Early intensification and autologous stem cell transplantation in patients with systemic AL amyloidosis: a single-centre experience

Primary systemic amyloidosis (AL amyloidosis) continues to have a very poor prognosis. Most therapeutic strategies remain unsatisfactory. Conventional chemotherapy is known to offer at best only moderate efficacy. Several studies have yielded higher complete response rates after high-dose chemotherapy and autologous stem cell transplantation (ASCT) in addition to improving outcomes in a subgroup of patients. However, the superiority of an intensive approach in AL amyloidosis has not been confirmed in a randomised trial. The precise role of ASCT remains unclear. We report our experience in 16 patients diagnosed with AL amyloidosis and treated in a multidisciplinary approach with high-dose melphalan and ASCT. Median age was 59 (39–71) years. The kidneys were predominantly affected in 75% of cases; two or more organs were affected in 38%. Median time from diagnosis to transplantation was 2 (1–4) months. Three patients (19%) developed acute renal failure and required transient dialysis. Transplant-related mortality was 6% after 100 days. Haematological complete response (CR) was obtained in nine (56%) and organ response in six (38%) patients. Nine out of 12 patients (75%) with kidney involvement exhibited a sustained clinical benefit at 12 months. Half of all the patients (n = 8) were alive after a median follow-up of 33 months, including two in continuous CR. This suggests that high-dose chemotherapy and ASCT are still valid treatment options in AL amyloidosis and that a significant number of patients with renal involvement might benefit from this approach.     

Physiologic response of the six‐minute walk test in children with juvenile idiopathic arthritis

Objective

To determine the physiologic response of the 6‐minute walk test (6‐mwt) in children with juvenile idiopathic arthritis (JIA).

Methods

Eighteen children with JIA (age 7–17 years; 6 boys, 12 girls) performed a 6‐mwt and a maximal exercise test.

Results

The physiologic response of the 6‐mwt was on average between 80% and 85% of the peak values of heart rate and oxygen uptake (VO _2peak) during the maximal exercise test, except for the minute ventilation, which had a mean percentage of 68.5%. Backward regression analysis showed that height and distance walked were the best predictors of VO _2peak during cycling (R² = 0.883, P < 0.001). During the 6‐mwt, the difference between the first and second minute was significant in every variable, except for heart rate. The range of walking distance of children with JIA was comparable with that of healthy elderly people.

Conclusion

The physiologic response of the 6‐mwt is at a submaximal, intense level of exercise. The course of the responses during the 6‐mwt was normal. The 6‐mwt can be regarded as a good test for measuring functional exercise capacity.

     

Outcomes of light‐chain amyloidosis patients treated with first‐line bortezomib: a collaborative retrospective multicenter assessment

Light‐chain amyloidosis (AL) is associated with low survival rates, particularly in patients with cardiac involvement. We evaluated the outcome of 73 consecutive, non‐selected ‘real‐world’ AL patients, treated with first‐line bortezomib‐based induction, focusing on the benefit of concurrent administration of alkylating agents. Most patients had renal (77%), cardiac (66%), or multiorgan (74%) involvement. Sixty‐eight per cent (n = 50) received alkylating agent (mostly cyclophosphamide). Severe adverse events were seen in 45%, most evident in patients with cardiac involvement, with no increased toxicity in patients receiving an alkylator agent. Hematological response (HemR) was obtained in 77% of patients, including 33% very good partial responses and 19% complete responses. Age <70 yr, lack of cardiac and peripheral neurologic involvement, and co‐administration of an alkylating agent were associated with significantly improved HemR. NYHA cardiac failure staging was the only independent factor affecting overall survival. Administration of an alkylating agent and the achievement of both HemR and organ response were associated with a statistically significant improved survival in those surviving the first 6 months of induction. First‐line bortezomib‐based regimen resulted in favorable response and survival in newly diagnosed patients. Co‐administration of an alkylating agent improved outcome without increasing treatment‐related toxicity.     

A longitudinal evaluation of health‐related quality of life in patients with AL amyloidosis: associations with health outcomes over time

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.     

Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients

We retrospectively investigated the feasibility and the toxicity of autologous stem cell transpantation (ASCT) in 21 cases of systemic amyloidosis (AL). The conditioning regimens consisted of high-dose melphalan (HDM) alone ( n  = 18) or in combination with 12 Gy total body irradiation ( n  = 3). Toxic death rate was high: 9/21 patients (43%) died within the first month following ASCT, and 10/12 surviving patients achieved a response. With a median follow-up of 14 months, the OS and the EFS rates at 4 years were 57.1% (±10.8) and 29.9% (±14.5) respectively for the whole group. The major prognostic factor for both response and survival was the number of clinical manifestations at the time of ASCT, of the following five criteria, i.e. creatinine clearance <30 ml/min, nephrotic syndrome with urinary protein excretion > 3000 mg/24 h, congestive heart failure, neuropathy, or hepatomegaly associated with alkaline phosphatase level > 200 IU/l. For patients presenting with two or more clinical manifestations the 4-year OS and EFS were both 11.1% compared with 91.7% and 46.3% respectively in patients with fewer than two clinical manifestations at the time of ACST. We conclude that ASCT is feasible in AL in a subset of patients with fewer than two clinical manifestations at the time of ASCT. Given the severe extra-haematological toxicity, ASCT should not be considered in other cases.     

Depression and anxiety in patients with AL amyloidosis as assessed by the SF-36 questionnaire: experience in 1226 patients#

Abstract

Background: Our study examines depression and anxiety in patients with immunoglobulin light chain (AL) amyloidosis, and determines the associations between the mental health problems and patient characteristics (age, gender, race, marital status, alcohol consumption, smoking status and cardiac involvement).

Methods: Patients with AL amyloidosis who completed the 36-item Short Form General Health Survey (SF-36) during initial evaluation at a single center were studied. The SF-36 included assessments of depression, anxiety, role limitation due to emotional problems and the mental health subscale score.

Results: From 1226 patients with AL amyloidosis, 37.0% reported depression and 46.7% reported anxiety. Patients with cardiac amyloidosis reported more anxiety (odds ratio (OR)?=?1.29, 95% confidence interval (CI) 1.03–1.61) and role limitation due to emotional problems (OR?=?1.32, 95%CI 1.05–1.65). No significant association between cardiac involvement and depression was found (OR?=?1.22, 95%CI 0.97–1.54). Men reported less anxiety (OR?=?0.72, 95%CI 0.57–0.91). Patients ≥65 years experienced greater role limitation (OR?=?1.36, 95%CI 1.08–1.71). Smokers (p?=?0.019) and women (p?=?0.006) scored lower on mental health subscales.

Conclusions: Many patients with AL amyloidosis suffer from depression, anxiety and functional limitations. Psychiatric assessment and treatment is important, and further research is needed to clarify the long-term effects of depression and anxiety in AL amyloidosis.

This current study was registered in ClinicalTrials.gov as NCT00898235.     

Immunoglobulin heavy light chain test quantifies clonal disease in patients with AL amyloidosis and normal serum free light chain ratio

Abstract

Background: Serum and urine immunofixation electrophoreses (SIFE/UIFE) are used for clonal detection in plasma cell dyscrasias, while serum free light chain (sFLC) testing provides quantitation of clonal disease. Up to 20% of patients with light chain (AL) amyloidosis may present with normal FLC ratio (FLCr).

Methods: We assessed the diagnostic, quantitative and prognostic potential of serum heavy light chain ratio (HLCr) in 199 untreated patients at initial evaluation.

Results: An abnormal HLCr was found in 37.2%, abnormal FLCr in 81.9% and positivity by SIFE/UIFE in 94% of patients. HLCr together with SIFE/UIFE identified clonality in 94% patients; the combination with FLCr yielded 100% sensitivity. An HLCr abnormality was significantly over-represented in normal compared to abnormal FLCr group (63.9% versus 31.3%). HLCr did not predict overall survival (OS) (log rank, p?=?0.09), while an abnormal FLCr was associated with decreased OS (log rank, p?=?0.03). The combined use of both ratios trended toward increased OS in the abnormal HLCr/normal FLCr group (log rank, p?=?0.11; Wilcoxon, p?=?0.04). On multivariate analysis, HLCr was not predictive of OS, whereas an abnormal FLCr was associated with shorter OS (HR?=?1.7, p?=?0.04).

Conclusions: The HLC assay has potential as a supplemental test to quantify monoclonal protein in patients with normal FLCr results.     

Heart rate variability as a predictor of mortality in patients with AA and AL amyloidosis.

AIMS: Patients with AA and AL amyloidosis have a limited life-expectancy. The aim of this study was to investigate whether heart rate variability can predict mortality in these patients. METHODS AND RESULTS: Twenty-two recently diagnosed patients with AA and 23 patients with AL amyloidosis were included. Fifteen patients (5 AA, 10 AL) died within 1 year. Twenty-four hour Holter recording was performed to quantify the mean of all normal to normal RR-intervals (mean NN) and the standard deviation of all normal to normal RR-intervals (SDNN). The SDNN predicted 1-year mortality in the total group of patients with amyloidosis. The median SDNN was 73 ms. In patients with an SDNN < or =73 ms, the risk of dying within 1 year was found to have increased 3.5-fold (P=0.0036; 95% CI 1.1-11.0). An SDNN < or =50 ms, a predictor of mortality in other patient groups, increased the risk of dying within 1 year 22-fold (P=0.0001; 95% CI 5.4-90.4). In contrast to patients with AA amyloidosis, in the subgroup analysis of patients with AL amyloidosis the SDNN remained a predictive parameter (SDNN < or =50 ms: risk ratio 11.5, 95% CI 2.4-56.2, P=0.0025). CONCLUSION: The SDNN is a strong predictor of short-term mortality in patients with AL amyloidosis.     

Physical activity and functional abilities in adult males with haemophilia: a cross‐sectional survey from a single US haemophilia treatment centre

Physical activity and functional ability are important determinants of quality of life and these metrics are affected by both haemophilia and ageing. Outside haemophilic arthropathy, risk factors leading to reduced physical activity and function in people with haemophilia (PWH) are under‐explored. The purpose of this analysis was to determine risk factors for reduced physical activity and functional limitations in PWH. A secondary analysis was conducted on data indexing physical activity and functioning of 88 PWH using data originally collected as part of a cross‐sectional study at a single large haemophilia treatment centre. The Framingham Physical Activities Index (PAI), the Hemophilia Activities List (HAL) and the Timed Up‐and‐Go Test (TUG) were the outcome measures. The World Federation of Haemophilia (WFH) orthopaedic joint score was used as a measure of arthropathy. Multiple linear regression analysis was used to assess the relationship between the outcome measures and covariates. Worsening WFH joint score was independently associated with all three outcome measures (P < 0.05). Increasing age was associated with reduced PAI and increased TUG time (P < 0.05). The HAL summary score was decreased in patients with chronic liver disease (P = 0.006). The adjusted R² for each model was ≤0.35. This study provides evidence for the relationship between arthropathy and reduced physical functioning/activity, but also highlights that much of the variation in physical functioning/activity is not explained by haemophilia‐related characteristics.     

Bortezomib-based chemotherapy reduces early mortality and improves outcomes in patients with ultra-high-risk light-chain amyloidosis: a retrospective case control study

Background: Patients with amyloid light-chain (AL) amyloidosis who have advanced cardiac damage are at risk of premature mortality. Currently, bortezomib is the mainstay in the treatment of AL amyloidosis, but the benefits of bortezomib in patients with ultra-high-risk (2004 Mayo stage IIIb or 2012 Mayo stage IV) AL amyloidosis have not been proved definitively.

Methods: We performed a retrospective analysis of patients newly diagnosed with ultra-high-risk AL amyloidosis who received a bortezomib-based regimen or supportive treatment. We aimed to establish the effects of bortezomib on early mortality and long-term outcomes in this high-risk population.

Results: Patients receiving bortezomib-containing chemotherapy (n?=?62) and patients receiving no chemotherapy (n?=?24) were included. Median overall survival (OS) was 30?months in the bortezomib group and 2?months in the control group (p?<?.001), and median progression-free survival (PFS) was 15.8?months (bortezomib) and 2?months (control; p?<?.001). The early-death rate (within 6?months of treatment) was 32.3% (bortezomib) and 66.7% (control; p?<?.001). In a landmark analysis assessing outcomes in patients surviving beyond 6?months, the 2-year OS and PFS in the bortezomib group were 77.3% and 65.8%, respectively.

Conclusions: Bortezomib-based regimens can help to reduce early mortality and improve long-term survival in patients with ultra-high-risk AL amyloidosis.     

Reproducibility and responsiveness of quality of life assessment and six minute walk test in elderly heart failure patients

Objective—To examine the reproducibility and responsiveness to change of a six minute walk test and a quality of life measure in elderly patients with heart failure.Design—Longitudinal within patient study.Subjects—60 patients with heart failure (mean age 82 years) attending a geriatric outpatient clinic, 45 of whom underwent a repeat assessment three to eight weeks later.Main outcome measures—Subjects underwent a standardised six minute walk test and completed the chronic heart failure questionnaire (CHQ), a heart failure specific quality of life questionnaire. Intraclass correlation coefficients (ICC) were calculated using a random effects one way analysis of variance as a measure of reproducibility. Guyatt''s responsiveness coefficient and effect sizes were calculated as measures of responsiveness to change.Results—24 patients reported no major change in cardiac status, while seven had deteriorated and 14 had improved between the two clinic visits. Reproducibility was satisfactory (ICC > 0.75) for the six minute walk test, for the total CHQ score, and for the dyspnoea, fatigue, and emotion domains of the CHQ. Effect sizes for all measures were large (> 0.8), and responsiveness coefficients were very satisfactory (> 0.7). Effect sizes for detecting deterioration were greater than those for detecting improvement.Conclusions—Quality of life assessment and a six minute walk test are reproducible and responsive measures of cardiac status in frail, very elderly patients with heart failure.