Vaishali Sanchorawala

Treatment patterns and health care resource utilization among patients with relapsed/refractory systemic light chain amyloidosis

Abstract Background: Treatment for patients with systemic light chain (AL) amyloidosis remains challenging. Our study aims to describe treatment patterns for both newly diagnosed and relapsed/refractory AL (RRAL) amyloidosis, and to assess clinical outcomes, healthcare costs, and resource utilization during the first year following a diagnosis of RRAL amyloidsis. Methods: This was a retrospective observational study of adult patients with AL amyloidosis using the US Optum administrative claims data during 1/1/2008 to 6/30/2015. Diagnosis was based on both ICD-9 codes and treatments with a claim for AL-amyloidosis-specific anticancer systemic agents. Results: Of 334 patients with AL amyloidosis, 43.1% were considered as RRAL amyloidosis. The majority (75%) of RRAL amyloidosis patients had organ involvement prior to the second line treatment. Proteasome-inhibitor-based regimens were most frequently used (41.0% for first-line AL, 30.6% for RRAL amyloidosis). Organ deterioration and mortality rates were 49.3% and 10.4%, respectively, during the two years following relapse. The average monthly cost was

Modified High-Dose Melphalan and Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis

14,369 per patient for RRAL amyloidosis including medical costs (

Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR)

9441) and drug costs (

Evaluation of a new continuous mononuclear cell collection procedure in a single transplant center cohort enriched for AL amyloidosis patients

4928). Conclusions: RRAL amyloidosis is associated with high morbidity from target organ failure and mortality, which emphasizes the need for novel medications to improve care for patients with RRAL amyloidosis.

High-dose melphalan and stem cell transplantation in AL amyloidosis with elevated cardiac biomarkers

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) have been used in patients with immunoglobulin light chain (AL) amyloidosis for over 2 decades now with durable responses, prolonged survival, and decreasing treatment-related mortality. Historically, patients with poorer baseline functional status, advanced age, renal compromise, and cardiac involvement have been treated with a risk-adapted modified conditioning dose of melphalan (mHDM) of 100 to 140 mg/m2 before SCT. In part because of these baseline characteristics, patients receiving mHDM/SCT have had poorer outcomes compared with patients receiving full-dose melphalan at 200 mg/m2. With the advent of novel therapeutic agents such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for the treatment of AL amyloidosis, it is imperative to understand the long-term effects of mHDM/SCT. Here we report the long-term outcomes of 334 patients with AL amyloidosis treated with mHDM/SCT. Median overall survival was 6.1 years and median event-free survival 4.3 years, with median overall survival reaching 13.4 years for patients who had achieved a hematologic complete response (CR). Overall hematologic response rate was 69%, and treatment-related mortality was 3% after 2010. Thus, mHDM/SCT leads to prolonged survival and favorable outcomes, especially if a hematologic CR is achieved.

Heparin-induced thrombocytopenia and thrombosis during high dose melphalan and autologous stem cell transplantation

Abstract Objective: To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin (ATTR) amyloidosis. Patients and methods: We performed a retrospective analysis of patients with biopsy-proven ATTRwt (wild-type transthyretin amyloid protein) and genopositive ATTR V122I (valine-to-isoleucine substitution at position 122 of the TTR gene) amyloidosis evaluated at the Amyloidosis Center at Boston University and Boston Medical Center between 1 January 2003 and 31 December 2016. Results: There were a total of 226 patients with ATTRwt and ATTR V122I amyloidosis evaluated during the specified time frame with 155 and 71 patients in each cohort, respectively. Those with complete medical records, 140 patients with ATTRwt and 57 V1221 ATTRm subjects, were included in the analyses. Fifty-five patients (39%) in the ATTRwt cohort and 28 patients (49%) in the ATTR V122I cohort had an MGUS, as indicated by an abnormality in the serum-free light-chain ratio and/or serum immunofixation electrophoresis. Conclusion: These data confirm the high prevalence of coexistent MGUS with ATTR amyloidosis in this patient population, with an MGUS rate that is higher than the general population. These findings also highlight the importance of a thorough diagnostic evaluation in patients with amyloidosis to determine the precursor protein, as the clinical course and treatment of AL (light-chain amyloid protein) and ATTR amyloidosis are distinct.

Once AL amyloidosis: not always AL amyloidosis

BACKGROUNDnThe Spectra Optia continuous mononuclear cell (CMNC) program is newly available, and herein validated in a single-center cohort enriched with AL amyloidosis patients to collect a target CD34+ yield of 2.5u202f×u202f106 cells/kg within 2 days.nnnMETHODSnConsecutive autologous transplant patients in 2016 are included. Patients undergo leukapheresis with Optia CMNC and Spectra v4.7 over a 2-day cycle. Data collection includes collection efficiency, adverse events and engraftment kinetics.nnnRESULTSn36 leukapheresis procedures on 18 patients are included. The diagnoses are AL amyloidosis (9), myeloma (7), lymphoma (2), and scleroderma (1). Median age is 60; 12 are men. Plerixafor was employed pre-emptively in 6 cycles. Median blood CD34+ on Day 1 of leukapheresis was 46 cells/uL. Median number of blood volumes processed on Day 1 was 3.1. All collection cycles were completed within 2 days; only one in a heavily pretreated lymphoma patient did not reach the target requiring a second mobilization attempt. Mean collection efficiencies were comparable between the two devices. There were 2 adverse events: tubing rupture on the Optia; and one case of hypotension. All 18 patients underwent high-dose chemotherapy: median cell dose infused was 7.7u202f×u202f106 CD34+ cells/kg. Median days to neutrophil and platelet engraftment were 10 and 13 respectively.nnnCONCLUSIONnThe Optia CMNC collection protocol is safe and effective in a small single-center autologous stem cell transplant cohort enriched for high-risk patients with AL amyloidosis and cardiac involvement. Caution is needed for tubing setup because there is less cumulative experience with Optia.

Outcomes of patients with AL amyloidosis and low serum free light chain levels at diagnosis

Immunoglobulin light-chain amyloidosis (AL amyloidosis) is a rare and often fatal disease caused by misfolded light chains. These misfolded light chains form soluble toxic aggregates that deposit as amyloid fibrils in tissues and organs, leading to significant and permanent organ dysfunction. Although nearly any organ or combination of organs can be affected by AL amyloidosis, ~ 70% of individuals diagnosed with AL amyloidosis experience cardiac involvement [1]. Cardiac involvement is a major determinant of survival in patients with AL amyloidosis. Untreated patients with cardiac amyloidosis have historically had a median survival of 6–12 months [2], though recent advances in treatments directed toward the plasma cell dyscrasia have led to tremendous improvements in overall survival (OS) [3]. The development of novel therapeutic options for patients with cardiac amyloidosis has highlighted the need for accurate prognostication to help with risk stratification. High-dose melphalan and stem cell transplantation (HDM/SCT) can induce hematologic responses and improve survival in carefully and highly selected patients with AL amyloidosis. However, patients with advanced cardiac involvement are at a higher risk of morbidity and mortality with this aggressive treatment and therefore may not be candidates for HDM/SCT [4]. The first reported staging system using serum troponin I (TnI) and then troponin T (TnT) along with N-terminal pro-brain natriuretic peptide (NTproBNP) was reported by the clinician scientists at the Mayo clinic [5]. Using a scoring system defined by an NTproBNP threshold of 332 ng/L and a TnT threshold of 0.035 mcg/L, predicted median survival of patients with newly diagnosed AL cardiac amyloidosis ranged from 26.4 months in patients without elevation of either biomarker (Mayo stage 1 disease) to 3.5 months in patients with elevations in both biomarkers (Mayo stage 3 disease). This staging system also proved useful in the prediction of survival among AL amyloidosis patients undergoing HDM/SCT [6]. In this patient cohort, TnI > 0.1 ng/mL correlated with higher treatment-related mortality (TRM), defined as death within 90 days of SCT, of 10%. Furthermore, investigators from the Mayo clinic have also proposed elevated cardiac biomarkers of TnT > 0.06 mcg/mL or NTproBNP > 5000 pg/mL as exclusion criteria for patients undergoing HDM/SCT for AL amyloidosis owing to early mortality [7]. In view of this, elevated cardiac biomarkers of TnT > 0.06 mcg/L, NTproBNP > 5000 pg/mL, or TnI > 0.1 ng/mL are considered prohibitive to HDM/SCT for AL amyloidosis. Despite these thresholds for elevation in cardiac biomarkers levels, Mayo Clinic and our group have reported on successful outcome of HDM/SCT for patients with AL amyloidosis and cardiac involvement with careful patient selection [8, 9]. There is relatively little data on the use of the biologically active Brain-type Natriuretic Peptide (BNP), instead of NTproBNP, in selecting candidates for HDM/SCT, although a ratio of 3.5:1 of NTproBNP to BNP has been proposed [7] and implemented in classifying patients in a modified cardiac staging system, using BNP > 100 pg/mL as a threshold [10]. Here we report on a retrospective analysis of patients with AL amyloidosis with elevated TnI > 0.1 ng/mL and BNP > 100 pg/mL, who underwent HDM/SCT between 2010 and 2017. A total of 692 patients had their initial evaluation at the Amyloidosis Center during this time period. Advanced cardiac involvement, defined as TnI > 0.1 ng/mL and BNP > 100 pg/mL, was present in 197 patients (30%). Of these, 20 patients (10%) were treated with HDM/ SCT as an initial treatment and 177 (90%) were not. All * Vaishali Sanchorawala vaishali.sanchorawala@bmc.org

A library of ATTR amyloidosis patient-specific induced pluripotent stem cells for disease modelling and in vitro testing of novel therapeutics

TO THE EDITOR:nnIn patients with complex medical conditions, determining the etiology of thrombocytopenia can be challenging. This is particularly true in patients undergoing treatment with high-dose melphalan and autologous stem cell transplantation (HDM/SCT). Virtually all patients receiving this

Echocardiography and Survival in Light Chain Cardiac Amyloidosis: Back to Basics

Amyloid cardiomyopathy could be related to AL amyloidosis, wild-type transthyretin amyloidosis (ATTRwt) or hereditary amyloidosis (ATTRm). It is crucial to distinguish and accurately type the precursor amyloidogenic protein in order to offer appropriate treatment, prognosis and genetic counseling. Treatment for AL amyloidosis is directed towards the plasma cell dyscrasia, whereas treatment for transthyretin amyloidosis is directed towards stabilization of misfolded TTR [1] or reduction in production of mutant TTR [2,3]. Median survival of patients with ATTRwt cardiomyopathy is 2.71 years from diagnosis compared to 0.87 years for cardiomyopathy from AL amyloidosis [4]. While ATTR amyloidosis can now be conclusively diagnosed by imaging [5] and blood testing alone, it is also important to note that the possible co-existence of AL amyloidosis and ATTRwt amyloidosis may be difficult to distinguish clinically, often requiring histologic identification of the amyloid precursor protein [6,7]. To illustrate the importance of amyloid typing when assigning the accurate cause of amyloid cardiomyopathy, we describe two such cases of patients with amyloidosis who required endomyocardial biopsy for accurate diagnosis.