Treatment Tolerability in Patients with Immunoglobulin Light-Chain Amyloidosis.
ABSTRACT: Background:Immunoglobulin light-chain amyloidosis (AL amyloidosis) is a rare and often fatal disease for which there is currently no treatment approved by the US Food and Drug Administration or the European Medicines Agency. Treatment options, which are typically based on therapies for multiple myeloma and are used off-label, are associated with substantial adverse events (AEs). Because the severity of AEs is often determined by clinicians, evaluations of treatment tolerability may not fully consider patients' own experience with treatment. Objectives:To explore the prevalence of AEs and treatment tolerability problems as reported by patients who received therapies for AL amyloidosis, and to examine the effects of AEs on treatment continuation and on health-related quality of life (HRQOL). Methods:Patients with AL amyloidosis were recruited for this noninterventional, longitudinal, online survey. The patients responded to survey items regarding demographics, disease characteristics, most recent AL amyloidosis treatment, and HRQOL. The study analyses are based on data collected during the 6-month follow-up survey and are restricted to patients who completed the baseline and 6-month surveys and received treatment for AL amyloidosis within 6 months before the follow-up survey. Results:A total of 100 patients met the inclusion criteria and were included in the study. The patients self-reported having a variety of AEs, which ranged in severity. Overall, 69.4% of patients had problems tolerating their treatment in the past 6 months, of whom 22% discontinued at least 1 therapy. In addition, approximately 33% of patients reduced their AL amyloidosis treatment because of AEs. Most often reported AEs included fatigue (83%), shortness of breath (53%), nausea (52%), and diarrhea (51%). Overall, 50% of the patients reported that their treatment was moderately well-tolerated and 41% said it was very well-tolerated. Those whose treatment was not well-tolerated had significantly worse HRQOL than patients whose treatment was well-tolerated. Conclusions:Patient-reported experiences should be considered by clinicians when making treatment-related decisions. More research is needed to explore additional factors that may contribute to treatment discontinuation in patients with AL amyloidosis.
Project description:PURPOSE:Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264). PATIENTS AND METHODS:Patients who had completed at least one previous anti-plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 mg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria. RESULTS:Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drug-related serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 mg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease. CONCLUSION:Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 mg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.
Project description:Light chain (AL) amyloidosis is a rare disease associated with significant, irreversible organ dysfunction and high case fatality. An observational study was conducted to assess health-related quality of life (HRQoL) in patients treated for AL amyloidosis between 1994 and 2014 with both high dose melphalan and stem cell transplantation (HDM/SCT) or non-SCT chemotherapy regimens. The SF-36v1® Health Survey (SF-36) was administered to assess HRQoL during clinic visits. Analysis of variance was used to compare pre- and post-treatment HRQoL within each treatment group to an age- and gender-adjusted general population (GP) normative sample. Cox proportional hazard models were fit to examine associations between pre-treatment levels of HRQoL and mortality within 1 and 5 years after initiating specific treatment regimens (HDM/SCT: n = 402; non-SCT chemotherapy regimens: n = 172). Among patients who received HDM/SCT, there were significant improvements following treatment in vitality, social functioning, role-emotional and mental health. Worse pre-treatment SF-36 physical component scores were associated with a greater risk of mortality in both treatment groups and follow-up periods (P ? 0·005 for both). [Correction added on 20 October 2017, after first online publication: This P value has been corrected]. Using HRQoL assessments in every physician visit or treatment may provide valuable insights for treating rare conditions like AL amyloidosis.
Project description:Background:Light chain (AL) amyloidosis, a rare and life-threatening protein misfolding disorder, causes organ damage and severely impacts health-related quality of life (HRQoL). No patient-reported outcome (PRO) HRQoL measure has been validated for use in an AL amyloidosis patient population, leaving a gap for researchers conducting observational studies and clinical trials for drug development. The SF-36 Health Survey (SF-36) has been the most frequently used PRO in AL amyloidosis studies to date, and early qualitative validation studies support its use in this population. The aim of this study was to assess the psychometric properties of the SF-36 among patients with AL amyloidosis. Methods:Data from community-based (n=341) and clinic-based (n=1,438) observational studies were used to document the psychometric properties of the SF-36 in this disease population. Reliability was estimated using internal consistency (Cronbach's alpha) and test-retest reliability (intraclass correlation). Convergent validity, known-groups validity, and the ability to detect change were assessed with available criterion variables. Results:Scale reliability (Cronbach's alpha ?0.780 for all scores) and test-retest reliability (intraclass correlation coefficients ?0.731 for all) were acceptable. Scale convergent validity was supported by strong correlations with conceptually related measures. Mean SF-36 scores varied by response to treatment (P<0.05 for all scores) and a self-reported measure of disease severity (P<0.001 for all scores). Data indicate that the SF-36 is sensitive to changes in other measures over time. Conclusion:This study provided clear and consistent evidence of the psychometric properties of the SF-36 in both community-based and clinic-based samples of patients with AL amyloidosis.
Project description:This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902 A phase 3 study is ongoing (#NCT01659658).
Project description:Autologous stem cell transplantation (ASCT) has been used as treatment for immunoglobulin light-chain (AL) amyloidosis for over two decades with improving outcomes; however, the majority of patients are not candidates for this therapy at diagnosis. Novel agents such as immunomodulatory drugs, proteasome inhibitors, and immunotherapy with monoclonal antibodies targeting CD38 have been adopted from the multiple myeloma spheres with encouraging results. Herein, we discuss the role of daratumumab, a monoclonal antibody to CD38, in the treatment of AL amyloidosis. We focus on its mechanism of action, tolerability, and the current published data on its use in AL amyloidosis. Early data from phase I and phase II studies show that daratumumab is tolerated well in this population and induces rapid and deep responses. Phase III trials are currently accruing and we envision daratumumab becoming a key component in the treatment of AL amyloidosis in the future.
Project description:BACKGROUND: Safety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal. METHODS: Two open-label, randomized trials were conducted in Nimba County, Liberia: i) the main tolerability trial with 1,000 Plasmodium falciparum malaria patients aged over five years (Study-T), and, ii) an efficacy trial with a secondary objective of collecting tolerability data among 300 children age six to 59 months (Study-E). In both studies patients were randomized to fixed-dose artesunate-amodiaquine (ASAQ Winthrop®) or artemether-lumefantrine (AL, Coartem®), respectively. Clinical- and laboratory-adverse events (AEs) were recorded until day 28. RESULTS: Study-T: most patients experienced at least one AE. Severe AEs were few, primarily asymptomatic blood system disorders or increased liver enzyme values. No treatment or study discontinuation occurred. Mild or moderate fatigue (39.8% vs 16.3%, p?<?0.001), vomiting (7.1% vs 1.6%, p?<?0.001), nausea (3.2% vs 1.0%, p?=?0.01), and anaemia (14.9% vs 9.8%, p?=?0.01) were more frequently recorded in the ASAQ versus AL arm. Study-E: mild or moderate AEs were common, including anaemia, fatigue, vomiting or diarrhoea. The few severe events were asymptomatic blood system disorders and four clinical events (pneumonia, malaria, vomiting and stomatitis). CONCLUSION: Both ASAQ and AL were well tolerated in patients of all age groups. No unexpected AEs occurred. Certain mild or moderate AEs were more frequent in the ASAQ arm. Standardised safety surveillance should continue for all forms of ACT. TRIAL REGISTRATION: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN40020296, ISRCTN51688713, (http://www.controlled-trials.com).
Project description:Information detailing the experience of patients with light chain (AL) amyloidosis is lacking. The primary aim of this study was to gather data on the patient experience to understand the challenges in diagnosis and to gain insight into barriers to accessing appropriate care.Patients with amyloidosis, family members, and caregivers were invited to participate in an online 16-question survey (available from January 29 to February 5, 2015). Participants with AL amyloidosis were sent an eight-question follow-up survey.The initial survey was completed by 533 participants (follow-up survey completed by 201 participants). AL amyloidosis was the most common diagnosis. For 37.1% of respondents, the diagnosis of amyloidosis was not established until ? 1 year after the onset of initial symptoms. Diagnosis was received after visits to 1, 2, 3, 4, or ? 5 physicians by 7.6%, 23.5%, 20.3%, 16.8%, and 31.8% of respondents, respectively. Correct diagnosis was most often made by hematologists/oncologists (34.1%). Treatments included chemotherapy (63.1%) and stem cell transplantation (38.9%) and were difficult to tolerate for 54.1% of respondents. A significant number of respondents felt uninformed about clinical trials. Nevertheless, approximately half (46.1%) believed that enrolling in a trial would enhance their care.Establishing a diagnosis of amyloidosis is difficult. Current treatments are difficult to tolerate and do not substantially improve quality of life for most patients. There is an urgent need for well-tolerated therapies with clear treatment benefit. Patient awareness of clinical trials can be improved, especially given that respondents indicated high willingness to participate.
Project description:OnabotulinumtoxinA was effective and well tolerated for prophylaxis of headache in patients with chronic migraine (CM) in two randomized, double-blind, placebo-controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxinA in CM prophylaxis in adults, the pooled safety data from four double-blind, placebo-controlled trials were analyzed.The pooled analysis included two phase 2 and two phase 3 double-blind, placebo-controlled trials. The safety population was 2436 patients, 1997 of whom received ?1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events (AEs), physical examination and clinical laboratory tests.OnabotulinumtoxinA was safe and well tolerated, with a low discontinuation rate (3.4%) due to AEs. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxinA injections, 1455 patients (72.9%) reported at least one AE. Neck pain (12.6%) was the most common onabotulinumtoxinA-associated AE, followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AEs were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxinA treatment and 3.0% of patients receiving placebo. AEs were consistent with the known tolerability profile of onabotulinumtoxinA.Multiple treatments with onabotulinumtoxinA at doses of 75-260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM.
Project description:This study examined the content validity of the SF-36v2® Health Survey (SF-36v2) in patients with AL amyloidosis using qualitative interviews with physicians and patients. The study included three distinct phases of qualitative research: concept elicitation interviews among physicians, concept elicitation interviews among patients, and cognitive debriefing interviews among patients. The concept elicitation interviews focused on areas of health-related quality of life that are affected by AL amyloidosis and may be affected by treatment, while patient cognitive debriefings aimed to confirm whether the SF-36v2 instructions, recall period, items, and response choices were comprehensive and understandable to AL amyloidosis patients.Physicians discussed the importance of measuring physical functioning, general health, mental/emotional health, sleep, fatigue, and work impact; though they also reported that they do not routinely use a standard Patient-Reported Outcome (PRO) measure of health-related quality of life. Patients described social, physical, role, and emotional impacts of AL amyloidosis and various treatments. Cognitive debriefing interviews confirmed the relevance of the concepts measured by the SF-36v2 and indicated that patients found the SF-36v2 both easy to understand and complete, that the SF-36v2 instructions and items were comprehensive and understandable without change, and the response choices and recall period were appropriate for use with patients with AL amyloidosis.The findings support the content validity of the SF-36v2 as an appropriate measure of health-related quality of life in patients with AL amyloidosis.
Project description:Light chain (AL) amyloidosis is a rare disease characterized by misfolded amyloid protein deposits in tissues and vital organs, and little is known about the burden of AL amyloidosis on health-related quality of life. This study aimed to quantify the burden of AL amyloidosis in terms of health-related quality of life in a diverse, community-based sample of AL amyloidosis patients.The SF-36v2® Health Survey (SF-36v2), a widely used generic measure of health-related quality of life (using physical and mental summary scales and subscales assessing eight aspects of functioning and well-being), was administered as an online survey of AL amyloidosis patients with AL amyloidosis (ClinicalTrials.gov, NCT02574676 ; n = 341). Compared with adjusted general population sample norms, health-related quality of life of AL amyloidosis patients was significantly worse across all SF-36v2 scales and summary measures based on analysis of variance (p < 0.05 for all). The largest decrement in AL amyloidosis patients was related to General Health (Δ = 9.7; p < 0.001). With the exception of Bodily Pain and Mental Health, differences were also clinically meaningful based on established clinically minimal important differences. The burden of AL amyloidosis overall and in key subgroups tended to be greater on physical health than on mental health. Stratified analyses indicated additional burden among patients with recently diagnosed disease and those with cardiac involvement than among their respective counterparts.Understanding the burden of AL amyloidosis highlights the unmet need for treatment, helps physicians identify ancillary treatments and services geared towards improving patients' functioning, well-being, and overall health-related quality of life. These findings also help to support the use of health-related quality of life end points as important outcome measures in current and future treatment studies.ClinicalTrials.gov, NCT02574676 . Registered October 5, 2015.