John Mark Sloan

Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation: 20-year experience.

To the editor: In immunoglobulin light chain (AL) amyloidosis, amyloid fibril deposits, derived from immunoglobulin light chains produced by a clonal plasma cell dyscrasia, accumulate in extracellular tissues and damage vital organs.[1][1] High-dose melphalan and autologous stem cell

Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement.

In Ig light chain (AL) amyloidosis, cardiac involvement is associated with worse prognosis and increased treatment-related complications. In this retrospective cohort study, we assessed survival, hematologic and cardiac responses to high-dose melphalan and auto-SCT (HDM/SCT) in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarkers brain natriuretic peptide and Troponin I, analogous to the Mayo cardiac staging. Forty-seven patients underwent HDM/SCT based upon functional measures; six patients had modified cardiac stage I disease, seventeen had modified cardiac stage II disease and twenty-four had modified cardiac stage III disease. Treatment-related mortality was 4% for all patients and 8% for patients with stage III disease. Three-year survival was 88% and EFS was 47%; these did not differ by stage. By intention-to-treat analysis, 27% of patients achieved a hematologic complete response and 32% a very good partial response, of whom 70 and 45%, respectively, have not required additional therapy at 36 months. Cardiac response was achieved in 53% of patients. We conclude that with appropriate patient selection and a risk-adapted treatment approach, HDM/SCT is safe and effective in patients with AL amyloidosis and cardiac involvement.

High-dose melphalan and autologous stem cell transplantation for AL amyloidosis: recent trends in treatment-related mortality and 1-year survival at a single institution

Treatment with high-dose melphalan chemotherapy supported by hematopoietic rescue with autologous stem cells produces high rates of hematologic responses and improvement in survival and organ function for patients with AL amyloidosis. Ongoing clinical trials explore pre-transplant induction regimens, post-transplant consolidation or maintenance approaches, and compare transplant to non-transplant regimens. To put these studies into context, we reviewed our recent experience with transplant for AL amyloidosis in the Amyloid Treatment and Research Program at Boston Medical Center and Boston University School of Medicine. Over the past 10 years, there was a steady reduction in rates of treatment-related mortality and improvement in 1-year survival, now approximately 5% and 90%, respectively, based upon an intention-to-treat analysis. Median overall survival of patients treated with this approach at our center exceeds 7.5 years. Introduction: Treatment of AL amyloidosis patients with high-dose intravenous melphalan chemotherapy and autologous hematopoietic stem cell support (HDM/SCT) produces a high rate of hematologic complete responses and improvement in organ function. Nephrotic syndrome can resolve [1], myocardial wall thickness can decline (MeierEwert et al., this volume), and quality of life improves [2]. Good outcomes are dependent upon the safe application of the therapy. Our first large patient series, published in 2004, reported a 100 day treatment-related mortality (TRM) of 14% [3]. Since then, we have refined patient selection and transplantation techniques and seen a concomitant decline in the rate of serious complications. Methods: Data on patients evaluated and treated in the Amyloid Treatment and Research Program at Boston University School of Medicine and Boston Medical Center were collected under protocols approved by the Boston University Medical Campus IRB after informed consent was signed. Data on patients enrolled into protocols using HDM/SCT from January 2000–December 2009 were reviewed retrospectively. Survival of all patients was determined through the end of December 2010, providing at least 1 year of follow-up on 100% of patients. Kaplan-Meier survival and confidence intervals for median overall and event-free survival were determined. Results and discussion: In the 10-year-period from January 2000 through December 2009, 323 patients began treatment on institutional or cooperative group protocols using HDM/SCT. The age range of enrolled patients was 28–80 years (median 57). The overall TRM was 8.4%, and the 1-year survival (1 YS) was 86.1% by intention-to-treat analysis. In the more recent 5-year-period from January 2005 through December 2009, 158 patients were treated; the age range was 28–77 years (median 57), the TRM was 5.1%, and the 1YS was 89.2%. Annual trends are plotted in Figure 1. The overall survival and progression free survival of all 323 patients are plotted in Figure 2. We attribute these improvements to two factors: firstly, rigorous selection of appropriate patients; and secondly, experienced multidisciplinary management during the peri-transplant period. Appropriate patient selection requires a comprehensive multidisciplinary clinical evaluation. The key evaluation components are summarized below. Chronological age is not a critical factor [4]. Patients who are potential candidates for HDM/SCT are assessed by sub-specialists highly familiar with the clinical manifestations of amyloidosis and with the complications of HDM/SCT. Cardiopulmonary function: Many studies have demonstrated that outcomes for patients with AL amyloidosis are driven by cardiac disease, defined by clinical parameters, echocardiographic parameters, and biomarkers for cardiac function. We use all of these to judge cardiac risk, including careful review of symptoms, physical examination for signs of heart Figure 1. Trends in TRM (lower line) and 1YS (upper line) each year in the 10-year-period from 2000 through the end of 2009, for a total of 323 patients. 127

Macroglossia – not always AL amyloidosis

AL amyloidosis and transthyretin (ATTR) amyloidosis are the most frequent forms of systemic amyloidosis diagnosed in the United States. Macroglossia is considered to be a pathognomonic feature of AL amyloidosis. We report on two cases of systemic amyloidosis with macroglossia that defied routine clinical diagnosis, in which the deposits were typed as ATTR in one case and AL in the other using immunoelectron microscopy. These cases highlight: (1) the difficulty of typing amyloidosis on clinical criteria alone; (2) the utility of immunoelectron microscopy and (3) that macroglossia, while occurring much more frequently in AL, can also accompany ATTR amyloidosis.

Clinical presentation and treatment responses in IgM-related AL amyloidosis

Abstract Amyloid light-chain (AL) amyloidosis is a multi-organ disease due to deposition of misfolded monoclonal immunoglobulin light chains. IgM AL amyloidosis is a rare variant, about 6% of AL amyloidosis cases, and more data are needed for treatment guidance. In IgM AL amyloidosis, the clonal cell of origin may be a plasma or lymphoplasmacytic cell, and treatments targeting each are employed. We describe presenting clinical and laboratory features of 95 patients with IgM AL amyloidosis treated at Boston University Amyloidosis Center from 1996 to 2012. The median diagnosis age was 66 years (range: 38–89) with 56% males. Organ involvement rates were: kidney (51%); heart (40%); lymph nodes (25%) and gastrointestinal tract (17%). Treatment responses were analyzed for 46 patients seen after 2003. Five treatment regimens were assigned by bone marrow pathology and patient-specific factors. Overall hematologic response rates and very good partial or complete hematologic response rates, respectively, were: high-dose melphalan/stem cell transplant (HDM/SCT) 100%;80%, Bortezomib 82%;27%, Rituximab 80%;27%, immunomodulatory agents (IMids) 75%;0%, and standard dose alkylating agents (Melphalan or cyclophosphamide) 63%;19%. Overall, 5-year survival rates were significantly higher in patients with a hematological response: 79.2 ± 8.5% versus 41 ± 14.9% in non-responders, which is more favorable than typically expected in AL amyloidosis.

Hospital admissions following outpatient administration of high-dose melphalan and autologous SCT for AL amyloidosis

Hospital admissions following outpatient administration of high-dose melphalan and autologous SCT for AL amyloidosis

Neuralgic amyotrophy following high-dose melphalan and autologous peripheral blood stem cell transplantation for AL amyloidosis

Neuralgic amyotrophy (also known as Parsonage-Turner syndrome, idiopathic brachial neuritis, or brachial plexopathy) is characterized by severe, sudden-onset upper limb pain followed by weakness within a few hours or days, not responsive to analgesics [1, 2]. The pathogenesis is unknown, but the idiopathic form is believed to be immunemediated. It is difficult to recognize because often the pain, paresis, and sensory symptoms are not all in the same nerve territory distribution, and so there is an average delay of 3 to 9 months before diagnosis is made [1, 2]. Although the brachial plexus can be affected in a patchy manner, upper and middle trunk distribution is most common. Neuralgic amyotrophy has been mainly described following surgery [3], viral infection, or immunosuppression [4]. A hereditary form also exists associated with a point mutation or duplication of the SEPT9 gene, and is much rarer. It is treated conservatively with analgesics, physical therapy, and occasionally steroids in the acute period [1]. Parrish et al. [5] reported three cases of neuralgic amyotrophy in patients with multiple myeloma following high-dose melphalan and autologous stem cell transplantation (HDM/SCT), but there has never been a reported case after treatment of immunoglobulin light chain (AL) amyloidosis following HDM/SCT. Here we report two cases of neuralgic amyotrophy following HDM/SCT for AL amyloidosis. These cases were prospectively identified from a population of 42 patients with AL amyloidosis who underwent HDM/SCT at Boston Medical Center between January 2014 and June 2017.

The incidence of atrial fibrillation among patients with AL amyloidosis undergoing high-dose melphalan and stem cell transplantation: experience at a single institution

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) can induce hematologic responses and prolong survival in selected patients with Immunoglobulin light chain (AL) amyloidosis.1 Complications related to cardiac events surrounding HDM/SCT remain an ongoing concern in patients with Immunoglobulin light chain (AL) amyloidosis. Prior studies have shown that atrial fibrillation (AF) can complicate SCT in up to 22% of cases,2, 3, 4, 5, 6, 7 and that pre-existing cardiac involvement may lead to a further increase in the risk of AF during SCT.2 Factors that may predispose patients with amyloid cardiomyopathy to develop AF include advanced age, heart failure, a low left ventricular ejection fraction, an enlarged left atrial diameter and a high-mean right atrial pressure; however, these risk factors are independent of SCT.8 Other studies have suggested that although AF can be successfully treated in these patients, the presence of AF can lead to more complicated hospital admissions with greater lengths of stay and increased mortality.2, 3 Although AF has been described in general as a complication of SCT, the factors specifically predisposing patients with AL amyloidosis to develop AF in the period surrounding SCT have yet to be established. This is the first report to describe the incidence, risk factors and outcomes related to AF in patients with AL amyloidosis undergoing SCT.

Effect of severe hypoalbuminemia on toxicity of high-dose melphalan and autologous stem cell transplantation in patients with AL amyloidosis

High-dose melphalan with stem cell transplantation (HDM/SCT) extends survival and induces hematologic and clinical responses in patients with light chain (AL) amyloidosis. Eighty percent of melphalan is bound to plasma proteins (60% albumin-bound). We hypothesized that patients with profound hypoalbuminemia have a greater free melphalan fraction and more toxicity. Patients with AL amyloidosis treated with HDM/SCT between 2011 and 2014 with severe hypoalbuminemia (SH), defined as serum albumin ⩽2 g/dL were studied retrospectively. Sixteen patients with SH were identified. Forty-one patients without severe hypoalbuminemia (WSH) treated between 2011 and 2012 served as control. The incidence of acute renal failure requiring hemodialysis was 25% among patients with SH, compared with 5% among patients WSH (P=0.05). Not all patients who needed dialysis required it long term; 6.25% for SH and 2.44% for WSH (P=0.49). The rates of grade 3 or 4 febrile neutropenia and gastrointestinal toxicities were not significantly different between the groups. Engraftment kinetics were similar for both groups. Grade 4 renal toxicity and grade 3 lightheadedness were more frequent in patients with SH undergoing HDM/SCT for AL amyloidosis. Further studies into the mechanism of increased renal toxicity in patients with SH are warranted.