Treatment Of AL Amyloidosis Research Articles

AL amyloidosis: advances in diagnosis and management.

Light chain (AL) amyloidosis is a disease in which malignant plasma cell clones affect multiple organs including the heart and kidney. The mechanism for organ function deterioration in AL amyloidosis differs from multiple myeloma. Thus, not all agents used to treat multiple myeloma shows similar efficacy in AL amyloidosis. In AL amyloidosis, both hematologic and organ responses after treatment are important to improve the clinical outcome. Especially, improving heart function is one of the key aspects in the treatment of AL amyloidosis. With recent advances in the understanding of the pathophysiologic mechanism of AL amyloidosis, novel treatment methods are under active trial. In this article, I have reviewed the advances in pathophysiology, diagnosis, risk stratification, and treatment of AL amyloidosis.

Cardiac amyloidosis: the need for early diagnosis.

Amyloidosis is a collection of systemic diseases characterised by misfolding of previously soluble precursor proteins that become infiltrative depositions, thereby disrupting normal organ structure and function. In the heart, accumulating amyloid fibrils lead to progressive ventricular wall thickening and stiffness, resulting in diastolic dysfunction gradually progressing to a restrictive cardiomyopathy. The main types of cardiac amyloidosis are amyloid light chain (AL) amyloidosis caused by an underlying plasma cell dyscrasia, amyloid transthyretin (TTR) amyloidosis of wild-type (normal) TTR at older age (ATTRwt) and hereditary or mutant amyloid TTR (ATTRm) in which a genetic mutation leads to an unstable TTR protein. Overall survival is poor once heart failure develops, underlining the need for early referral and diagnosis. Treatment for AL amyloidosis has improved markedly over the last decades, and TTR amyloidosis gene silencers and orally available transthyretin stabilisers are ready to enter the clinical arena after recent positive outcome trials. Novel therapies aiming at fibril degradation with monoclonal antibodies are under investigation. In this review, we focus on ‘red flag’ signs and symptoms, diagnosis and management of cardiac amyloidosis which differs considerably from the general management of heart failure. Only by increasing awareness, prognosis for patients with this devastating disease can be improved.Electronic supplementary materialThe online version of this article (10.1007/s12471-019-1299-1) contains supplementary material, which is available to authorized users.

Orphan designation: Recombinant monoclonal antibody to human serum amyloid P component (dezamizumab), Treatment of AL amyloidosis

Orphan designation: Recombinant monoclonal antibody to human serum amyloid P component (dezamizumab), Treatment of AL amyloidosis

S876 GILTERITINIB SIGNIFICANTLY PROLONGS OVERALL SURVIVAL IN PATIENTS WITH FLT3-MUTATED (FLT3MUT+) RELAPSED/REFRACTORY (R/R) ACUTE MYELOID LEUKEMIA (AML): RESULTS FROM THE PHASE 3 ADMIRAL TRIAL

Background: The achievement of deep and sustained hematologic response in AL amyloidosis is needed to improve organ function and overall survival. Daratumumab-based combinations have resulted in deep responses and minimal additional toxicity in multiple myeloma, making such combinations potentially ideal in the treatment of AL amyloidosis. Aims: We present the 1-year follow up on safety and efficacy data for the 28 patients enrolled in the safety run-in cohort of ANDROMEDA (NCT03201965), a phase 3 study investigating subcutaneous DARA + CyBorD in patients with newly diagnosed AL amyloidosis. Methods: Eligible patients had ≥1 involved organs, Eastern Cooperative Oncology Group (ECOG) score ≤2, estimated glomerular filtration rate ≥20 mL/min/1.73m2, and NT-ProBNP ≤8,500 ng/L. In the safety run-in, patients received DARA (1,800 mg in 15 mL) co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) administered subcutaneously (SC) qw Cycles 1–2, q2w Cycles 3–6, and q4w thereafter for ≤2 y. Cy 300 mg/m2 PO or IV, Bor 1.3 mg/m2 SC, and D 40 mg were administered qw ≤6 cycles. Hematologic response evaluations (per international amyloidosis consensus criteria, Comenzo Leukemia 2012) were q4w cycles 1–6 and every other month thereafter. Results: Patients (N = 28) had a median (range) age of 68 (35–83) years and a median of 2 (1–4) involved organs. Heart and kidney involvement affected 54% and 61% of patients, respectively; 21% were Mayo cardiac stage IIIA at screening. Median (range) follow-up was 341 (17–449) days. Median treatment duration was 11 (0.2–14) months. Patients received a median of 11 (1–16) treatment cycles; 79% received DARA SC maintenance (>6 cycles). The overall hematologic response rate was 96% and the rate of very good partial response (VGPR) or better was 82%; 10 (36%) patients achieved CR. An additional 5 (18%) patients achieved CR based on normalization of involved free light chain (iFLC) level and negative serum and urine immunofixation, but due to suppression of uninvolved FLC (uFLC) below the lower limit of normal did not normalize the FLC ratio and thus could not be formally classified as CR. Median time to first response was 23 days, and median time to CR and VGPR were 85 (29–226) and 22 (7–228) days, respectively. At the time of data cutoff (median follow-up 341 days), one patient (with no response to treatment) experienced disease progression. All of the 10 patients achieving CR and the 5 patients with normalized iFLC level and negative serum and urine immunofixation without normalized FLC ratio continue to respond to treatment. Median duration of CR was not reached. Six patients received subsequent autologous stem cell transplant (ASCT). Four patients have died (2 due to disease progression and 2 due to events following ASCT). The most common treatment emergent adverse events included diarrhea (64%), fatigue and peripheral edema (50% each). Two patients (7%) experienced infusion related reactions, all of which were grade 1. Summary/Conclusion: DARA-CyBorD provides high overall hematologic response and CR rate in patients with newly diagnosed AL amyloidosis with a well-tolerated safety profile. Enrollment into the randomized portion of ANDROMEDA is ongoing.

PS1394 FLOW-MEDIATED DILATATION AND AORTIC BLOOD PRESSURE PREDICT CARDIOVASCULAR ADVERSE EVENTS DURING CARFILZOMIB TREATMENT: A PROSPECTIVE STUDY IN PATIENTS WITH RELAPSED/ REFRACTORY MULTIPLE MYELOMA

Background: Bortezomib/dexamethasone with cyclophosphamide or melphalan are commonly used as primary treatment for AL amyloidosis, but limited data exist on the safety and activity of bortezomib with IMiDs combinations. Aims: To evaluate the safety and activity of VRD combination in newly diagnosed, previously untreated patients with AL amyloidosis. Methods: Between March 2017 and March 2018, 34 consecutive newly diagnosed patients with AL amyloidosis were treated with VRD; standard organ involvement and updated organ and hematologic response criteria were used. Results: The median age of all patients was 66.5 years (range 46–84); 71% were males, 75% had cardiac involvement, median NTproBNP was 3649 pg/ml (81- >30000), per Mayo stage 14%, 54%, 14% and 18% were stage 1, 2, 3A and 3B respectively; 54% had renal involvement, median eGFR was 59 ml/min/1.73 m2 (range 10–133) and renal stage distribution was 13%, 53% and 33% for stages 1, 2 & 3. Measurable FLCs (i.e. a dFLC≥40 mg/L) were present in 29 (85%) patients; in 4 patients baseline dFLC was >20 mg/dl and were also evaluable for response. Twenty-two patients completed the planned 8 cycles, 9 died prior to completion of planned therapy, 1 patient discontinued therapy for personal reasons (while in VGPR), 1 discontinued therapy after physician's decision (while in VGPR) and one discontinued due to bortezomib-related toxicity (while in CR). After the first cycle of VRD, 24/34 (70.5%) patients had achieved a hematologic response (42% a VGPR or CR and 27% a PR). After 3 months of VRD, 82% of the evaluable patients (N = 27) had achieved at least VGPR, including CR in 6 (22%), and PR in 5 (18%). After 6 VRD cycles, CR, VGPR and PR rates among evaluable (N = 24) patients were 9 (37.5%), 13 (54%), and 2 (8%) respectively. On intent to treat, best hematologic response was CR in 11/34 (32%) and among CR patients 5/11 were MRD negative by NGF; 17/34 (50%) achieved VGPR and in 9 of them dFLC was <10 mg/dl; 2/34 (7%) achieved a PR. Median time to first response (at least a PR) was 28 days (1 treatment cycle), median time to at least VGPR was 84 days (3 cycles of therapy). Cytogenetics were available in 28 patients; among patients with t(11;14) (N = 7), all achieved at least a VGPR (3 a CR and 4 a VGPR). Organ responses were documented in 12 (35%) patients. Median follow up for all patients is 12.5 months and 6 and 12 month survival is 73.5% (100%, 85% and 71% for stage 1, 2 & 3A patients respectively, but only 20% for stage 3B). Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; common non-hematologic toxicities included rash (Gr3/4:16%), infections (≥Gr3:12%), constipation (≥Gr3:9%), peripheral neuropathy (Gr2:20%), while, 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide before planned therapy completion, 38% required bortezomib dose reduction and 12% discontinued bortezomib. We then compared the efficacy of VRD to that of CyBorD given in 68 patients matched for Mayo stage and baseline dFLC and found a trend for deeper responses at 3 months in patients treated with VRD (≥VGPR in 82% vs 45%) and at 6 months (≥VGPR in 92% vs 61%, p = 0.049). Summary/Conclusion: VRD with weekly bortezomib and low dose lenalidomide is a very effective and rapidly acting regimen that can induce deep hematologic responses within 3 months of therapy. However, toxicity of VRD in patients with AL amyloidosis is significant, despite the use of low doses of lenalidomide.

Delay treatment of AL amyloidosis at relapse until symptomatic: devil is in the details

AbstractThis article has a companion Point by Palladini and Merlini.

Current diagnosis and treatment of AL amyloidosis in Japan: a nationwide epidemiological survey

Immunoglobulin light chain (AL) amyloidosis is a plasma cell disorder characterized by the deposition of insoluble fibrillary protein derived from misfolded immunoglobulin light chains in several organs, resulting in organ failure and death. However, little information is available about the prevalence and demographic characteristics of AL amyloidosis and the treatment strategy for the condition in Japan. The Amyloidosis Research Committee, Intractable Disease Division, of the Japanese Ministry of Health and Welfare, retrospectively conducted a nationwide survey of Japanese patients with AL amyloidosis who visited affiliated hospitals from January 2012 to December 2014. The number of patients with AL amyloidosis who visited the hospitals during the study period was 3170, and its incidence was estimated to be 4.2 per million person-years in Japan. For the second questionnaire, we collected 741 patients with AL amyloidosis (median age, 65 years; 59% males). The most commonly affected organ was the kidneys, followed by the heart, gastrointestinal tract, and autonomic nervous system. Only 53% of patients were accurately diagnosed by immunohistochemistry using an anti-light chain antibody. Cardiac amyloidosis was diagnosed at later stages. The leading non-transplant regimen was the bortezomib-combined regimen.

Clonal Plasma Cells in AL Amyloidosis Are Dependent on Anti-Apoptotic BCL-2 Family Proteins

Background: Immunoglobulin light chain (AL) amyloidosis is characterized by the production of clonal serum free light chains, which misfold and accumulate in tissues causing life threatening organ dysfunction and ultimately death. The treatment of AL amyloidosis targets the underlying population of clonal plasma cells, but existing therapies are not curative and ineffectively control the disease in many patients. Recent data have shown tremendous success in targeting anti-apoptotic BCL-2 family proteins as a novel therapy in hematologic disorders due to alterations in apoptosis and the function of anti-apoptotic proteins in malignant cells. BH3 profiling, a quantitative and functional assay that measures apoptotic priming and dependence on anti-apoptotic BCL-2 family members, has been used to identify and target apoptotic dependencies in hematologic disorders. Novel inhibitors of anti-apoptotic proteins, referred to as BH3 mimetics, have not yet been explored in AL amyloidosis due to insufficient understanding of apoptotic dependencies in this disease.Methods: To date, bone marrow aspirates have been collected from 44 patients with newly diagnosed or relapsed/refractory AL amyloidosis being evaluated at the Amyloidosis Center at Boston University. BH3 profiling was performed on clonal plasma cells to measure dependencies on anti-apoptotic BCL-2 family proteins. Clonal cells were also treated with BH3 mimetics in vitro, including BCL-2, BCL-xL, and MCL-1 inhibitors as single agents, as well as in combination with current standard therapies (bortezomib, ixazomib, lenalidomide, and pomalidomide).Results: Of the 44 enrolled patients, 16 are female (36%) and 28 are male (64%). The median age is 70 years (range, 47 to 84). Six patients were treatment naïve and the remainder had previous or current treatment for AL amyloidosis. Data obtained with BH3 profiling demonstrated that clonal plasma cells exhibit strong dependencies on anti-apoptotic BCL-2 family proteins, which may be altered by concurrent treatment with standard therapies. In the majority of patients, clonal plasma cells are highly dependent on the anti-apoptotic protein MCL-1 and undergo apoptosis when treated with an MCL-1 inhibitor. Intriguingly, this dependence is altered by treatment with proteasome inhibitors: clonal plasma cells become highly dependent on BCL-2 and undergo apoptosis in response to co-treatment with bortezomib and the FDA-approved BCL-2 inhibitor venetoclax.Conclusions: BH3 profiling can effectively measure apoptotic dependencies in clonal plasma cells derived from bone marrow aspirates in patients with AL amyloidosis. Dependencies on BCL-2 family proteins (particularly MCL-1) are strong, but some variability between patients was observed, especially in combination with standard therapies. Biomarker-driven deployment of BH3 mimetics for treatment of AL amyloidosis would likely be highly effective. DisclosuresNo relevant conflicts of interest to declare.

Bortezomib-Based First Line Treatment for AL Amyloidosis Patients Who Are Not Candidate for Stem Cell Transplantaion

IntroductionSystemic AL amyloidosis is characterised by deposition of misfolded immunoglobulin light chains within organs. Treatment for amyloidosis is generally derived from that for multiple myeloma (MM). Combinations of immunomodulatory drugs and proteasome inhibitors are standard frontline MM therapy, but there is little experience with such regimens in AL. For patients not receiving autologous stem cell transplantation (ASCT), bortezomib-based regimens have been first-line treatment in AL amyloidosis over the last few years. The purpose of this study is to investigate the efficacy of bortezomib-based regimens for patients with newly diagnosed AL amyloidosisMethodsWe performed a retrospective study of all newly diagnosed patients with AL amyloidosis treated at our center between 4/1/11 and 12/31/17. Data pertaining to demographics, diagnosis, treatment and follow-up were extracted from electronic medical records. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. All statistical analyses were performed by using the SPSS 24.0 software. Time to progression (TTP) is defined as time from the date of diagnosis or the start of treatment for a disease until the disease starts to get worse or spread to other parts of the body. The primary endpoint was overall response rate and secondary endpoints were overall survival (OS) and TTP.ResultsA total 63 patients with newly diagnosed AL amyloidosis who did not receive ASCT were analyzed. Clinical characteristics are shown in Table 1. They included 32 men and 31 women with a median age of 66 years (range, 42-82). Autonomic nerve, Cardiac, peripheral nerve, renal, soft tissue, and liver involvement were found in 46 (73%), 41 (65.1%), 23 (36.5%), 20 (31.7%), 16 (25.4%), 4(6.4%), respectively. The Mayo 2012 stage was: Stage 2 3.8%, Stage 3 30.8% and stage 4 65.4%. Hematological responses were: complete response (CR) 33.3 %, VGPR 19.0%, partial response (PR) 12.6% and no-response (NR) 17.4%. Organ response was 26.9% (n=17). With a median follow-up of 34 months, median OS was 40 months (95% CI 30-50) (Figure 1A) and median TTP was 27 months (95% CI 18-36) (Figure 1B). The rate of early death within 6 months was 28.5% (n=18). Patients were classified according to first-line treatment; bortezomib-based regimens (VMP, n=37; VD (bortezomib and dexamethasone), n=9; VCD, n=8; VMD, n=8; VTD (bortezomib with thalidomide and dexamethasone, n=1). Hematological responses of VMP, VD, VCD, VMD, and VTD were: 75.6%, 55.5%, 50.0%, 50.0%, 100%, respectively. Organ responses of VMP, VD, and VMD were: 35.1%, 22.2%, 25.0%, respectively.ConclusionsIn this retrospective analysis, bortezomib-based regimens in newly diagnosed AL amyloidosis showed results that appear comparable to those seen at other centers. These findings therefore continue to support the emerging roles for bortezomib-based regimens for the purposes of improving response. Larger scale analyses in multi-center trials would be beneficial to further study these roles. [Display omitted] DisclosuresKim:Kyowa-Kirin: Research Funding; Roche: Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Celltrion: Research Funding; J&J: Research Funding; Takeda: Research Funding.

Pomalidomide and Dexamethasone Grant Rapid Hematologic Responses in Patients with Relapsed and Refractory AL Amyloidois: A European Retrospective Series of 150 Patients

Background: The immunomodulatory agent pomalidomide is active in patients with relapsed/refractory multiple myeloma, including those who failed prior lenalidomide and bortezomib. Phase II clinical trials showed that pomalidomide is also effective in previously treated AL amyloidosis. The combination of pomalidomide and dexamethasone (PDex) showed a good hematologic response rate (more than partial response from 48 to 68%). Aim of this study is to report the efficacy of PDex in a retrospective real-world series of patients with AL amyloidosis from three European referral centers.Methods: The databases of the Pavia Amyloid Research and Treatment Center (Italy), the Heidelberg Amyloidosis Center (Germany) and the National Amyloidosis Center of London (United Kingdom) were searched for patients with a diagnosis of AL amyloidosis treated with pomalidomide and dexamethasone (PDex). The patients received 28-day cycles of pomalidomide (from day 1 to 21) and dexamethasone (once weekly). All patients gave written informed consent for their clinical data to be used for research purposes. Hematologic and organ responses were assessed according to the International Society of Amyloidosis criteria.Results: One hundred and fifty patients were included, 91 treated in Pavia, 30 in Heidelberg and 29 in London. Median age at the time of PDex initiation was 65 years (range: 34-85 years) and 92 (61%) patients were males. The heart was involved in 92 (61%) patients, the kidney in 87 (58%) and 91 (60%) of patients had two or more organs involved. The median NT-proBNP concentration at the time of PDex initiation was 1.670 ng/L (interquartile range, IQR: 527-4.963 ng/L) and 23 (15%) had NT-proBNP >8.500 ng/L. The estimated glomerular filtration rate was <30 mL/min per 1.73 m2 in 13 (9%) of patients and 16 (11%) were on dialysis at the time of PDex initiation. Median bone marrow plasma cells infiltrate at diagnosis was 18% (IQR: 10-30%) and this was ≥10% in 114 (76%) subjects. The median difference between involved and uninvolved concentration of free light chains (dFLC) was 150 mg/L (IQR: 76-397 mg/L). Median time from AL amyloidosis diagnosis to PDex treatment initiation was 11 months (IQR: 5-24 months). The median number of previous lines of therapy was 3 (range: 2-7) with 98 (65%) patients refractory to previous lines. One hundred and thirty-eight (92%) patients had previously received bortezomib, 120 (80%) lenalidomide and 114 (76%) melphalan and 39 (26%) underwent autologous stem cell transplant. The median number of PDex cycles performed was 3 (range: 1-30). Pomalidomide dosage was 4 mg in 56% of patients, 2 mg in 27%, 3 mg in 14% and 1 mg in 3% of subjects. Adverse events observed in 42 (28%) of subjects. With the limit of the retrospective setting, the more frequently reported were infections in 13 (31%), cardiac heart failure in 11 (26%), creatinine increase in 7 (16%) and cytopenia 4 (9%). The hematologic response rate at the end of cycle 3 was 36%, with 14 (16%) very good partial responses (VGPR) and 20 (20%) partial responses (PR). After cycle 6, the overall hematologic response rate was 56%, with 15 (26%) VGPR and 17 (30%) PR. A hematologic response to therapy was noted in 16 out of 39 subjects who were previously refractory to bortezomib, lenalidomide and melphalan. Median follow-up of living patients was 12 months (IQR: 7-27 months) and 64 (42%) patients died. Obtaining at least partial response at the end of cycle 3 was associated with a significant survival advantage (median survival not reached vs. 25 months, P=0.007, Figure). Cardiac responses were observed in 7 of 74 patients with measurable NT-proBNP (10%), but this can be underestimated due to the pomalidomide-related increase of NT-proBNP, and renal response in 13 of the 56 evaluable patients (23%).Conclusions: The combination of pomalidomide and dexamethasone is active, with a 56% of response rate at cycle 6, in heavily pretreated patients with AL amyloidosis. The hematologic response rate of this real word retrospective study compares with those reported in phase 2 clinical trials, improved over time and patients who obtained a quick reduction of the burden of free light chains, had a significant survival benefit. Pomalidomide is an effective rescue agent for relapsed refractory AL amyloidosis. [Display omitted] DisclosuresMerlini:Akcea: Consultancy; Janssen: Consultancy; Ionis: Consultancy; Millenium: Consultancy; Prothena: Consultancy; Pfizer: Consultancy. Wechalekar:Janssen: Honoraria. Palladini:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel support; Prothena: Honoraria.

Znaczenie oceny minimalnej choroby resztkowej w amyloidozie AL

Light chain amyloidosis (AL amyloidosis) is a systemic disease leading to organ damage due to deposition of amyloid fibers arising from accumulation of amyloid precursors – monoclonal immunoglobulin light chains produced by clonal bone marrow plasmocytes. The aim of AL amyloidosis therapy is the inhibition amyloidogenic immunoglobulin light chains, what should result in stabilization or often even improvement of involved organs’ function. Treatment effectiveness evaluation is based on hematological and organ response. Despite achievement of complete hematological remission, in some of the patients even a trace number of plasmocytes persisting following treatment may lead to production of low amount of monoclonal immunoglobulins capable of deepening organ damage. These plasmocytes remain undetectable to routine diagnostic approaches and are regarded as minimal residual disease (MRD). Considering the results of the so far published research, it is possible that MRD assessment based on flow cytometric technique may constitute a basic tool of response assessment of AL amyloidosis treatment in the future. In this publication the methodology and results of latest research concerning MRD assessment in AL amyloidosis are presented.

Therapies for cardiac light chain amyloidosis: An update

Light-chain (AL) amyloidosis is the most common type of systemic amyloidosis, affecting around 10 people per million per year. This serious disorder is characterized by the presence of a clone of bone marrow plasma cells that produces monoclonal light chains (LCs) of the κ or predominantly λ type. These amyloidogenic LCs undergo extracellular misfolding and aggregation into proteotoxic soluble oligomers and amyloid fibrils that deposit within tissues. The lethal consequences of AL amyloidosis are due to the toxic products (the LCs) and not to the malignant behaviour of the plasma cell clone. Almost 80% of patients with AL amyloidosis have some degree of cardiac involvement, manifesting as heart failure (HF), and carrying a particularly poor prognosis.The past decade has seen major advances in the treatment of AL amyloidosis, and a rapidly fatal disease has become a treatable and possibly curable condition. The number of therapeutic options is rapidly expanding, offering hope to address currently unmet needs (most notably, the treatment of frail patients). The treatment of AL amyloidosis consists in a combination of agents targeting multiple steps of the amyloid cascade, associated with effective HF management, and there is ground for hope for dramatically improving the outcome in the near future.In the present review we will summarize our current knowledge on therapy for cardiac AL amyloidosis, targeting clinical cardiologists involved in the care of this serious disorder.

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.

Myocardial Edema and Prognosis in Amyloidosis

BackgroundPrognosis in light-chain (AL) and transthyretin (ATTR) amyloidosis is influenced by cardiac involvement. ATTR amyloidosis has better prognosis than AL amyloidosis despite more amyloid infiltration, suggesting additional mechanisms of damage in AL amyloidosis. ObjectivesThe aim of the study was to assess the presence and prognostic significance of myocardial edema in patients with amyloidosis. MethodsThe study recruited 286 patients: 100 with systemic AL amyloidosis, 163 with cardiac ATTR amyloidosis, 12 with suspected cardiac ATTR amyloidosis (grade 1 on 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid), 11 asymptomatic individuals with amyloidogenic TTR gene mutations, and 30 healthy volunteers. All subjects underwent cardiovascular magnetic resonance with T1 and T2 mapping and 16 underwent endomyocardial biopsy. ResultsMyocardial T2 was increased in amyloidosis with the degree of elevation being highest in untreated AL patients (untreated AL amyloidosis 56.6 ± 5.1 ms; treated AL amyloidosis 53.6 ± 3.9 ms; ATTR amyloidosis 54.2 ± 4.1 ms; each p < 0.01 compared with control subjects: 48.9 ± 2.0 ms). Left ventricular (LV) mass and extracellular volume fraction were higher in ATTR amyloidosis compared with AL amyloidosis while LV ejection fraction was lower (p < 0.001). Histological evidence of edema was present in 87.5% of biopsy samples ranging from 5% to 40% myocardial involvement. Using Cox regression models, myocardial T2 predicted death in AL amyloidosis (hazard ratio: 1.48; 95% confidence interval: 1.20 to 1.82) and remained significant after adjusting for extracellular volume fraction and N-terminal pro–B-type natriuretic peptide (hazard ratio: 1.32; 95% confidence interval: 1.05 to 1.67). ConclusionsMyocardial edema is present in cardiac amyloidosis by histology and cardiovascular magnetic resonance T2 mapping. T2 is higher in untreated AL amyloidosis compared with treated AL and ATTR amyloidosis, and is a predictor of prognosis in AL amyloidosis. This suggests mechanisms additional to amyloid infiltration contributing to mortality in amyloidosis.

Management of the elderly patient with AL amyloidosis

Systemic immunoglobulin light chain (AL) amyloidosis is an aging-associated protein misfolding and deposition disease. This condition is caused by a small and otherwise indolent plasma cell (or B cell) clone secreting an unstable circulating light chain, which misfolds and deposits as amyloid fibrils possibly leading to progressive dysfunction of affected organs. AL amyloidosis can occur in the typical setting of other, rarer forms of systemic amyloidosis and can mimic other more prevalent conditions of the elderly. Therefore, its diagnosis requires a high degree of clinical suspicion and reliable diagnostic tools for accurate amyloid typing, available at specialized referral centers. In AL amyloidosis, frailty is dictated by the type and severity of organ involvement, with heart involvement being the main determinant of morbidity and mortality. Still, given a similar disease stage, elderly patients with AL amyloidosis are often an even frailer group, due to significant comorbidities, associated disability and polypharmacotherapy, socioeconomic restrictions, and limited access to clinical trials. Recent improvements in the use of biomarkers for early diagnosis, risk stratification and response monitoring, the flourishing of novel, effective anti-plasma cell therapies developed against multiple myeloma and adapted to treat AL amyloidosis, and possibly the introduction of anti-amyloid therapies are rapidly changing the clinical management of this disease and are reflected by improved outcomes. Of note, hematologic and organ responses in elderly patients with AL amyloidosis do translate in better outcome, advocating the importance of treating these patients and striving for a rapid response to therapy also in this challenging clinical setting.

Transplantace srdce a následující léčba AL-amyloidózy u 5 pacientů

The prognosis for patients with cardiac impairment due to AL-amyloid deposition and severe cardiac insufficiency is poor, with a survival median in the order of months. The classical treatment of AL-amyloidosis in combination with cardiac insufficiency is very poorly tolerated and the treatment of such patients is associated with considerably higher mortality than among other patients with AL-amyloidosis. If, however, patients with an isolated or another dominating cardiac impairment, without severe damage to other organs and tissues, have a heart transplant performed, their cardiovascular condition will significantly improve as a result, along with their ability to tolerate any kind of treatment for AL-amyloidosis including that using high-dose chemotherapy with a transplant of autologous hematopoietic stem cells. The achievement of complete remission of AL-amyloidosis is a precondition for long-term survival, since when not achieved, amyloid deposition also arises in the transplanted heart. At the Centre for Cardiovascular and Transplantation Surgery, Brno, the first heart transplant due to its impairment by AL-amyloidosis was performed in 2010. By the year 2017 the number of patients with AL-amyloidosis, who had first undergone a heart transplant with subsequent treatment for AL-amyloidosis, increased to 5. The median age at which a heart transplant was performed is 60 (48-65) years. Four patients were men, one was a woman. The median monitoring equals 65 (88-15) months. Complete remission of AL-amyloidosis was achieved in all the patients. There were 5 lines of treatment needed for the first patient to attain it, of that twice high-dose melphalan with autologous stem cell transplantation, for the second patient a second-line treatment, high-dose melphalan and bortezomib-based therapy. No specific therapy was needed for the third patient, as immunosuppressive therapy following the heart transplant containing prednison led to complete remission of AL-amyloidosis. In the fourth case, sustainable complete remission was reached by high-dose melphalan and in the fifth case by one line of bortezomib-based therapy. The aforementioned data illustrate that a heart transplant is the first step which makes the patients with a severe heart failure, not tolerating any efficient therapy of AL-amyloidosis, capable of undergoing intense treatment of AL-amyloidosis. Sometimes one high-dose chemotherapy is sufficient, while at other times multiple treatment lines are needed to reach complete remission of AL-amyloidosis.Key words: AL-amyloidosis - autologous hematopoietic stem cells transplantation - bortezomib - cardiomyopathy - lenalidomide - thalidomide - heart transplantation.

The Effect and Safety of Bortezomib in the Treatment of AL Amyloidosis: A Systematic Review and Meta-Analysis.

Bortezomib began to be used in the treatment of light chain (AL) amyloidosis in recent years. We performed the first meta-analysis of randomized clinical trials and clinical controlled trials to evaluate the effect and safety of bortezomib treatment for AL amyloidosis. We conducted a search (until July 2016) in electronic databases (PubMed databases and the Cochrane Central Register of Controlled Trials bases from the year 2003). There were 205 records we searched and eight studies was included (n = 617 persons). We demonstrated that bortezomib treatment significantly improved overall response rate (ORR), complete response, a cardiac response rate, 2-year overall survival and the risk of neuropathy and reduced overall mortality compared to controls without bortezomib therapy. From the comparison and subgroup analysis of ORR between bortezomib group and no bortezomib group, the patients with bortezomib had a higher ORR, especially patients pretreated with bortezomib before high-dose melphalan followed by autologous stem cell transplant compared to no pretreatment. In addition, patients with bortezomib in standard dosage had significantly higher ORR. According to our results, bortezomib should be used in AL amyloidosis patients to improve response rate and survival rate and future relevant randomized controlled trials require to be performed.

Presentation and outcome with second-line treatment in AL amyloidosis previously sensitive to nontransplant therapies

AbstractThe management of light chain (AL) amyloidosis has improved in recent years thanks to accurate biomarker-based staging systems and response criteria and availability of novel effective therapies. However, previous studies have focused on newly diagnosed patients, and little is known on relapsed patients, despite the fact that trials of new agents are often performed in this setting. In the present study, we report the outcome of 259 patients who responded to up-front therapy. Ninety-two patients (35%) needed second-line therapy after a median of 49 months. Cardiac and renal progression were observed in 22% and 12% of patients who received second-line therapy, respectively. Complete response after up-front treatment and frontline therapy with combined bortezomib, melphalan, and dexamethasone independently prolonged time to second-line therapy. Median survival of relapsing patients was 59 months. Patients who had a “high-risk dFLC progression,” which we defined as a difference between involved and uninvolved free light chains (dFLC) of >20 mg/L, a level >20% of baseline value, and a >50% increase from the value reached at best response, had a shorter survival after initiation of second-line therapy on univariate, but not on multivariate, analysis, where cardiac progression was the only independent predictor of survival after starting rescue treatment. Patients with AL amyloidosis who need second-line therapy after response to up-front treatment generally have a good outcome. A “high-risk dFLC progression” should trigger rescue treatment, and cardiac progression should not be awaited.

Paraneoplastic neuropathies.

To review recent advances in paraneoplastic neuropathies with emphasis on their definition, different forms and therapeutic development. A strict definition of definite paraneoplastic neuropathies is necessary to avoid confusion. With carcinoma, seronegative sensory neuronopathies and neuronopathies and anti-Hu and anti-CV2/Contactin Response Mediator Protein 5 antibodies are the most frequent. With lymphomas, most neuropathies occur with monoclonal gammopathy including AL amyloidosis, Polyneuropathy-Organomegaly-Endocrinopathy-M component-Skin changes (POEMS) syndrome, type I cryoglobulinemia and antimyelin-associated glycoprotein (MAG) neuropathies and Waldenström's disease. Neuropathies improving with tumor treatment are occasional, occur with a variety of cancer and include motor neuron disease, chronic inflammatory demyelinating neuropathy and nerve vasculitis. If antibodies toward intracellular antigens are well characterized, it is not the case for antibodies toward cell membrane proteins. Contactin-associated protein-2 antibodies occur with neuromyotonia and thymoma with the Morvan's syndrome in addition to Netrin 1 receptor antibodies but may not be responsible for peripheral nerve hyperexcitability. The treatment of AL amyloidosis, POEMS syndrome, anti-MAG neuropathy and cryoglobulinemia is now relatively well established. It is not the case with onconeural antibodies for which the rarity of the disorders and a short therapeutic window are limiting factors for the development of clinical trials. A strict definition of paraneoplastic neuropathies helps their identification and is necessary to allow an early diagnosis of the underlying tumor.

A Peptide-Fc Opsonin with Pan-Amyloid Reactivity.

There is a continuing need for therapeutic interventions for patients with the protein misfolding disorders that result in systemic amyloidosis. Recently, specific antibodies have been employed to treat AL amyloidosis by opsonizing tissue amyloid deposits thereby inducing cell-mediated dissolution and organ improvement. To develop a pan-amyloid therapeutic agent, we have produced an Fc-fusion product incorporating a peptide, p5, which binds many if not all forms of amyloid. This protein, designated Fcp5, expressed in mammalian cells, forms the desired bivalent dimer structure and retains pan-amyloid reactivity similar to the p5 peptide as measured by immunosorbent assays, immunohistochemistry, surface plasmon resonance, and pulldown assays using radioiodinated Fcp5. Additionally, Fcp5 was capable of opsonizing amyloid fibrils in vitro using a pH-sensitive fluorescence assay of phagocytosis. In mice,125 I-labeled Fcp5 exhibited an extended serum circulation time, relative to the p5 peptide. It specifically bound AA amyloid deposits in diseased mice, as evidenced by biodistribution and microautoradiographic methods, which coincided with an increase in active, Iba-1-positive macrophages in the liver at 48 h postinjection of Fcp5. In healthy mice, no specific tissue accumulation was observed. The data indicate that polybasic, pan-amyloid-targeting peptides, in the context of an Fc fusion, can yield amyloid reactive, opsonizing reagents that may serve as next-generation immunotherapeutics.