scholarly journals European Collaborative Study Defining Clinical Profile Outcomes and Novel Prognostic Criteria in Monoclonal Immunoglobulin M–Related Light Chain Amyloidosis

2016 ◽  
Vol 34 (17) ◽  
pp. 2037-2045 ◽  
Author(s):  
Sajitha Sachchithanantham ◽  
Murielle Roussel ◽  
Giovanni Palladini ◽  
Catherine Klersy ◽  
Shameem Mahmood ◽  
...  
Keyword(s):  
Light Chain ◽  
Cardiac Involvement ◽  
Collaborative Study ◽  
Immunoglobulin M ◽  
Clinical Entity ◽  
Disease Stage ◽  
Response Criteria ◽  
Liver Involvement ◽  
Al Amyloidosis ◽  
Hematologic Response

Purpose Immunoglobulin M (IgM)–related light chain (AL) amyloidosis, which accounts for 6% to 10% of all AL amyloidosis cases, is a rare and poorly studied clinical entity. Its natural history and management is not clearly defined. Prognostic and response criteria for AL amyloidosis in general have not been validated in this population. Patients and Methods We retrospectively gathered data for 250 patients diagnosed with IgM AL amyloidosis from three European amyloidosis centers. Clinical features, hematologic response, and overall survival (OS) were analyzed. The current staging and response criteria in non-IgM AL amyloidosis was applied to this series to assess its utility in this patient cohort. Results Patients with IgM AL amyloidosis have a significant IgM paraprotein (median, 10 g/L), less frequent lambda light chain isotype, and evaluable difference between involved and uninvolved free light chains (dFLCs; > 50 mg/L) in only two thirds of patients. Bone marrow showed clear non-Hodgkin lymphoma as the underlying disorder in 54% of patients. Cardiac involvement (45%) is less common but there is more frequent lymph node (20%) and neuropathic (28%) involvement compared with non-IgM AL. Fifty-seven percent of patients achieved a hematologic response (14% very good partial response/complete response [VGPR/CR]), with median OS not reached for patients achieving VGPR/CR, 64 months for PR, and 28 months for nonresponders (P < .001). On multivariate analysis, cardiac involvement, advanced Mayo disease stage, neuropathic involvement, and liver involvement were independent factors that had an impact on survival. Combining abnormal N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin T with liver involvement and the presence of neuropathy gives a better risk model: median OS of patients with none, one, or two or more abnormal factors was 90, 33, and 16 months, respectively. Conclusion IgM AL amyloidosis is a distinct clinical entity. Low-risk disease can be defined by combining cardiac involvement with novel prognostic markers. Deeper hematologic responses translate into improved outcomes, yet deep responses remain dismally poor, which highlights the urgent need for novel therapies.

scholarly journals Difference in Involved and Uninvolved Free Light Chain (dFLC) of Less Than 1mg/DL Early Post Risk Adapted Melphalan and Autologous Stem Cell Transplantation (RA-ASCT) Predicts Renal Response at 1 Year in Light Chain (AL) Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4577-4577
Author(s):  
Sneha Purvey ◽  
Kenneth Seier ◽  
Sean M. Devlin ◽  
Josel D Ruiz ◽  
Molly A. Maloy ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Plasma Cells ◽  
Al Amyloidosis ◽  
Organ Function ◽  
Advisory Committees ◽  
Renal Response ◽  
Hematologic Response

Background: Deep and durable hematologic remissions following RA-ASCT are associated with improved organ function and extended overall survival (OS) in AL amyloidosis. Achieving at least a very good partial response (VGPR) defined by a dFLC <4mg/dL is an accepted goal of therapy based on favorable outcomes, including improved renal survival (REF: Palladini JCO 2012, Palladini Blood 2014). Recently more profound clonal suppression as indicated by no evidence of minimal residual plasma cell disease (MRD) in bone marrow (BM) (Muchtar Blood 2017) and achieving dFLC <1mg/dL (Manwani Blood 2018) have shown additional benefit. While depth of hematologic response by standard criteria are important, this study assessed additional factors that influence renal response and time to renal response. Methods: All patients (pts) with AL and renal involvement (biopsy proven renal tissue diagnosis and/or 24hr proteinuria >500mg/day) undergoing RA-ASCT at Memorial Sloan Kettering Cancer Center between January 1, 2007 to December 31, 2016 were included. Pts with follow up less than 12 months post RA-ASCT, hemodialysis prior to RA-ASCT and Waldenstrom macroglobulinemia were excluded. Melphalan dose was assigned based on age, cardiac involvement and renal compromise (Landau Leukemia 2013). Hematologic response was assessed at 3 and 12 months (mos) post RA-ASCT (Palladini JCO 2012) and those with less than complete response (CR) were offered consolidation therapy with bortezomib and dexamethasone (BD). All pts underwent serial organ function assessment (Palladini Blood 2014). Logistic regression models were used to assess association with renal response by 12 mos. Covariates for adjustment in multivariate models were chosen based on univariate analyses and clinical relevance. Results: Sixty-four patients with renal AL meeting the inclusion criteria were identified; 3 pts died within a year post RA-ASCT were excluded. Median age (range) was 61 years (44-73), M:F 49%:51%, white 90% and 34% had cardiac involvement. Median (IQR) 24 hr proteinuria pre RA-ASCT was 5014 mg/day (2632-7514) and eGFR 68 ml/min/1.73 m2 (44-91). Renal amyloid stage I:II:III was 33%:52%:15%. Mayo cardiac stage (2004) I:II:III was 28%:61%:11% and revised Mayo stage (2012) I:II:III:IV was 13%:57%:21%:8%. Median BM plasma cells pre RA-ASCT was 9% (IQR 2-14%). 46% pts received treatment prior to ASCT. Melphalan dose (mg/m2) 200:140:100 was 44%:43%:11%. 46% pts received BD consolidation. Hematologic response at 3 mos post RA-ASCT was CR 44%, VGPR 29%, partial response (PR) 20% and stable disease (SD) 7%. MRD in BM by 10-color flow cytometry was assessed in 33 pts and 13 (39%) were MRD negative. dFLC <1mg/dL was achieved in 63% of pts. Renal response by 12 mos following RA-ASCT was achieved in 32 pts (53%). Median (IQR) time to renal response in these pts was 5.8 mos (5.1 - 11.3). Amongst renal responders, 50% were in CR, 53% had MRD negative BM (of 15 pts) and 78% with dFLC <1mg/dL early post RA-ASCT. In pts who achieved dFLC <1mg/dL early post RA-ASCT, 66% had renal response. By univariate analysis (Table 1) OR (95% CI) Mayo cardiac Stage (2004) II and III 0.23 (0.07-0.83, p=0.025), early post RA-ASCT dFLC <1mg/dL 3.00 ( 1.01-8.93, p=0.048), VGPR early post RA-ASCT 7.80 (1.69-36.06, p=0.009), dFLC <1mg/dL at 12 mos 7.20 (2.14-24.21, p=0.001) and CR at 12 mos 10.27 (1.14-92.26, p=0.038) were significantly associated with renal response. Neither renal stage, Mayo stage (2012), MRD negativity, melphalan dose nor consolidation was associated with renal response. By multivariate analysis (Table 2), early post RA-ASCT dFLC <1mg/dL continued to be the most significant factor predicting renal response, OR (95% CI) 4.52 (1.26-16.24, p=0.021), when adjusted for renal amyloid stage and Mayo cardiac stage (2004). Conclusion: In this single center study, we report that RA-ASCT results in renal response in more than half (53%) of the patients at 1 year. Achieving dFLC <1mg/dL early post ASCT is significantly associated with renal response. Renal response is independent of baseline proteinuria and BM plasma cells or MRD status post ASCT. Our study supports that pathologic entity in organ damage is not the plasma cells but rather light chains. Further studies using dFLC <1mg/dL should be evaluated in organ response. Mass spectrometric light chain monitoring may even be more sensitive and could potentially serve as a non-invasive way to measure disease burden. Disclosures Shah: Janssen: Research Funding; Amgen: Research Funding. Hassoun:Janssen: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Hematologic Responses and Cardiac Organ Improvement in Patients with Heavily Pretreated Cardiac Immunoglobulin Light Chain (AL) Amyloidosis Receiving Daratumumab

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4525-4525 ◽  
Author(s):  
Gregory Kaufman ◽  
Ronald Witteles ◽  
Matthew Wheeler ◽  
Patricia Ulloa ◽  
Marie Lugtu ◽  
...  
Keyword(s):  
Light Chain ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Prior Therapy ◽  
Hematologic Response ◽  
Heavily Pretreated ◽  
Organ Response

Abstract Introduction: In immunoglobulin light chain (AL) amyloidosis, cardiac involvement is the primary cause of premature death. Light chain suppression, with therapies targeting the underlying plasma cell clone producing amyloidogenic free light chains, has been difficult to achieve in a relapsed/refractory disease setting. Hematologic response is required to obtain a cardiac organ response, which is predictive of survival and is an important, if not primary, therapeutic goal. We have previously reported rapid and favorable hematologic response rates with the monoclonal anti-CD38 antibody daratumumab in a cohort of heavily pretreated relapsed/refractory AL patients. The aim of this study was to evaluate cardiac organ response following light chain suppressive therapy with daratumumab in patients with relapsed/refractory AL. Materials & Methods:Consecutive patients with biopsy-proven AL and cardiac involvement, followed at the Stanford University Amyloid Center, who received daratumumab were retrospectively evaluated for hematologic and cardiac organ response. In accordance with IRB approval, demographic and clinical information was obtained from medical records. Hematologic and cardiac organ response criteria were defined per consensus guidelines in AL (Comenzo et al, Leukemia 2012). Results: Twelve patients with previously treated AL with cardiac involvement received a median of 12 doses (range 5-18) of single agent daratumumab. The antibody was given intravenously at 16 mg/kg weekly for 8 weeks, followed by every other week infusion for 8 doses and then monthly infusions. The median patient age was 67 and 75% of patients were male. The median number of lines of prior therapy was 3; notably, none of the patients had previously achieved a hematologic complete response to prior therapy including high dose melphalan and autologous stem cell transplant in 2 patients. Ten of 12 patients (83%) achieved a partial hematologic response or better with daratumumab (3 complete responses (25%), 3 very good partial responses (25%), and 4 partial responses (33%)). Median NT-pro BNP was 2516 pg/mL prior to daratumumab therapy. Of all 12 treated patients, seven patients were evaluable for cardiac response based on baseline NT-proBNP >650 ng/L. Of these, 3 patients achieved a cardiac organ response by NT-pro BNP criteria (>30% reduction and >300 ng/l decrease). Two patients had cardiac progression by NT-pro BNP criteria (no echocardiographic progression was observed) despite hematologic response with one patient discontinuing therapy to pursue hospice care. Infusion reactions were observed in 8/12 patients with only 1 grade 3 infusion reaction. Conclusions: Daratumumab yielded rapid and significant hematologic responses in our retrospective single institution cohort of heavily pretreated AL patients. At a median daratumumab duration of therapy of only 4 months, evidence of cardiac organ improvement was observed. Daratumumab represents a well tolerated and exceptionally promising new treatment for patients with AL amyloidosis; larger prospective trials to evaluate this agent are warranted. Disclosures Liedtke: Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Pfizer: Consultancy, Research Funding.

Validation of the Criteria of Response to Treatment In AL Amyloidosis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1364-1364 ◽  
Author(s):  
Giovanni Palladini ◽  
Angela Dispenzieri ◽  
Morie Abraham A Gertz ◽  
Ashutosh Wechalekar ◽  
Philip N Hawkins ◽  
...  
Keyword(s):  
Light Chain ◽  
The United States ◽  
Cardiac Response ◽  
Response To Treatment ◽  
Response Criteria ◽  
Al Amyloidosis ◽  
Absolute Value ◽  
Hematologic Response ◽  
Organ Response ◽  
Definition Of

Abstract Abstract 1364 In light chain (AL) amyloidosis, as well as in multiple myeloma, response to treatment is increasingly being used as a surrogate endpoint in clinical trials. In 2005 a consensus statement of the International Society of Amyloidosis (ISA) established the criteria for hematologic and organ response. Since then, several studies emphasized the prognostic relevance of the measurement of the amyloidogenic precursor, the circulating free light chain (FLC). Moreover, it was reported that patients who with treatment achieved decreases in the cardiac biomarker N terminal natriuretic peptide type B (NT-proBNP) had longer survival, although echocardiographic criteria of response were not attained. The ISA Consensus Panel reconvened in 2010 to update hematologic and organ response criteria. The panel felt that any new criteria should be validated in a large patient population. Thus, we systematically gathered from 7 referral centers in Europe and in the United States a cohort of 649 patients with systemic AL amyloidosis who had been evaluated for hematologic and organ responses at diagnosis and 6 months after treatment initiation, excluding patients who died earlier. At diagnosis, 430 patients (66%) had heart involvement, 377 (58%) had NT-proBNP ≥650 ng/L, 455 (70%) had renal involvement (95, 15%, with glomerular filtration rate <30 mL/min) and 100 (15%) had liver involvement. Two-hundred eighty-nine patients (44%) were treated with melphalan and dexamethasone, 118 (18%) received thalidomide based therapy, 73 (11%) underwent autologous stem cell transplant, 35 (5%) were treated with regimens including lenalidomide, 20 (3%) received bortezomib-based therapy, and the rest received other alkylating agents, nucleoside analogues or dexamethasone. The median follow-up of living patients was 24 months, and 233 patients (34%) died. The ability of response criteria to identify patients who died was compared by evaluating the areas under Receiver Operator Characteristic curves based on death at 1 year, and by calculating the Harrell C statistic and the Royston explained variation. Survival was calculated from the time of evaluation of response. We maintained the category of complete response (CR: negative serum and urine immunofixation, normal FLC kappa/lambda ratio and normal marrow studies) and examined candidate criteria for partial (PR) and very good partial responses (VGPR), based on percentage changes or absolute values achieved after treatment of involved (amyloidogenic) FLC (iFLC), and alternatively on the difference between iFLC and uninvolved FLC (dFLC). With respect to cardiac response and progression, NT-proBNP-based criteria were defined as a decrease or an increase of both >30% and >300 ng/L, and a threshold of evaluability based on NT-proBNP baseline level >650 ng/L was chosen. The most powerful criteria for PR were those based on dFLC percent decrease, and a 50% cutoff was preferred because of easier clinical use. Among candidate criteria for VGPR, the best were based on iFLC absolute value achieved after therapy, but the performance of those based on dFLC absolute value was only slightly lower. Therefore, a definition of VGPR based on dFLC (<40 mg/L) was adopted for the sake of harmonization with the dFLC-based definition of PR. The adopted hematologic response criteria and their prognostic significance are reported in Table 1. These criteria identified 4 groups with significantly different survivals (Figure 1). Also the proposed criteria of NT-proBNP response and progression were significantly associated with survival (Figure 2). Our 2010 revised consensus criteria for hematologic response include maintenance of the definition of CR, and with use of dFLC re-casting the definition of PR and introducing a VGPR category, and for cardiac response and progression introducing the use of changes in NT-proBNP levels. In a further analysis we will address the definition of measurable dFLC at baseline and evaluate the applicability of the response criteria to earlier evaluation of response. The revised criteria improve the framework for clinical research in AL. Disclosures: Off Label Use: Thalidomide, lenalidomide, bortezomib for systemic AL amyloidosis. Dispenzieri:The Binding Site: Honoraria. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Ortho-Biotech: Honoraria; Celgene: Honoraria; Millennium: Honoraria. Merlini:Millennium: Honoraria; Ortho-Biotech: Honoraria.

scholarly journals Light Chain Deposition Disease: First Analysis of an International Study in 359 Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Paolo Milani ◽  
Nelson Leung ◽  
Efstathios Kastritis ◽  
Stefan Schönland ◽  
Ute Hegenbart ◽  
...  
Keyword(s):  
Light Chain ◽  
Research Funding ◽  
Univariate Analysis ◽  
Response Criteria ◽  
Al Amyloidosis ◽  
Light Chain Deposition Disease ◽  
Hematologic Response ◽  
Bone Marrow Plasma ◽  
Light Chain Deposition ◽  
Serum And Urine

Introduction: Light chain deposition disease (LCDD) is a rare complication of monoclonal gammopathies, defined by non-amyloid linear monoclonal light chain (most commonly kappa) deposits in the kidney and other organs. The rarity of LCDD has hampered clinical studies and staging systems and response criteria are lacking. The International Kidney Myeloma Working Group (IKMG) started a clinical data collection from all participating centers in order to define the natural history of LCDD, and to establish prognostic factors and response criteria in a large, international, unselected patient population. Methods: Eight referral centers have yet participated in the data collection at the data lock of July 31, 2020. Patient inclusion is ongoing and expected accrual is 500 patients. The diagnosis of LCDD had to be biopsy-proven. The patients were diagnosed between 1992 to 2020. Response was assessed 6 months after treatment initiation according to the criteria used in light chain (AL) amyloidosis. Renal survival (RS) was defined as time from diagnosis to dialysis or last follow-up. Patients who died without requiring dialysis were censored at the time of death. The analysis of factors predicting RS was performed in patients whose baseline estimated glomerular filtration rate (eGFR) was &gt;15 mL/min. The cutoffs of baseline variables, as well as the cutoffs measured at the time of response, best predicting RS or OS at 12 months were identified by means of Receiver Operator Characteristics (ROC) analyses. All patients gave written informed consent for their clinical data to be used for research purposes. Results: Overall, 359 patients have been included in this first analysis. Sixteen (4%) subjects had concomitant cast nephropathy. The main clinical characteristics are reported in the Table. Median overall survival (OS) was 13 years and RS was 12 years (Figure1 A and 1B) and median survival of living patients is 4.5 years. At univariate analysis the only baseline variables predicting RS were proteinuria [best cutoff 2.5 g/24h, HR 2.25 (95%CI 1.13-4.60), P=0.02], and eGFR [best cutoff &gt;30 mL/min, HR 0.50 (95%CI 0.26-0.96) P=0.037], but at multivariate analysis only proteinuria predicted RS [HR 2.17 (95% CI 1.08, 4.33), P=0.027]. At univariate analysis, a higher bone marrow plasma cell infiltrate (best cutoff ≥20%) at diagnosis was associated with a significantly lower OS [HR 1.96 (95% CI 1.23-3.13) P=0.004], as was having end stage renal disease (ESRD) defined as an eGFR &lt;15 mL/min [HR 1.81 (95%CI 1.11-2.92) P=0.015]. We then tested the ability of the hematologic response criteria for AL amyloidosis to discriminate groups with different survival after treatment in a 6 months landmark analysis. Our choice of adopting the amyloidosis response criteria was corroborated by the results of the ROC analysis showing that the difference between involved and uninvolved free light chains (dFLC) cutoff (40 mg/L) used in AL amyloidosis to define very good partial response (VGPR) had 87% sensitivity and 65% specificity in identifying patients who needed dialysis within 12 months. Partial response (PR, 19% requiring dialysis at 3 years) was not associated with a RS benefit over no-response (29% requiring dialysis at 3 years, P=0.511). However, VGPR conferred a significant RS advantage (10% requiring dialysis at 3 years) over PR (P=0.002). No significant difference in RS was seen between complete response (CR, 0% requiring dialysis at 3 years) and VGPR (P=0.178). Thus, achieving VGPR or CR by amyloidosis response criteria [post-treatment dFLC&lt;40 mg/L (VGPR by AL criteria), with or without negative serum and urine immunofixation and normal FLC-ratio (CR by AL criteria)] was adopted as a provisional criterion for hematologic response in LCDD (Figure 1D). LCDD response was also associated with prolonged OS (Figure 1C). Conclusions: Almost one-third of patients with LCDD are diagnosed when they already have ESRD resulting in shorter OS. The degree of proteinuria and of bone marrow plasma cell infiltration predict RS and OS, respectively. Achievement of post treatment dFLC &lt;40 mg/L or negative serum and urine immunofixation at 6 months is proposed as a provisional criterion for hematologic response, being able to predict both improved RS and OS. Planned expanded recruitment might allow a validation analysis of the results, the analysis of organ response data and the evaluation of different time-points for response assessment. Disclosures Milani: Celgene: Other: Travel support; Janssen: Other: Speaker honoraria; Pfizer: Other: Speaker honoraria. Kastritis:Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Bridoux:Baxter: Consultancy; Janssen: Honoraria; Celgene: Honoraria. Tuchman:Celgene: Honoraria, Research Funding, Speakers Bureau; Oncopeptides: Consultancy; Amgen: Research Funding; Caelum: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Research Funding; Roche: Research Funding; Karyopharm: Honoraria, Research Funding. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. Palladini:Jannsen Cilag: Honoraria, Other; Celgene: Other: Travel support. Wechalekar:Celgene: Honoraria; Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel.

scholarly journals Development and validation of a survival staging system incorporating BNP in patients with light chain amyloidosis

Blood ◽  
2019 ◽  
Vol 133 (3) ◽  
pp. 215-223 ◽  
Author(s):  
Brian Lilleness ◽  
Frederick L. Ruberg ◽  
Roberta Mussinelli ◽  
Gheorghe Doros ◽  
Vaishali Sanchorawala
Keyword(s):  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Light Chain ◽  
Cardiac Involvement ◽  
Staging System ◽  
Stage I ◽  
Stage Iiib ◽  
Stage Ii ◽  
Al Amyloidosis ◽  
Derivation Cohort

Abstract Immunoglobulin light chain amyloidosis (AL amyloidosis) is caused by misfolded light chains that form soluble toxic aggregates that deposit in tissues and organs, leading to organ dysfunction. The leading determinant of survival is cardiac involvement. Current staging systems use N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponins T and I (TnT and TnI) for prognostication, but many centers do not offer NT-proBNP. We sought to derive a new staging system using brain natriuretic peptide (BNP) that would correlate with the Mayo 2004 staging system and be predictive for survival in AL amyloidosis. Two cohorts of patients were created: a derivation cohort of 249 consecutive patients who had BNP, NT-proBNP, and TnI drawn simultaneously to create the staging system and a complementary cohort of 592 patients with 10 years of follow-up to determine survival. In the derivation cohort, we found that a BNP threshold of more than 81 pg/mL best associated with Mayo 2004 stage and also best identified cardiac involvement. Three stages were developed based on a BNP higher than 81 pg/mL and a TnI higher than 0.1 ng/mL and compared with Mayo 2004 with high concordance (κ = 0.854). In the complementary cohort, 25% of patients had stage I, 44% had stage II, 15% had stage III, and 16% had stage IIIb disease with a median survival not reached in stage I, 9.4 years in stage II, 4.3 years in stage III, and 1 year in stage IIIb. This new Boston University biomarker scoring system will allow centers without access to NT-proBNP the ability to appropriately stage patients with AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00898235.

scholarly journals Diagnostic approach to light-chain cardiac amyloidosis and its differential diagnosis

2018 ◽  
Vol 49 (1) ◽  
pp. 9-14
Author(s):  
Monika Adamska ◽  
Anna Komosa ◽  
Tatiana Mularek ◽  
Joanna Rupa-Matysek ◽  
Lidia Gil
Keyword(s):  
Differential Diagnosis ◽  
Light Chain ◽  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Diagnosis And Treatment ◽  
Diagnostic Approach ◽  
Al Amyloidosis ◽  
Delay In Diagnosis ◽  
Light Chain Amyloidosis ◽  
Novel Approaches

AbstractCardiac amyloidosis is a rare and often-misdiagnosed disorder. Among other forms of deposits affecting the heart, immunoglobulin-derived light-chain amyloidosis (AL amyloidosis) is the most serious form of the disease. Delay in diagnosis and treatment may have a major impact on the prognosis and outcomes of patients. This review focuses on the presentation of the disorder and current novel approaches to the diagnosis of cardiac involvement in AL amyloidosis.

scholarly journals Effectiveness of Bortezomib in Cardiac AL Amyloidosis: A Report of Two Cases

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Santi Nigrelli ◽  
Giuseppe Curciarello ◽  
Piercarlo Ballo ◽  
Stefano Michelassi ◽  
Francesco Pizzarelli
Keyword(s):  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Chronic Kidney Disease Stage ◽  
Clinical Results ◽  
Disease Stage ◽  
Comorbid Condition ◽  
Al Amyloidosis ◽  
Therapeutic Approaches ◽  
Hematologic Disease ◽  
Total Remission

Cardiac involvement is a major prognostic determinant in patients with primary AL amyloidosis. The clinical results of standard therapeutic approaches are suboptimal. It has been recently shown that bortezomib, an inhibitor of the proteasome, can induce rapid favourable responses in AL amyloidosis improving cardiac function and survival. Herein we report on two patients with cardiac amyloidosis treated by bortezomib who experienced partial or total remission of hematologic disease and of cardiac involvement. However, death of one patient, suffering from chronic kidney disease stage 5, due to fulminant respiratory syndrome suggests the need for caution in bortezomib use if patients have this comorbid condition.

scholarly journals Patients with light-chain amyloidosis and low free light-chain burden have distinct clinical features and outcome

Blood ◽  
2017 ◽  
Vol 130 (5) ◽  
pp. 625-631 ◽  
Author(s):  
Paolo Milani ◽  
Marco Basset ◽  
Francesca Russo ◽  
Andrea Foli ◽  
Giampaolo Merlini ◽  
...  
Keyword(s):  
Clinical Features ◽  
Light Chain ◽  
Free Light Chain ◽  
Al Amyloidosis ◽  
Renal Survival ◽  
Light Chain Amyloidosis ◽  
Hematologic Response ◽  
Heart Involvement ◽  
Key Points

Key PointsPatients with AL amyloidosis and low dFLC burden (<50 mg/L) have less severe heart involvement and better survival. These patients are evaluable for hematologic response with adapted criteria predicting improvement of overall and renal survival.

Baseline Serum Albumin and Proteinuria Predict Renal Response after Autologous Stem Cell Transplantation in AL Amyloidosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1166-1166
Author(s):  
Nelson Leung ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
Mark R. Litzow ◽  
Shaji K. Kumar ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Light Chain ◽  
Al Amyloidosis ◽  
Baseline Serum ◽  
Monoclonal Protein ◽  
Renal Response ◽  
Hematologic Response ◽  
Organ Response

Abstract Introduction: High dose melphalan followed by autologous stem cell transplantation (ASCT) is an effective treatment for patients with light chain associated (AL) amyloidosis. Longer patient survival and higher rates of organ response have now been documented by multiple studies. However, predictors of organ response remain unknown. Previously, we have reported the benefits of renal response after ASCT in this population. This study was conducted to investigate the characteristics that would predict renal response after ASCT. Methods: The study was performed retrospectively on consecutive patients that underwent ASCT at our institution from March of 1996 to December of 2004. Exclusion criteria include baseline proteinuria &lt; 1 g/d, dialysis prior to ASCT and lack of laboratory data at follow up to determine renal response. Renal response was defined by &gt; 50% reduction in baseline proteinuria with &lt; 25% decline in renal function as measured by serum creatinine. Treatment related mortality and dialysis dependence prior to meeting criteria of response were viewed as treatment failures. Hematologic response was determined by 50% reduction of monoclonal protein (free light chain) or complete eradication if the monoclonal protein was too small to be quantified. Results: A total of 135 patients met criteria for study. Median age was 56.2 years at the time of transplant, 53.7% were male. Median baseline proteinuria and GFR were 6.4 g/d and 70 ml/min/1.73m2 respectively. Renal response was achieved in 35.6% of the patients while hematologic response was 71.1% in the 128 patients evaluated. Patient’s age, sex, albumin, GFR, proteinuria, conditioning regimen, and hematologic response were evaluated and the following were found to be associated with renal response: albumin (p = 0.001), proteinuria (p = 0.008), and hematologic response (p = 0.0002). The cutoff for albumin was found to be 1.6 mg/dl and proteinuria was 3.5 g/d. Multivariate analysis using a logistic regression model showed hematologic response and proteinuria to be independent predictors of renal response. The impact of proteinuria and hypoalbuminemia was then investigated together (Table 1). When combined, they were a better predictor then either one alone (Hazard ratio = 6.34 for combined, 3.43 for proteinuria, 3.32 for hypoalbuminemia). The combination was also a better independent predictor of renal response in the multivariate analysis. In this group of patients, renal response was associated with longer survival but hematologic response was not (p = 0.02). Discussion: Our study showed that besides hematologic response, baseline serum albumin and proteinuria are independent predictors of renal response in AL patients after ASCT. Hypoalbuminemia and nephrotic range proteinuria, both markers of the severity of renal disease, have strong negative impact on response. This implies that there may be a limit to the reversibility of organ damage even when hematologic response is achieved. This study also points out the importance of organ (renal) response in this disease as hematologic response alone did not predict long term outcome. Our results suggest ASCT should be done early for AL to insure optimal organ response and patient outcome. Table 1 The Effects of Hypoalbuminemia and Proteinuria on Renal Response after ASCT Hypoalbuminemia & Proteinuria No Renal Response Renal Response None 39.3% 60.7% One 66.2% 33.8% Both 81.8% 18.2%

Response to Bortezomib Based Induction Therapy in Newly Diagnosed Light Chain (AL) Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1867-1867 ◽  
Author(s):  
Veerpal Singh ◽  
Ayman Saad ◽  
Jeanne Palmer ◽  
Jasleen K Randhawa ◽  
Parameswaran N. Hari
Keyword(s):  
Light Chain ◽  
Liver Dysfunction ◽  
Cardiac Involvement ◽  
Response Rate ◽  
Initial Therapy ◽  
Al Amyloidosis ◽  
Karnofsky Performance Score ◽  
Significant Activity ◽  
Newly Diagnosed ◽  
Organ Response

Abstract Abstract 1867 Poster Board I-892 Bortezomib has been shown to have significant activity in the suppression of light chain production and induction of responses in patients with relapsed refractory AL Amyloidosis. We analyzed the outcomes of 16 (9 male) newly diagnosed biopsy proven AL Amyloidosis patients treated with Bortezomib based regimens at our institution. All patients received initial therapy with Bortezomib and dexamethasone (dex). Patients with a Karnofsky performance score ( KPS) >70 received Bortezomib at starting doses of 1.3 mg/m2 along with dexamethasone 40 mg on days 1,4,8, 11 ( with a 10 day rest period). Patients with a lower KPS received Bortezomib/Dex on a weekly schedule as tolerated. Dose adjustments were made based on side effects such as neuropathy, hypotension, GI disturbances or electrolyte imbalances. Patients tolerating Bortezomib/dex with improvement in KPS had cyclophosphamide (4) or lenalidomide (1) added to their initial therapy. Patients: Median age was 64 years (39–88). Nine had kappa light chain involvement. Organ involvement was renal (73%), cardiac (63%), hepatic (25%), tongue or soft tissue (20%), GI (30%). Median KPS was 70 (50 –100). Ten of the 16 patients were treated as in-patients due to multi-organ dysfunction. Five patients required hemodialysis within a month of diagnosis. Cardiac involvement was stage 3 (Mayo risk group) in 25%. Three patients were unevaluable: 2 dying before 2 cycles and 1 discontinued therapy (Grade 3 liver dysfunction). Median follow up was 5 months (range 2–33 mo). Results: Evaluable (receiving at least 2 cycles) patients have all had a free light chain response. The overall hematological response rate was 100% with 55% partial remission (PR) and 45% complete remission (CR). Median cycles to achievement of a light chain response was 2 (range 1–4). Four patients underwent autologous stem cell transplantation with no mortality. Five (40%) of the responders have had an organ response (3 renal, 1 macroglossia, 1 cardiac) with only patients alive for >5 months having any evidence of organ response. Five (40%) of the evaluable patients have died with progressive cardiac involvement (2), relapsed disease (2) or renal failure (1) with refusal of dialysis. In patients receiving at least one dose of bortezomib, non-hematologic toxicity (>grade 2) included -neuropathy (20%), hypotension (20%), severe diarrhea (12%), sepsis (12%), paralytic ileus (6%), liver dysfunction (6%), sudden death (6%). Conclusions: Bortezomib in combination with dexamethasone has a high response rate in newly diagnosed AL amyloidosis. This regimen was well tolerated in a cohort of severe, multisystem amyloidosis patients with low treatment related mortality. Light chain responses were fast whereas organ responses were not seen prior to 5 months of therapy. The regimen also served as a platform for further intensification with the addition of lenalidomide, cyclophosphamide or autologous transplant in responders. Disclosures: Off Label Use: Bortezomib for the therapy of amyloidosis. Hari:Millenium: Honoraria, Research Funding.

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