Dina Brauneis

Induction Therapy with Bortezomib Followed by Bortezomib-High Dose Melphalan and Stem Cell Transplantation for Light Chain Amyloidosis: Results of a Prospective Clinical Trial

The depth of hematologic response has been shown to correlate with survival and organ responses for patients with light chain (AL) amyloidosis. We conducted a prospective trial of 2 cycles of induction with bortezomib and dexamethasone on a twice a week schedule followed by conditioning with bortezomib and high-dose melphalan (HDM) and autologous stem cell transplantation (SCT). The objectives were hematologic responses, tolerability, and survival. Thirty-five patients were enrolled from 2010 to 2013. Of these, 30 proceeded with SCT, whereas 5 did not because of clinical deterioration during induction (n = 3) or complications after stem cell collection (n = 2). Two patients developed features of an autologous graft-versus-host disease-like syndrome post-SCT, which responded to steroids; no other unusual complications were seen. Treatment-related mortality occurred in 8.5% (3/35). Hematologic responses were achieved by 100% of the 27 assessable patients (63% complete response, 37% very good partial response [VGPR]) who completed the planned treatment. By intention-to-treat, hematologic responses occurred in 77% of patients (49% complete response, 29% VGPR). With a median follow-up of 36 months, the median overall survival and progression-free survival were not reached. In conclusion, incorporating bortezomib into induction and conditioning yielded a high rate of hematologic responses after HDM/SCT in patients with 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

High-Dose Melphalan and Stem Cell Transplantation in Patients on Dialysis Due to Immunoglobulin Light-Chain Amyloidosis and Monoclonal Immunoglobulin Deposition Disease

The kidney is the most common organ affected by immunoglobulin light-chain (AL) amyloidosis and monoclonal immunoglobulin deposition disease (MIDD), often leading to end-stage renal disease (ESRD). High-dose melphalan and stem cell transplantation (HDM/SCT) is effective for selected patients with AL amyloidosis, with high rates of complete hematologic response and potential for improved organ dysfunction. Data on tolerability and response to HDM/SCT in patients with ESRD due to AL amyloidosis and MIDD are limited. We analyzed data on toxicity, efficacy, and hematologic and renal response of HDM/SCT in 32 patients with AL amyloidosis and 4 patients with MIDD who were dialysis-dependent for ESRD treated at Boston Medical Center between 1994 and 2016. The most common grade 3/4 nonhematologic toxicities were infections (75%), metabolic abnormalities (56%), mucositis (42%), constitutional symptoms (39%), pulmonary complications (39%), and diarrhea (28%). Treatment related mortality (defined as death within 100 days of SCT) occurred in 8% (3 of 36). A complete hematologic response was achieved in 70% of evaluable patients (19 of 27) at 1 year after HDM/SCT. In the entire cohort, median overall survival (OS) after HDM/SCT was 5.8 years; median OS was 1 year for those who did not achieve a complete hematologic response and 8 years for those who did achieve a complete hematologic response. Twelve patients (33%) underwent kidney transplantation after successful treatment with HDM/SCT at a median of 2.4 years after SCT. HDM/SCT is safe and effective in inducing hematologic complete responses and prolonging survival in patients with ESRD from AL amyloidosis and MIDD. Achievement of a durable hematologic response can make these patients possible candidates for renal transplantation.

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

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.

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

BACKGROUND The 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 2.5 × 106 cells/kg within 2 days. METHODS Consecutive 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. RESULTS 36 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 7.7 × 106 CD34+ cells/kg. Median days to neutrophil and platelet engraftment were 10 and 13 respectively. CONCLUSION The 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.

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.

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

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

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

TO THE EDITOR: In 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

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.

Optimal dosing of high-dose melphalan prior to autologous hematopoietic stem cell transplantation in a patient with AL amyloidosis and a solitary kidney.

http://dx.doi.org/10.1016/j.hemonc.2015.08.001 1658-3876/ 2015 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). * Corresponding author at: Boston Medical Center, 820 Harrison Avenue, FGH-1007, Boston, MA 02118, USA. Tel.: +1 617 638 7002; fax: +1 617 414 1831. E-mail address: vaishali.sanchorawala@bmc.org (V. Sanchorawala). Shin Yin Lee , Dina Brauneis , Lauren Stern , Vaishali Sanchorawala a,b,*