M Skinner

Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes.

OBJECTIVE: To determine whether patients with myocardial amyloidosis due either to AL (primary) amyloid or familial amyloid have distinguishing echocardiographic or electrocardiographic features; and to compare the prevalence of heart failure and survival in the two types of amyloidosis in relation to echocardiographic findings. DESIGN: Blinded group comparison of randomly selected cases of cardiac amyloidosis. SETTING: International referral centre for amyloid research and treatment. PATIENTS: 36 patients with cardiac amyloid heart disease, of whom 12 had familial and 24 had primary AL amyloidosis. RESULTS: Familial and AL echocardiograms were morphologically indistinguishable, with similar left ventricular wall thickness, mean (SD) 15.4 (2.3) nu 15.8 (2.5) mm, respectively; right ventricular wall thickness was also similar between amyloid types: 9.6 (2.8) nu 9.7 (6.5) mm, respectively. Doppler indices of left and right ventricular function, left ventricular volume, and ejection fraction were also similar. Low voltage electrocardiograms (< 0.5 mV) were more common in the AL (16/24, 67%) than in the familial group (4/12, 25%), P < 0.05. The one year survival for familial and AL forms was 92% (11/12) nu 38% (6/24), respectively, with virtually all deaths due to cardiac causes. CONCLUSIONS: Although cardiac involvement is echocardiographically indistinguishable, cardiac mortality is very different between the two forms of amyloidosis. Preservation of electrocardiographic voltage in familial amyloidosis suggests that the particular biochemical characteristics of distinct types of amyloid fibril have different pathological effects on the myocardium. This distinction becomes critical in the evaluation, treatment, and management of patients who have a diagnosis within the spectrum of the protein deposition diseases.

An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis

Primary or AL amyloidosis results from a plasma cell dyscrasia in which fibrillar light chain protein deposition leads to organ failure and death. Standard treatment for AL amyloidosis has been oral melphalan and prednisone. However, this form of treatment modifies the natural history of this lethal disease only marginally, extending median survival from 13 months following diagnosis to 17 months. At Boston University Medical Center, we have developed treatment protocols using high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT) to treat AL amyloidosis, and we have treated over 200 patients with HDM/SCT during the past six years. This extensive experience has shown that patients with AL amyloidosis, despite multisystem involvement and compromised organ function can tolerate this aggressive form of treatment. Furthermore, HDM/SCT results in durable hematologic responses in a substantial proportion of patients, and such responses are associated with clinical improvement, decreased amyloid-related organ dysfunction, and prolonged survival. However, toxicity from treatment is high (overall peri-transplant mortality, 14%), particularly for those patients with clinically significant cardiac involvement. For this reason, we believe a multidisciplinary management approach is essential when using HDM/SCT for treatment of AL amyloidosis. Based on our experience, we believe that HDM/SCT is the treatment of choice for patients with AL amyloidosis who have a good performance status and limited cardiac involvement at the time of diagnosis. HDM/SCT offers the best chance for hematologic remission, prolongation of survival, and reversal of amyloid-related disease. At the same time, we believe that HDM/SCT should continue to be examined in the context of clinical trials, directed at developing approaches to broaden the applicability of this therapy by minimizing toxicity and to increase the likelihood of complete hematologic responses. Bone Marrow Transplantation (2001) 28, 637–642.

Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis.

This manuscript summarizes the recommendations that emerged from the first Roundtable on Clinical Research in Immunoglobulin Light-chain Amyloidosis (AL), a meeting sponsored by the Amyloidosis Foundation (Clarkston, MI, USA) to develop a consensus of experts on a modern framework for clinical trial design and drug development in AL. Recent diagnostic and technical advances in AL, and updated consensus guidelines for assessing hematologic and organ responses, enable us to define study populations, appropriate end points, and other criteria for all phases of clinical research. This manuscript provides a framework for the design and conduct of systematic collaborative clinical research in AL to encourage more rapid testing of therapies and to expedite new drug development and approval.

Tracheobronchial amyloidosis. The Boston University experience from 1984 to 1999.

Tracheobronchial amyloidosis (TBA), an idiopathic disorder characterized by deposition of fibrillar proteins in the tracheobronchial tree, occurred in 10 patients referred to the Amyloid Program at Boston University over the past 15 years. Fewer than 100 cases of TBA have been described; only 1 series encompassed more than 3 patients. We analyzed our experience with biopsy-proven TBA to define better its natural history. Follow-up averaged approximately 8 years and was obtained in all cases, making this outcome reporting the largest and most complete to date. Three of these patients were prospectively studied for up to 24 months to examine the utility of bronchoscopy, computerized tomography (CT) imaging, and pulmonary function tests (PFTs) in monitoring disease progression. No patient with TBA developed signs or symptoms of systemic amyloidosis during the period reviewed. Conversely, tracheobronchial disease was not diagnosed in 685 patients with primary systemic (AL) amyloidosis during the 15-year study period at Boston University. Bronchoscopy proved most useful in establishing the diagnosis by biopsy. Narrowing of major airways limited its inspection of the tracheobronchial tree, however. In contrast, CT imaging provided quantitative assessment of airway narrowing and mural thickening--2 major consequences of amyloid infiltration. These CT features, in the presence of mural calcifications sparing the posterior tracheal membrane, have been reported in few disorders other than TBA. The ability of CT to map airway involvement and identify extraluminal manifestations of TBA made it the study of choice for establishing disease extent. Three patterns of disease were evident by CT imaging and bronchoscopic examination: proximal, mid, and distal airways involvement. Those with severe proximal disease had significantly decreased air flows, air trapping, and fixed upper airway obstruction on PFTs. Patients with distal disease had normal airflows. PFTs could not clearly distinguish proximal from severe mid airways disease. Thirty percent of patients died within 7-12 years after diagnosis, all having proximal or severe mid airways disease. Repeated rigid bronchoscopic debridement and laser treatments did not prevent progressive airways narrowing in patients dying from TBA. Most patients with mid airways involvement, and all distal airway cases, had either stagnant disease or slowly increasing amyloid deposits when followed for up to 14 years. In a small subset of patients followed prospectively, serial PFTs were most sensitive to disease progression. CT-derived measures of airway lumen diameter and wall thickness did not change significantly despite marked improvements in airflow after rigid bronchoscopy. Our experience suggests that serial PFTs and CT imaging together offer the best assessment of airway involvement and disease progression in patients with TBA. In the future, radiation therapy may provide more definitive treatment of TBA than debulking procedure have to date.

High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective randomized trial

Summary:A prospective randomized trial was conducted to study the timing of high-dose intravenous melphalan and autologous stem cell transplantation (HDM/SCT) in AL amyloidosis. In all, 100 newly diagnosed patients were randomized to receive HDM/SCT, either as initial therapy (Arm-1) or following two cycles of oral melphalan and prednisone (Arm-2). The objectives of the trial were to compare survival and hematologic and clinical responses. With a median follow-up of 45 months (range 24–70), the overall survival was not significantly different between the two treatment arms (P=0.39). The hematologic response and organ system improvements after treatment did not differ between the two groups. Fewer patients received HDM/SCT in Arm-2 because of disease progression during the oral chemotherapy phase of the study, rendering them ineligible for subsequent high-dose therapy. This affected patients with cardiac involvement particularly, and led to a trend for an early survival disadvantage in Arm-2. Hence, newly diagnosed patients with AL amyloidosis eligible for HDM/SCT did not benefit from initial treatment with oral melphalan and prednisone, and there was a survival disadvantage for patients with cardiac involvement if HDM/SCT was delayed by initial oral chemotherapy.

Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation.

Thrombus formation in the left atrium is rare in patients in sinus rhythm. In three patients with extensive cardiac amyloidosis transthoracic echocardiography showed large atrial thrombi in or protruding into the body of the left atrium during sinus rhythm. Doppler studies showed no A wave on mitral inflow. Severe atrial and ventricular infiltration by amyloid may have resulted in mechanical atrial standstill with resultant thrombus formation. These findings suggest that patients with severe cardiac amyloidosis may require anticoagulation when atrial function is impaired.

Mobilized CD34+ cells selected as autografts in patients with primary light‐chain amyloidosis: rationale and application

BACKGROUND: Concern about tumor cell contamination in stem cell preparations has led to the use of CD34+ cell selection as a means of purging. Increasing the number of CD34+ cells per leukapheresis may help to provide an adequate dose of CD34+ cells. STUDY DESIGN AND METHODS: The reverse transcriptase polymerase chain reaction (RT‐PCR) was employed to clone overexpressed clonotypic immunoglobulin light‐ chain variable region genes (Ig VL) from bone marrows of patients with primary light‐chain amyloidosis (AL). Patient‐specific primers were designed to evaluate stem cell collections for contamination. CD34+ cell selection was performed on components from AL patients who underwent mobilization with granulocyte‐colony‐stimulating factor (G‐ CSF) (filgrastim; 16 microg/kg/d for 4 days) and collection by large‐ volume leukapheresis (LVL;25L) on Days 4 and 5. The selected cells alone were transfused after patients received mephalan (200 mg/m2). RESULTS: Contamination was found in collections from 4 to 7 patients, which provided the rationale for a subsequent trial of CD34+ cell selection. The median number of CD34+ cells per kg collected on Days 4 and 5, and in toto, was 4.0 × 10(6)(1.1‐12.7), 7.9 × 10(6)(1.8‐12.7), and 10.7 × 10(6)(2.9‐25.4), respectively (n = 9 patients). The median yield per selection was 38 percent, with a purity of 85 percent (45‐ 97%), and the viability of CD34+ cells averaged 96.4 +/− 3.6 percent (n = 18 selections). The median number of CD34+ cells infused was 5.9 × 10(6) per kg (2.1‐10.1). In comparison with AL patients given unselected autografts, patients receiving selected CD34+ cells experienced similar reconstitution of neutrophils and platelets but slower lymphocyte recovery. CONCLUSION: Patients with AL often have contamination with clonotypic cells in their blood autografts. G‐CSF mobilization and LVL provide components that allow the selection of adequate doses of CD34+ cells. The use of CD34+ cells in patients with AL achieves rapid neutrophil and platelet recovery but delayed lymphocyte recovery. CD34+ cell selection is feasible in the treatment of AL, but its effectiveness in purging clonotypic cells remains to be ascertained.

Clinical features and survival in senile systemic amyloidosis: comparison to familial transthyretin cardiomyopathy

Senile systemic amyloidosis (SSA) features cardiomyopathy resulting from amyloid deposits of wild-type transthyretin (TTR). From 1994 to 2009, 82 patients with SSA were diagnosed at our center; 79 were men (96%) and median age at diagnosis was 73.8 years (range, 59.1–86.0). Most patients (77/78) presented with abnormal echocardiography; median values for interventricular septal thickness and left ventricular ejection fraction were 16 mm (range, 9–24) and 50% (range, 20–70), respectively. Fat aspirates were positive for amyloid in 27% of patients. Mean levels of brain natriuretic peptide (n = 41) and troponin I (n = 19) were 422 ± 279 pg/ml and 0.151 ± 0.107 pg/ml. Median survival was 4.3 years (95% CI, 3.7–5.0). SSA and familial TTR cardiomyopathy were compared; survival distribution was significantly different across groups (log-rank test = 11.97, p-value = 0.0075). We conclude that patients with SSA are primarily men who present with dominant cardiac involvement at an older age than patients with familial TTR cardiomyopathy.

Regression of cardiac wall thickness following chemotherapy and stem cell transplantation for light chain (AL) amyloidosis

Increased cardiac wall thickness (WT) is a hallmark of amyloid cardiomyopathy. Sporadic reports have suggested that there may be a regression of cardiac WT after successful therapy of primary amyloidosis (AL), however no systematic studies exist. We retrospectively analyzed measures of WT in sequential patients with AL disease and cardiac involvement (ALC) undergoing high-dose melphalan chemotherapy and stem cell transplant (HDM/ SCT) at our center between 2003 and 2006. WT data were available for 55 patients, of which 21 (38%) were classified as complete hematological response (CR) and 34 (62%) as non-CR. In subjects with CR, average WT decreased 1.07+ 1.98 mm. In non-CR, average WT increased 0.37+ 2.21 mm. The between group difference in change in WT was statistically significant. In this analysis, echocardiographic regression of WT was observed in a substantial fraction of subjects with ALC and CR after HDM/SCT. Introduction: Increased cardiac wall thickness (WT) is a hallmark of cardiac amyloidosis [1]. HDM/SCT can induce a sustained complete hematologic response in about 40% of patients treated for AL [2]. Sporadic reports have described a decrease in cardiac WT in patients with cardiac amyloidosis and successful therapy of underlying AL [3,4]. Our aim was to systematically assess the change in WT in patients treated with HDM/SCT at our center. Methods: Consecutive patients with AL undergoing a first HDM/SCT at our center between January 2003 and December 2006 were included in this study. ALC was diagnosed by experienced clinicians taking into account clinical history, laboratory, electrocardiographic, and echocardiographic data. Response to HDM/SCT was determined by clinical and hematologic assessment 6 and 12 month after therapy and then annually. Echocardiography was repeated at each evaluation. WT recordings were obtained from the medical record. Hematologic response was graded as CR (defined as absence of monoclonal protein in serum and urine by immmunofixation electrophoresis, absence of clonal plasma cells in bone marrow biopsy, and normalization of serum free light chain concentration and ratio) or non-CR. Patients were grouped by hematologic response to HDM/SCT assessed after 6 or 12 months. WT immediately prior to HDM/SCT was compared to the most recent measurement after a period of stable hematologic response from HDM/SCT over time, to obtain a group of CR subjects with homogenous hematologic response data (i.e. a patient with CR for 36 months after HDM/SCT who subsequently relapses was included in the CR group and WT immediately before treatment was compared to WT measured at 36 months). Results and discussion: Eighty-five patients with cardiac amyloidosis underwent a first HDM/SCT therapy at our center between January 2003 and December 2006. Serial echocardiographic data were available for 55 patients. Pre-treatment echo data were obtained a median 52 days (range 0–170 days) prior to HDM/SCT. Twenty-one patients (38%) were grouped as CR with a median interval of 1131 days (range 408–2076 days) between WT assessments. Thirty-four patients (62%) were grouped as non-CR with a median interval of 468 days (range 203–1993 days) between WT assessments. Average changes in WT are displayed in Figure 1. In CR, WT decreased from a baseline of 12.1+ 2.5 mm to 11.1+ 2.3 mm (p1⁄4 0.0016, paired t-test). In nonCR, WT remained unchanged (12.7+ 2.5 mm to 13.0+ 3.5 mm; p1⁄4 0.21, paired t-test). WT was not different between CR and non-CR group at baseline (p1⁄4 0.28, unpaired t-test). After HDM/SCT WT in CR was lower than in non-CR (p1⁄4 0.0018, unpaired t-test). Averaged WT decreased 41 mm in nine patients (43%) with CR and in eight patients (24%) with non-CR (see Figure 2). Findings were similar when only patients with WT 12 mm at baseline [5] were included in the analysis. Plotting of WT change against time interval between assessments did not show a linear relationship between these two variables, either when all patients were considered, Figure 1. Wall thickness preand postHDM/SCT (mean+SD). 130

Immunologic recovery after autologous blood stem cell transplantation in patients with AL-amyloidosis

We prospectively studied absolute lymphocyte (ALC) and monocyte counts (AMC), lymphocyte subsets and proliferative in vitro responses to mitogen and antigen in 12 patients with AL-amyloidosis (AL) undergoing autologous blood stem cell transplantation (SCT) with high-dose i.v. melphalan. Myeloid and lymphoid recovery (>500 per μl) occurred in a median of 10 days post SCT. While there was a continuous decline in the number of CD4+ T cells at 3 months, ALC, AMC, B cells (CD19+), CD8+ T cells, and NK cells (CD16+/56+) returned to baseline. While T cell proliferative responses to phytohemagglutinin (PHA) remained depressed, B cell function measured by the proliferative response to staphylococcal antigen returned to baseline by 3 months. To supplement our findings, we retrospectively evaluated ALC, AMC and serum immunoglobulin levels in a separate group of patients treated with the same protocol at our institution. ALC and AMC recovery was similar to the pattern observed in the initial study group. Immunoglobulin levels remained within normal ranges at 3 and 12 months after SCT. Of 50 patients who were followed for a minimum of 1 year following SCT, seven (14%) developed shingles and one (2%) had PCP pneumonia. In conclusion, cellular immune function, reflected by absolute numbers of CD4+ T cells and PHA responsive T cell proliferation, is significantly suppressed at 3 months after SCT in patients with AL, and this post-transplant immunosuppression is associated with a low but clinically meaningful occurrence of opportunistic infections typical of T cell immunosuppression.Bone Marrow Transplantation (2001) 28, 1105–1109.