standard parameter along with serum cardiac biomarkers when evaluating eligibility for HCT or other investigational therapies.Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.
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Plasma cell proliferative index predicts outcome in immunoglobulin light chain amyloidosis treated with stem cell transplantation
Sidiqi, M. H., Aljama, M., Jevremovic, D., Morice, W. G., Timm, M., Buadi, F. K., Warsame, R., Lacy, M. Q., Dispenzieri, A., Dingli, D., et al
Haematologica. 2018
Abstract
The plasma cell proliferative index provides an insight into plasma cell biology in plasma cell disorders and is an important prognostic marker in myeloma and smoldering myeloma. We analyzed the prognostic impact of the plasma cell proliferative index in 513 patients with systemic AL Amyloidosis undergoing stem cell transplantation at the Mayo Clinic between January 2003 and 31 August 2016. Two cohorts were identified; Low or Elevated plasma cell proliferative index. Patients with an Elevated plasma cell proliferative index had more cardiac involvement (56% vs 44%; p=0.01), less renal involvement (55% vs 70%; p=0.001) and were more likely to have bone marrow plasma cells ≥ 10% (58% vs 32%, p<0.0001) compared to those with a Low plasma cell proliferative index. Both progression free survival and overall survival were lower in patients with an Elevated compared to Low plasma cell proliferative index (Median progression free survival 44 vs 95 months, p<0.0001 and Median overall survival 102 vs 143 months, p=0.0003). All-cause mortality at 100 days was higher in patients with an elevated plasma cell proliferative index (Elevated 10.3% vs Low 4.3%, p=0.008). On multivariate analysis Elevated plasma cell proliferative index was an independent prognostic factor for overall survival (Hazard ratio 1.5, 95% CI 1.1-2.1, p=0.021). The plasma cell proliferative index is an important prognostic tool in patients with AL Amyloidosis undergoing stem cell transplant.
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Prognostic significance of stringent complete response post stem cell transplantation in AL amyloidosis
Sidiqi, M. H., Aljama, M., Jevremovic, D., Muchtar, E., Buadi, F. K., Warsame, R., Lacy, M. Q., Dispenzieri, A., Dingli, D., Gonsalves, W. I., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Hematologic response has emerged as a powerful prognostic factor for survival in patients with immunoglobulin light chain amyloidosis. Patients achieving a complete response (CR), based on serum and urine analysis, survive longest. However data regarding the impact of bone marrow features post therapy on response and survival is limited. We evaluated impact of achieving a stringent complete response (sCR), defined as undetectable bone marrow clonal plasma cells by flow cytometry, in patients with AL amyloidosis receiving an autologous stem cell transplant. 573 consecutive patients transplanted for AL amyloidosis at the Mayo Clinic between April of 2002 and August of 2016 were included in the analysis. Of 540 patients in whom response was evaluable, 220 (41%) patients achieved a CR of whom 212 (96%) had a bone marrow biopsy at time of response assessment and were further analyzed for determination of sCR. 166 (78%) patients with a CR achieved a sCR representing 31% of the whole cohort. Patients achieving a CR had a higher median percentage of BMPCs (10% for CR vs 6% for sCR, p=0.03), more patients with BMPCs≥10% (50% for CR vs 33% for sCR, p=0.04), and less likely to receive chemotherapy prior to transplantation (30% for CR vs 49% for sCR, p=0.03) compared to those achieving sCR. Median OS for all patients achieving a CR was 175 months and was not statistically different between those achieving a sCR compared to those achieving a CR only (median not reached for sCR vs 175 months for CR, p=0.65). PFS however was significantly shorter in patients failing to achieve a sCR (151 months for sCR vs 72 months for CR, p=0.0003). Bone marrow examination post transplant in AL amyloidosis is important and identifies patients who fail to achieve a sCR and progress earlier.