High-Sensitivity Troponin Assay Improves the Detection of Cardiac Involvement in AL Amyloidosis and Is the Most Powerful Prognostic Determinant.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1782-1782
Author(s):  
Giovanni Palladini ◽  
Alessandra Barassi ◽  
Gabriele Sarais ◽  
Ruggero Capra ◽  
Andrea Foli ◽  
...  
Keyword(s):  
Cardiac Involvement ◽  
Conflicts Of Interest ◽  
High Sensitivity ◽  
Left Ventricular ◽  
Response To Therapy ◽  
Al Amyloidosis ◽  
Cardiac Damage ◽  
Hematologic Response ◽  
Heart Involvement ◽  
The Impact

Abstract Abstract 1782 Poster Board I-808 The heart is involved in approximately two thirds of patients with AL amyloidosis and the prognosis of the disease is largely dependent on the severity of cardiac damage. Heart dysfunction can be assessed by measuring the serum concentrations of N terminal natriuretic peptide type B (NT-proBNP) and of cardiac troponins (cTn). The combination of these biomarkers allows an accurate prognostic stratification of patients with AL amyloidosis. Recently, new generation of more sensitive assays for cTn, characterized by low limits of detection and low imprecision, have been developed, aiming at identifying minimal cardiac damage. We report the impact of a highly sensitive (hs) cTnT assay on detection of heart involvement, prognosis and response to therapy in 109 consecutive newly diagnosed patients with AL amyloidosis. The hs-cTnT was measured on the Modular E instrument with a precommercial immunoassay from Roche Diagnostics on frozen sera collected at the time of diagnosis and stored at -80°C. The 99th centile of hs-cTnT concentration in sera from 546 healthy volunteers is 14 ng/L (95%CI 12.4-24.9 ng/L). NT-proBNP and cTnI were measured with commercially available assays. The upper reference limit of NT-proBNP is 332 ng/L and for cTnI is 40 ng/L. Heart involvement was defined according to the International Society of Amyloidosis consensus criteria as a mean left ventricular wall thickness (mLVW) >12 mm in the absence of other causes. Sixty-nine of the 109 patients (63%) fulfilled the echocardiographic criteria of heart involvement. Among these patients, 74% had elevated cTnI, 96% had high hs-cTnT and 100% had elevated NT-proBNP. Fifteen patients who did not have echocardiographic heart involvement at presentation reached a mLVW >12 mm within 6 months from diagnosis. Among them, cTnI was elevated at presentation in 33% of cases, hs-cTnT in 80% (p=0.01 compared to cTnI) and NT-proBNP in 73%, indicating that hs-cTnT and NT-proBNP can detect amyloid cardiac involvement when it is still unapparent by conventional echocardiographic criteria. Thirty-seven (34%) patients died and the median follow-up of living patients was 38 months (range 14-67 months). Survival was reduced in patients with hs-cTnT >14 ng/L (58% vs. 84% surviving at 3 years, p=0.01) and NT-proBNP >332 ng/L (58% vs. 86% surviving at 3 years, p=0.02) and cTnI >40 ng/L (52% vs. 75% surviving at 3 years, p=0.007). At multivariate analysis ln(hs-cTnT) was the only variable significantly associated with survival (HR 1.576, 95%CI 1.048-2.371, p=0.03). All the patients were treated with melphalan-dexamethasone and 66 (60%) reached hematologic response. The hs-cTnT cutoff best predicting survival after treatment was 68 ng/L (45% vs. 80% surviving at 3 years, p=0.0003). This cutoff, in combination with hematologic response to therapy, could differentiate the patient population into 3 groups with significantly different survival. Estimated survival at 3 years was 30% in non responders with hs-cTnT >68 ng/L, 51% in those who obtained either hematologic response or had hs-cTnT <68 ng/L (p=0.05) and 95% in responders with hs-cTnT <68 ng/L (p<0.0001). Cardiac troponin measured with a high-sensitivity assay significantly improved the sensitivity, compared with commercially available troponin assay, for cardiac damage caused by AL amyloidosis and represents now the most powerful prognostic determinant. Patients who obtain hematologic response and a hs-cTnT concentration below the threshold of 68 ng/L enjoy prolonged survival. Disclosures No relevant conflicts of interest to declare.

Weekly Combination Chemotherapy with Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) for Newly Diagnosed Patients with Advanced Cardiac Disease Due to Systemic AL Amyloidosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5139-5139
Author(s):  
Furha I. Cossor ◽  
Adam Boruchov ◽  
Michael Danso ◽  
Michael Edward Lee ◽  
Ayan Patel ◽  
...  
Keyword(s):  
Standard Therapy ◽  
Cardiac Involvement ◽  
Troponin I ◽  
Single Agent ◽  
Left Ventricular ◽  
Stage Iii ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Hematologic Response

Abstract Abstract 5139 The treatment of systemic AL amyloidosis (AL) with advanced cardiac involvement (cardiac biomarker stage III) at diagnosis remains challenging and unsatisfactory. Median survival with melphalan and dexamethasone (MDex) in stage III patients is about 10 months from diagnosis with one quarter of patients dying within 3 months of starting therapy (BJH 2008;143:369; Blood 2010;116:522). Bortezomib has been shown to be the most active single agent in the treatment of AL (Blood 2011;118:865) and, when incorporated into CyBorD, clinical studies have shown a > 90% hematologic response rate in both myeloma and in AL (Blood 2010;115:3416; Leukemia 2009;23:1337; Amyloid 2010;17(S1):171a). In addition, bortezomib has been shown to have limited cardiac toxicity and no arrhythmogenicity in patients with AL and cardiac involvement (QJM 2011 published online July 13, 2011). Based on these data we have used CyBorD as initial standard therapy in patients with newly diagnosed systemic AL amyloidosis with advanced (stage III) cardiac involvement who are ineligible for stem cell transplant or clinical trials. We now retrospectively report the outcomes in the 11 consecutive stage III patients who have been treated thus far with CyBorD as initial standard therapy (6F, 5M). Patients were a median of 57 years old (range, 44–74) with median brain natriuretic peptide (BNP) of 709 (145–1490), troponin I of 0.29 (0.11–0.77), involved free light chains of 322mg/L (101–4325) and marrow plasma cells of 20% (4–41%). Median left ventricular (LV) ejection fraction and LV wall thickness (average of IVSd+LVPWd) by echocardiogram were 52% (35–70%) and 1.7cm (1.2–2.1) respectively. Patients received CyBorD on a 35-day cycle on days 1, 8, 15 and 22 with cyclophosphamide (300mg/m2) and dexamethasone (20 or 40mg flat dose) given orally or IV and bortezomib (1.3mg/m2) given IV or subcutaneously. Routine prophylactics included acyclovir, fluconazole and omeprazole. Patients have received a median of 4 cycles (1–8). Of the 11 patients, 2 died suddenly at 1 and 5 months, and 9 are alive with a median follow up of 8 months (3–15). Three patients experienced worsening congestive heart failure requiring hospitalization, medication adjustments and in 1 case pericardiocentesis. The gastrointestinal (GI) side-effects of bloating and constipation were common and usually manageable although 1 patient stopped therapy after 2 cycles because of lower GI bleeding. Of 10 patients evaluable for hematologic response, 8 responded (1 CR, 4 VGPR, 3 PR) (response criteria from Blood 2010;116:586a) and 2 had no response. Median time to response was 1 cycle (1–3). Thus far, there have been 4 patients (2 VGPR, 2 PR) who within months of starting therapy have had BNP reductions of 40% to 76% of baseline (median BNP reduction of 434pg/ml (282–712)). In conclusion, these retrospective data are encouraging and hopefully will spur the development of phase II and III trials in newly diagnosed patients with advanced cardiac involvement due to AL. Disclosures: Off Label Use: Pentostatin and Extracorporeal photopheresis are not FDA approved for conditioning prior to allogeneic transplant.

Assessment of disease severity and outcome in patients with systemic light-chain amyloidosis by the high-sensitivity troponin T assay

Blood ◽  
2010 ◽  
Vol 116 (14) ◽  
pp. 2455-2461 ◽  
Author(s):  
Arnt V. Kristen ◽  
Evangelos Giannitsis ◽  
Stephanie Lehrke ◽  
Ute Hegenbart ◽  
Matthias Konstandin ◽  
...  
Keyword(s):  
Light Chain ◽  
Cardiac Involvement ◽  
Troponin T ◽  
Interventricular Septum ◽  
High Sensitivity ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
Blood Levels ◽  
Al Amyloidosis ◽  
Light Chain Amyloidosis

Abstract Cardiac biomarkers provide prognostic information in light-chain amyloidosis (AL). Thus, a novel high-sensitivity cardiac troponin T (hs-TnT) assay may improve risk stratification. hs-TnT was assessed in 163 patients. Blood levels were higher with cardiac than renal or other organ involvement and were related to the severity of cardiac involvement. Increased sensitivity was not associated with survival benefit. Forty-seven patients died during follow-up (22.3 ± 1.0 months). Nonsurvivors had higher hs-TnT than survivors. Outcome was worse if hs-TnT more than or equal to 50 ng/L and best less than 3 ng/L. Survival of patients with hs-TnT 3 to 14 ng/L did not differ from patients with moderately increased hs-TnT (14-50 ng/L), but was worse if interventricular septum was more than or equal to 15 mm. Discrimination according to the Mayo staging system was only achieved by the use of the hs-TnT assay, but not by the fourth-generation troponin T assay. Multivariate analysis revealed hs-TnT, NT-proBNP, and left ventricular impairment as independent risk factors for survival. hs-TnT and NT-proBNP predicted survival, even after exclusion of patients with impaired renal function. Plasma levels of the hs-TnT assay are associated with the clinical, morphologic, and functional severity of cardiac AL amyloidosis and could provide useful information for clinicians on cardiac involvement and outcome.

scholarly journals The Effect of Cytogenetic Abnormalities on Organ Involvement and Survival in Patients with AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1833-1833
Author(s):  
Michael Ozga ◽  
Qiuhong Zhao ◽  
Don M. Benson ◽  
Patrick Elder ◽  
Nita Williams ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Plasma Cell ◽  
Cardiac Involvement ◽  
Response To Therapy ◽  
Al Amyloidosis ◽  
Prognostic Impact ◽  
Cytogenetic Abnormalities ◽  
Kidney Involvement ◽  
The Impact

Introduction: Systemic light chain amyloidosis (AL) is a clonal plasma-cell neoplasm that carries a poor prognosis. Efforts are being made at recognizing this disease earlier and developing better prognostic tools as AL is frequently diagnosed at an advanced stage. Cytogenetic analysis and its prognostic relevance have been well studied in multiple myeloma (MM), a related disorder, but remain relatively unknown and less widely reported in AL literature. Previous studies have demonstrated that AL amyloidosis exhibits an increased incidence of translocation t(11;14). However, with an extensive array of fluorescence-in-situ hybridization (FISH) probes now available, multiple other cytogenetic abnormalities are being identified in AL at diagnosis. In addition, it is well known that cardiac involvement in AL is an independent negative prognostic factor for these patients; however, the implications of cytogenetics for these high-risk patients remains largely unexplored. Finally, with the advent of novel non-transplant therapy options for AL patients, we look to evaluate the relevance of daratumumab in this setting. As such, the present study aims to a) determine the most relevant FISH abnormalities in AL patients and establish their importance as independent prognostic factors for response to therapy and in survival, b) assess the impact of cytogenetics on the survival of cardiac AL patients, and c) determine the effect of daratumumab on the survival of patients with AL. Methods: A retrospective chart review was performed on 140 consecutive AL patients treated at The Ohio State University. This cohort included 20 patients who received daratumumab. Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis. Hyperdiploidy was defined as trisomies of at least 2 chromosomal loci. Primary endpoints were progression free survival (PFS) and overall survival (OS), and Kaplan Meier curves were used to calculate PFS and OS. Results: The median age at diagnosis was 62 years (range: 33-88) and 55% were male. Median number of organs involved was 2, and 49% and 65% had cardiac and kidney involvement, respectively. Chromosomal abnormalities were detected in 86 (61%) patients. Translocation t(11;14) was the most prevalent (44%) aberration followed by hyperdiploidy (43%). We observed a statistically significant relationship between several FISH abnormalities and increased plasma cell burden (PC) (≥10%), including gain (+) 5p/5q (p=0.025), del13q (0.009), +11q (p<0.001), and hyperdiploidy (p<0.001). In addition, hyperdiploidy was associated with worsening of PFS (p=0.019) and OS (p=0.032) (Figure 1A). In multivariable analysis, hyperdiploidy was confirmed to be a poor prognostic marker after adjusting for other confounding variables. In patients with cardiac involvement, hyperdiploidy was also associated with worsening of PFS (p=0.0497) and OS (p=0.006) (Figure 1B). Del 13q was found to be associated with cardiac involvement (p=0.01) but showed no prognostic impact on survival. Conversely, survival benefit was seen among these patients with cardiac involvement who had no FISH abnormalities at diagnosis, both in terms of OS and PFS (p=0.019 and p=0.042, respectively). In addition, the overall presence of t(11;14) did not have any prognostic impact on OS (p=0.76) or PFS (p=0.41). However, on further stratification, we did observe a marginal difference in PFS (p=0.09) among four groups (Figure 1C), and more specifically, patients with presence of only t(11;14) did worse compared to those patients with normal FISH in terms of PFS (p=0.021). This potentially suggests that patients with t(11;14) only are at risk for earlier progression. Finally, we evaluated the efficacy of daratumumab, and observed a median OS of 6.1 years and median PFS 2.6 years. Of note, presence of gain 1q was associated with a trend toward better response to daratumumab. 100% of patients (5/5) with gain 1q achieved a hematologic partial response (PR) or better versus only 60% of patients without +1q. Conclusion: Our findings reveal the effect of hyperdiploidy on PC tumor burden, overall survival, and its importance within the high-risk cardiac AL patient population. The results with daratumumab in our patient subset with gain 1q is intriguing in its own right but identification of the mechanism by which the effect of this mutation is abrogated merits further exploration as its use only continues to grow. Disclosures Rosko: Vyxeos: Other: Travel support. Efebera:Takeda: Honoraria; Akcea: Other: Advisory board, Speakers Bureau; Janssen: Speakers Bureau.

scholarly journals Echocardiografic Abnormalities in Patients with Sickle Cell/β-Thalassemia Do Not Depend on the β-Thalassemia Phenotype

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 987-987
Author(s):  
Bruno Deltreggia Benites ◽  
Ianara Silva Cisneiros ◽  
Stephany Oliveira Bastos ◽  
Ana Paula Beppler Lazaro Lino ◽  
Fernando Ferreira Costa ◽  
...  
Keyword(s):  
Disease Severity ◽  
Sickle Cell ◽  
Cardiac Involvement ◽  
Myocardial Hypertrophy ◽  
Conflicts Of Interest ◽  
Systolic Function ◽  
Transferrin Saturation ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Acute Chest Syndrome

Abstract Introduction: Heart disease represents an important cause of mortality and morbidity in sickle cell disease and beta-thalassemia, however the impairment of cardiac function in compound heterozygotes, namely sickle cell/β-thalassemia (HbS/β-thal) remains less known. Studies with patients of Greek origin demonstrated abnormal diastolic function in both ventricules, with unchanged systolic function, and biventricular dilatation along with pulmonary hypertension (Aessopos, A., et al., Ann Hematol, 88(6), 2009, Moyssakis, I., et al., Postgrad Med J, 81(961), 2005). The aim of this study was to evaluate echocardiographic findings and clinical and laboratory parameters in a cohort of Brazilian HbS/β-thal patients to better understand the cardiac involvement in this particular ethnic background. Methods: A retrospective chart review was performed on thirty-six HbS/β-thal patients followed from 1998 to 2016. Medical records were reviewed for laboratory and clinical data, and hospital admissions were recorded for sickle related complications: acute chest syndrome, retinopathy, avascular bone necrosis, stroke, priapism, leg ulcers and venous thromboembolism. Echocardiographic evaluation was performed in all patients in steady-state disease, with pulsed, continuous, two-dimensional and color Doppler. Results: Among the studied population, 21 (58%) were women and 15 (42%) were men. The median age was 38 (18-70) years; 22 (61%) patients were diagnosed as Sβ0, and 14 (39%) as Sβ+. As expected, when the Sβ-thalassemia phenotype was considered, the two groups of patients differed significantly: hemoglobin levels were lower in Sβ0 patients, who also presented a higher proportion of HbS and HbF and higher transferrin saturation indexes. Sβ0 patients also demonstrated significantly lower body mass index and higher number of platelets highlighting disease severity in this subgroup of patients. Left atrial (LA) and left ventricular (LV) dilation were found in 19.5 and 11% of patients, respectively. These prevalences are considerably lower than observed in patients with SS phenotype: 78 and 35%, respectively (Damy et al, Eur Heart J, 37(14), 2016). Systolic LV disfunction (defined as LV ejection fraction &lt;59%) was present in only one patient of our cohort, though also uncommon in SS patients (8.5% in the study of Damy et al). There were no significant differences in masses and volumes of cardiac chambers comparing Sβ0 with Sβ+ patients, and we found no relationship between these parameters and the occurrence of specific complications of the disease. However, a significant correlation was found regarding parameters of myocardial hypertrophy with serum creatinine, hepatic transaminases and bilirubin levels. Moreover, among the 36 patients studied, 3 of them (1 Sβ+ and 2 Sβ0) presented stroke; these patients were significantly older (median 53 years x 37.5 years, p = 0.048), had higher values of left ventricular posterior wall diastolic thickness [8 (6-14) x 10 (10-11), p= 0.03], greater left ventricular mass [147 (69-537) x 226 (194-260), p= 0.039] and a significantly higher left atrium / aortic ratio (1.26 (0.9-1,48) x 1.545 (1.48-1.61), p= 0.032). No differences were found in pulmonary artery systolic pressure (PASP) between Sβ+ and Sβ0 patients and there was no relationship between PASP and the occurrence of acute or chronic complications. Discussion: In this cohort of Brazilian patients, we observed significant differences in hematological and clinical parameters between Sβ+ and Sβ0 patients, highlighting the difference in disease severity between the two groups. However, the profile of cardiac involvement analyzed by echocardiography was similar in both groups: higher prevalence of diastolic dysfunction with little systolic function impairment, which follows the patterns of the patients of greek origin. Nevertheless, parameters of myocardial hypertrophy were related to multiorgan impairment, and rendered a higher propensity for stroke in older patients. Thus, cardiac involvement in this disease seems to not depend on the thalassemia phenotype. This may also reflect the older age of subjects evaluated, demonstrating that the exposure to the disease features (anemia/hemolysis/inflammation) renders homogeneity in cardiac damage over time, and represents an alert for greater vigilance and control of associated factors, as hypertension and diabetes. Disclosures No relevant conflicts of interest to declare.

P0067PREDICTORS OF LONG-TERM OUTCOME IN A SPANISH COHORT OF PATIENTS WITH FABRY DISEASE ON ENZYME REPLACEMENT THERAPY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Marian Goicoechea ◽  
Francisco Gomez-Preciado ◽  
Silvia Benito ◽  
Joan Torras ◽  
Roser Torra ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Fabry Disease ◽  
Replacement Therapy ◽  
Left Ventricular ◽  
Response To Therapy ◽  
Clinical Event ◽  
Enzyme Replacement ◽  
Clinical Events ◽  
The Impact

Abstract Background and Aims Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in Fabry disease patients on ERT. Method Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). Results In 69 patients (42 males, 27 females, mean age 44.6 ±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242 to 128 mg/g (p = 0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR ≤60 ml/min/1.73 m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043), being these differences more relevant in females (log Rank 18.514, p&lt;0.001) than males (logRank: 3.442, p=0.064). Lower baseline eGFR was associated with a 3- to 7-fold increase in the risk of clinical events in different Cox models. Conclusion GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes. For the first time, we show that initiation of ERT in women before renal function deteriorates has a similar or even larger impact as in Fabry males to prevent clinical events.

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.

Increases In B-Type Natriuretic Peptide (BNP) During Treatment with Lenalidomide In AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3021-3021
Author(s):  
Umit Tapan ◽  
David C Seldin ◽  
Kathleen T Finn ◽  
Salli Fennessey ◽  
Anthony C Shelton ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Cardiac Involvement ◽  
Troponin I ◽  
Medical Center ◽  
Nyha Class ◽  
Early Time ◽  
Response To Therapy ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis

Abstract Abstract 3021 The combination of lenalidomide and dexamethasone can produce partial and complete hematologic responses in previously treated patients with AL amyloidosis (Blood 2007; 109: 492–496). Since this prospective study was initiated, NT-proBNP and BNP have been found to be useful biomarkers for cardiac involvement, prognosis, and response to therapy in AL amyloidosis patients. Here we report on the retrospective analysis of the prospectively collected data on changes in BNP during lenalidomide therapy on this trial. Increase in BNP was defined as > 30% increase from baseline value at enrollment on the trial after cycles 1 and 3. Patients with BNP of < 100 pg/mL at baseline, and after 1 and 3 cycles as well as patients in whom BNP levels were not measured were excluded in this analysis. Sixty-eight patients with AL amyloidosis were treated with lenalidomide and dexamethasone (ClinicalTrials.gov: NCT00091260) at Boston Medical Center. The median age was 64 years (range, 42 to 85); and 69% were male. Fifty-one patients (75%) had lambda clonal plasma cell dyscrasia, and 38 (56%) had cardiac involvement. All patients received lenalidomide and dexamethasone as described in our previous report. Twenty-four of the 68 total patients enrolled did not meet the eligibility to be included in this analysis due to either BNP levels of < 100 pg/mL at baseline and at 1 and 3 months after treatment or unavailability of BNP measurement after 1 or 3 cycles of lenalidomide. Therefore, 44 patients are included in this analysis. Thirty-eight patients (86%) had > 30% increase in BNP level from baseline after initiation of lenalidomide treatment. Of these 38 patients, 30 (79%) had an increase after 1 cycle and additional 8 (21%) patients after 3 cycles of lenalidomide. The mean dose of lenalidomide for patients with increase in BNP after 1 cycle was 15 mg (range, 5–25) and after 3 cycles was 10 mg (range, 5–15). Forty % (n=12/30) and 63% (n=5/8) of patients did not receive dexamethasone with lenalidomide when increase in BNP was seen after 1 and 3 cycles, respectively. Of the patients with increase in BNP, only 5 patients (13%) had worsening of renal function from baseline. Moreover, increase in BNP after 1 and 3 cycles occurred in 23 of 29 patients (79%) with cardiac involvement. Cardiac troponin I levels were not measured after 1 and 3 cycles of lenalidomide. All the patients with increase in BNP were asymptomatic without association of modification in NYHA class congestive heart failure. The median survival of these 44 patients is 53 months since initiation of lenalidomide therapy. At these early time pointsof 1 and 3 months, 20% (n=9/44) of patients had >50% improvement in serum free light chain levels, and 2% (n=1/44) of patients had improvement in BNP of 30% or more. In conclusion, BNP increased by > 30% in a substantial proportion of patients with AL amyloidosis during treatment with lenalidomide. The mechanism for asymptomatic rise in BNP is not clear; however, the temporal relationship with lenalidomide initiation, the relatively rapid increase, and the absence of other identifiable precipitants for most of the patients suggest that lenalidomide may be playing a role. Moreover, patients with AL amyloidosis receiving lenalidomide whose BNP rises should not be assumed to be failing therapy without other signs of disease progression, but should be monitored closely and treated as needed for signs or symptoms of congestive heart failure should they occur. Disclosures: Off Label Use: Use of lenalidomide in AL amyloidosis. Zeldis:Celgene Corp: Employment.

Bortezomib with Dexamethasone in Newly Diagnosed Patients with Primary Systemic Light Chain Amyloidosis or Multiple Myeloma-Associated AL Amyloidosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5036-5036 ◽  
Author(s):  
Beihui Huang ◽  
Juan Li ◽  
Junru Liu ◽  
Dong Zheng ◽  
Mei Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
Hematologic Response ◽  
Best Response ◽  
Organ Response

Abstract Abstract 5036 Objective: To assess the efficacy and tolerability of bortezomib with dexamethasone for patients with primary systemic light chain (AL) amyloidosis or multiple myeloma-associated AL amyloidosis. Methods: Twelve newly diagnosed patients with primary systemic AL amyloidosis and six patient with multiple myeloma-associated AL amyloidosis were treated with a combination of bortezomib (1. 3 mg/m2 d1, 4, 8, 11) and dexamethasone (20 mg d1–4). Results: Sixteen patients was evaluable. 12/16 had a hematologic response and 6/16 (37. 5%) a hematologic complete response. Median cycles to response was 1 cycle and median cycles to best response was 2 cycles. In patients with primary AL amyloidosis, 8/10 (80. 0%) had a hematologic response and 5/10 (50. 0%) a hematologic complete response. In patients with myeloma-associated AL amyloidosis, 7/10 (70. 0%) had a hematologic response and 1/6 (16. 7%) a hematologic complete response. Twelve patients (75. 0%) had a response in at least one affected organ, in which 7 in patients with primary AL amyloidosis and 5 in myeloma-associated AL amyloidosis. Person correlation between hematologic response and organ response was 0. 667 (p=0. 005). Fatigue, diarrhea and infection were the most frequent side effects. Three patients developed herpes zoster and had to stop chemotherapy. Conclusions: VD produces rapid and high hematological responses in the majority of patients with newly diagnosed AL regardless of primary or associated with myeloma. It is well tolerated with few side effects. This treatment may be a valid option as first-line treatment for newly diagnosed patients with primary systemic AL amyloidosis and multiple myeloma-associated AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

A Prospective Study of Treatment Outcomes in 179 Patients with Advanced Cardiac Stage STAGE IIIb Amyloidosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5357-5357
Author(s):  
Belen Sevillano ◽  
Ashutosh Wechalekar ◽  
Darren Foard ◽  
Carol Whelan ◽  
Marianna Fontana ◽  
...  
Keyword(s):  
Partial Response ◽  
Prospective Study ◽  
Treatment Outcomes ◽  
Cardiac Involvement ◽  
Left Ventricular ◽  
Stage Iiib ◽  
Stage Iii ◽  
Al Amyloidosis ◽  
Hematological Response ◽  
A Prospective Study

Abstract A PROSPECTIVE STUDY OF TREATMENT OUTCOMES IN 179 PATIENTS WITH ADVANCED CARDIAC STAGE IIIB AMYLOIDOSIS Authors: Belen Sevillano, Darren Foard, Carol Whelan, Mariana Fontana, Critina Quarta, Shameem Mahmood, Helen Lachmann, Julian Gillmore, Philip Hawkins and Ashutosh Wechalekar INTRODUCTION The prognosis of systemic light chain amyloidosis is determined by extent of cardiac involvement. The Mayo cardiac staging system (Dispenzieri et al JCO 2004) is widely used for prognosis and we defined a particularly poor prognostic subgroup within Mayo stage III patients (Wechalekar et al Blood, 121(17), 2013) characterized by NT-proBNP >8500 ng/L with a median survival of 4 months-stage IIIb disease. All such patients are excluded from clinical trials and treatment outcomes of this group are not known. We report the treatment outcomes of a cohort of stage IIIb cardiac AL patients prospectively followed up in the ALChemy study PATIENTS AND METHODS. All patients from the ALChemy study (a prospective observational study of all patients with AL amyloidosis undergoing chemotherapy) at the UK National Amyloidosis Centre (identified from first 1000 patients recruited into the study from 2009 to Jan 2015) with Mayo stage IIIb cardiac AL (defined as NT-proBNP >8500 ng/L and cardiac troponin T >0.035 μg/L) were included. All were treated according to nationally agreed protocols. Organ involvement and hematologic/amyloidotic organ responses were assessed according to 2010 amyloidosis consensus criteria. The primary outcome measure was overall survival (OS) and impact of hematological response on survival. Statistical analysis was undertaken using SPSS software package. Survival was assessed by the Kaplan-Meier method and compared by log-rank test. RESULTS A total of 179 patients were included. The median age was 65 yrs, 77 (43 %) were female and 102 (57 %) male. All patients had cardiac involvement, renal involvement was seen in 131 (73.2 %) and liver involvement in 28 (15.6 %). The median NT-proBNP was 19056 ng/L (range 8500 - 70084 ng/L). The median left ventricular (LV) wall thickness was 14.2 mm (range 11-22 mm) and median ejection fraction (EF) was 48.7 % (23-75 %). 34 % had dyspnea ≥ NYHA grade 3 and 16.8 % had ECOG performance status ≥3. Only 68 (38 %) patients managed a 6 min walk test and median distance was 130.5 m. 30 (17 %) patients died prior to treatment initiation. Initial treatment regimens were: Bortezomib combinations - 48 % (87); Thalidomide or Lenalidomide combinations in 28 % (51), alkylators based regimens - 5 % (9) and rituximab based in 1 %. The hematological best responses on an intention to treat basis were: complete response (CR) - 35w (20%), very good partial response (VGPR) 25 (13%), partial response (PR) 32 (18%) and no response (NR) 87 (47%) (NR included patients who died before treatment). The median OS for the cohort was 6 months (mo). Univariate and ROC analysis identified LVEF >55%, dFLC <400 mg/L and SBP >110 mm of Hg predictors of OS. The median OS was significantly better for patients with LVEF>55% (13 mo); for dFLC < 400 mg/L was 7 mo (vs. 3 mo for dFLC >400 mg/L); and for those with SBP > 110 mmHg was 10 mo (vs. 5 mo in those with lower SBP). Median OS for patients achieving a CR/VGPR at day 30 was 26 mo compared to 5 mo for patients with <VGPR at that time. The median OS for patients who finally achieved CR/VGPR was 38 mo, PR 7 mo and NR was 2.6 mo (log rank p<0.0001) (Fig 1). In a multivariate model, achieving a hematological CR/VGPR (HR 5.3), LVEF <55% (HR1.5), dFLC >400 mg/L (HR 1.3) and SBP <110 mm of Hg (HR 1.5) were independent predictors of outcomes. CONCLUSIONS: The survival of stage IIIb AL remains poor but has improved compared with historical reported series. The survival of patients who achieve a CR or VGPR is over 3 years. Early achievement of ≥VGPR, as early as end of cycle 1, seems to predict for a better survival challenging the practice of treating stage III patients with "low" dose chemotherapy which often leads to slower clonal responses. This study confirms that, even in this advanced group of patients, a rapid hematological response will translate into improved outcomes. Since most non-responders to the first 1 or 2 cycles succumb to progressive disease, prospective studies are urgently needed to design rapidly effective well tolerated regimes possibly with combination of anti-amyloid therapy. Disclosures No relevant conflicts of interest to declare.

Impact of Cardiac Stage and Hematologic Response on AL Amyloidosis Patients with Renal Involvement

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2136-2136
Author(s):  
Sandy W. Wong ◽  
Denis Toskic ◽  
Melissa Warner ◽  
Alejandro Moreno-koehler ◽  
Daniel Fein ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Renal Involvement ◽  
Al Amyloidosis ◽  
Employment Equity ◽  
Intention To Treat ◽  
Hematologic Response ◽  
Equity Ownership ◽  
Stage 1

Abstract Cardiac stage and depth of hematologic remission are major predictors of survival for AL amyloidosis patients (Wechalekar et al., Blood, 2013; Dispenzieri et al., JCO, 2004; Palladini et al., JCO, 2012). Renal staging in AL amyloidosis (AL) has been studied in the context of renal survival (Palladini et al., Blood 2014). Influences on survival for renal patients have yet to be fully defined. We performed a retrospective study of all AL patients with renal involvement diagnosed at our center between 7/1/08 and 6/30/15. In this cohort of consecutive patients (n=80) median age was 63 (IQR 55-70) and 56% were men. Eighty-eight percent had lambda plasma cell disease and median involved FLC was 140mg/L (69-485). Thirty-nine percent were renal stage 1, 44% stage 2, and 16% stage 3. Median 24-hour proteinuria and serum creatinine were 6.23 g (3.47-10.70) and 1.03 mg/dL (0.80-1.80) respectively, and median eGFR was 72 mL/min (41-90). Fifty-eight percent had cardiac involvement, of whom 11% were cardiac stage 1, 54% stage 2, and 34% stage 3, while 18% had GI and 9% peripheral nerve involvement. As first-line therapy, 70% received bortezomib-based regimens and 25% melphalan-based autologous stem cell transplant. By intention-to-treat, at 6 months after beginning therapy, 54% of patients had a hematologic response of PR or better, and renal and cardiac responses occurred in 13% and 14% of patients respectively, while renal progression occurred in 6%. Median overall survival (OS) for this cohort (n=80) was 67 months. Those with cardiac involvement (n=45) had a median OS of 41 months and, while median OS was not reached for cardiac stage ≤ 2, it was 31 months for those who were stage 3 (P<0.05) (Figure). Median OS was also not reached for patients achieving hematologic response ≥ VGPR with a median follow-up of 19 months. In conclusion, for AL patients with renal involvement, both cardiac stage and depth of hematologic response are important contributors to overall survival. Furthermore, as this real world intention-to-treat analysis demonstrates, there is a continuing need for better therapies for both the hematologic disease and the organ damage associated with AL. Figure. Figure. Disclosures Oliver: Prothena Biosciences, Inc.: Employment, Equity Ownership. Guthrie:Prothena: Employment, Equity Ownership, Other: Leadership. Comenzo:Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Karyopharm: Research Funding; Janssen: Consultancy, Research Funding.

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