The Prognostic Importance of the 6-Minute Walk Test in AL Amyloidosis

Background The six-minute walk test (6MWT) is an easy-to-implement objective measure of functional capacity. This standardised reproducible measure of individual function may have value in systemic AL amyloidosis to provide an additional objective measure of fitness for chemotherapy, impact of chemotherapy and, within the clinical trial setting, both as a potential clinical endpoint and exclusion criteria. We aim to validate its prognostic value in AL amyloidosis. Methods All patients from a prospective observational study of newly diagnosed AL amyloidosis, (ALchemy) over a 5-year period, were studied. Six-minute walk testing was performed at baseline and 6, 12, 18, 24, 36 and 48-month follow up. Both the median 6MWT and percentage predicted for age, sex, height and weight were analysed. Results In total, 799 evaluable patients were included of whom 564 (70.6%) had cardiac involvement. Baseline 6MWT distance was 418.5 metres (m) / 80.5% predicted, and diminished with increasing cardiac Mayo stage (p<0.0001). A baseline 6MWT ≥300m was independent of Mayo staging in predicting survival (Mayo II Hazard ratio [HR] 2.21 [1.35-3.64], p=0.002; Mayo IIIa HR 3.92 [2.42-6.34], p<0.0001; Mayo IIIb HR 6.08 [3.63-10.12], p<0.0001; 6MWT ≥300m HR 2.97 [2.38-3.72], p<0.0001). Baseline 6MWT correlated strongly with other prognostic factors including Eastern Cooperative Oncology Group (ECOG) performance status (p<0.0001) and New York Heart Association (NYHA) Classification of Heart Failure (p=0.008). Patients were followed up for a median of 32 (1-90) months following diagnosis. Median overall survival (OS) was 70.0 (56.8-83.2) months. The median OS of patients achieving ≥300m on baseline 6MWT was not reached whilst those achieving <300m had a median OS of 25.0 (18.1-31.9) months. Patients unable to attempt the test had a median OS of 5.0 (2.8-7.2) months (p<0.0001). Patients achieving ≥300m at any time point had a significantly better OS (at 6, 12, 24 and 36 months p<0.0001 whilst at 48 months p=0.03). Patients unable to attempt a 6MWT at any point in time has a median OS of 10 (6.4-13.6) months from that point. In patients with Mayo IIIb disease, the 6MWT remained prognostic (≥300m: 61 [4.2-117.8] months vs. <300m: 4.0 [1.3-6.9] months vs. unable to walk: 1.0 [0.3-1.7] months, p<0.0001). The 6MWT fell significantly by 6 months (391.0m/73.5%, p=0.0002) then rose again by 12 months (median 415.0m/78.0%, p=0.02). There was no significant change in 6MWT thereafter. When stratified by haematological response and censoring deaths before 12 months, only patients in a complete response (CR) improved at 12 months (431.0m/83.0% vs. 437.0m/85%, p=0.001) whilst those with a lesser haematological response got worse (Very good partial response [VGPR]: 403.5m/75.0% to 395.5m/76.5%, p=0.02; Partial Response [PR]: 413.0m/79.0% to 362.5m/74.0%, p=0.0007; Nil response [NR]: 437.0m/83.0% to 355.0m/70%, p=0.0002). A 33m improvement in 6MWT, a value reported to be clinically meaningful in cardiopulmonary disorders, was independent of haematological response in predicting survival (CR [reference], VGPR: HR 2.02 [1.08-3.80], p=0.03; PR: HR 3.51 [1.83-6.73], p<0.0001; NR: HR 5.61 [2.88-10.92], p<0.0001; 6MWT improvement ≥33m: HR 1.61 [1.01-2.59], p=0.047). Patients in whom 6MWT improved by ≥33m at 12 months survived longer although median OS was not reached in either category (p=0.01). In patients who achieved a baseline 6MWT of <300m but improved by ≥33m at 12 months, median OS was superior to those who improved by <33m (not reached vs. 35.0 [25.7-44.3] months, p=0.006). Among patients with Mayo stage IIIb disease and censoring all deaths within 12 months, those who improved by ≥33m at 12 months lived longer (OS NR vs. 70.0 [51.4-88.6] months, p<0.0001). Conclusion The 6MWT is prognostic in AL amyloidosis at multiple time points and a baseline distance of ≥300m is independent of current Mayo stage criteria in predicting survival. Inability to undertake a 6MWT at baseline is an extremely poor prognostic indicator. At 12 months, improvement in 6MWT of ≥33m predicts survival independent of haematological response. The 6MWT is a useful prognostic indicator in systemic AL amyloidosis and could be used as an inclusion/exclusion criterion in the clinical trial setting. Disclosures Wechalekar: Celgene: Honoraria; Takeda: Honoraria, Other: Travel; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory.

Download Full-text

P4-045: Longitudinal ADC changes in Alzheimer's disease in a multi-center clinical trial setting

Alzheimer s & Dementia ◽

10.1016/j.jalz.2011.05.2065 ◽

2011 ◽

Vol 7 ◽

pp. S713-S713

Author(s):

Luc Bracoud ◽

Angelika Caputo ◽

Chahin Pachai ◽

Boubakeur Belaroussi ◽

Ana Graf ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trial ◽

Clinical Trial Setting ◽

Trial Setting

Download Full-text

Data Security in Clinical Trials Using Blockchain Technology

Political and Economic Implications of Blockchain Technology in Business and Healthcare - Advances in Data Mining and Database Management ◽

10.4018/978-1-7998-7363-1.ch010 ◽

2021 ◽

pp. 250-268

Author(s):

Marta de-Melo-Diogo ◽

Jorge Tavares ◽

Ângelo Nunes Luís

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Literature Review ◽

Data Security ◽

Critical Issue ◽

The Other ◽

Clinical Trial Setting ◽

Blockchain Technology ◽

Current Utilization ◽

Trial Setting

Blockchain technology in a clinical trial setting is a valuable asset due to decentralization, immutability, transparency, and traceability features. For this chapter, a literature review was conducted to map the current utilization of blockchain systems in clinical trials, particularly data security managing systems and their characteristics, such as applicability, interests of use, limitations, and issues. The advantages of data security are producing a more transparent and tamper-proof clinical trial by providing accurate, validated data, therefore producing a more reliable and credible clinical trial. On the other hand, data integrity is a critical issue since data obtained from trials are not instantly made public to all participants. Work needs to be done to establish the significant implications in security data when applying blockchain technology in a real-world clinical trial setting and generalized conditions of use to establish its security.

Download Full-text

Ibrutinib monotherapy outside of clinical trial setting in Waldenström macroglobulinaemia: practice patterns, toxicities and outcomes

British Journal of Haematology ◽

10.1111/bjh.16168 ◽

2019 ◽

Vol 188 (3) ◽

pp. 394-403 ◽

Cited By ~ 9

Author(s):

Jithma P. Abeykoon ◽

Saurabh Zanwar ◽

Stephen M. Ansell ◽

Morie A. Gertz ◽

Shaji Kumar ◽

...

Keyword(s):

Clinical Trial ◽

Practice Patterns ◽

Clinical Trial Setting ◽

Trial Setting

Download Full-text

Implementing a standard-of-care clinic for stroke prevention in children with sickle cell disease in Nigeria: a feasible strategy outside a clinical trial setting

Blood Advances ◽

10.1182/bloodadvances.2017gs101266 ◽

2017 ◽

Vol 1 (Suppl) ◽

pp. 23-25

Author(s):

Najibah A. Galadanci ◽

Shehu U. Abdullahi ◽

Leah D. Vance ◽

Musa A. Tabari ◽

Shehi Abubakar ◽

...

Keyword(s):

Clinical Trial ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Stroke Prevention ◽

Standard Of Care ◽

Cell Disease ◽

Care Clinic ◽

Clinical Trial Setting ◽

Trial Setting

Download Full-text

Challenges of Using NT-Probnp for Response Assessment in Systemic AL Amyloidosis - Analysis of a Prospective Study

Blood ◽

10.1182/blood.v128.22.4511.4511 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4511-4511 ◽

Cited By ~ 2

Author(s):

Ashutosh Wechalekar ◽

Darren Foard ◽

Carol Whelan ◽

Mariana Fontana ◽

Thirusha Lane ◽

...

Keyword(s):

False Negative ◽

Response Assessment ◽

Cardiac Response ◽

Al Amyloidosis ◽

Walk Test ◽

End Point ◽

Negative Results ◽

False Negative Results ◽

Impact On Survival ◽

Minute Walk

Abstract INTRODUCTION Treatment outcomes in AL amyloidosis are dependent on the hematological response to chemotherapy translating into organ responses. Cardiac biomarker, N-terminal brain pro-natriuretic peptide (NT-proBNP), is the main determinant of cardiac response in AL amyloidosis. Strongly supported by the amyloidosis community, the FDA is considering use of NT-proBNP as the primary end point for clinical trials. A number of questions on the exact details on NT-proBNP in AL remain unanswered - rate of decrease over time, timing of NT-proBNP measurement (6 months or 12 months) and values to use as a baseline. We report the use of serial NT-proBNP measurements for cardiac response assessment at 6 months and 12 months addressing some of these questions. PATIENTS AND METHODS All patients (n=650) recruited in the ALChemy study (a prospective observational study of all patients with AL amyloidosis undergoing chemotherapy) at the UK National Amyloidosis Centre from Sept 2009 to Jan 2014 with a minimum follow of 12 months and available NT-proBNP at 0, 6 and 12 months were included in this study. Organ involvement and hematologic/amyloidotic organ responses were assessed according to 2010 amyloidosis consensus criteria. The primary outcome measure was cardiac response as defined by NT-proBNP (Palladini et al JCO 2012). Correlation with 6 minute walk test was done where available. RESULTS A total of 343 patients were identified. The median age was 64 yrs. Organ involvement was: cardiac - 72%, renal - 73% and liver - 12% (median - 2 organs). The median creatinine was 90 _mol/L, median dFLC was 150 mg/L (range 10-15898 mg/L). The median NT-proBNP was 966 ng/L (range 33-30872 ng/L). The Mayo disease stage was: stage 1 - 26%, stage 2 - 47% and stage 3 Ð 27%. Serial six minute walk test results were available in 71 patients. Treatment was: thalidomide based regimes (mainly CTD) 56%, CyBorD Ð 30%, Melphalan-Dexamethasone - 5% and SCT 1%. A total of 204 patients had baseline NT-proBNP >650 ng/L (the threshold defined for NT-proBNP to be assessable for cardiac response) and were included in response analysis. Partial hematological response (or better) was seen in 92%, ³ VGPR in 66% and 22 (8%) were non-responders. The median decrease in dFLC was 85% over baseline at six months. The median NT-proBNP at baseline (for the response assessable group n=204) was 2669 ng/L. At six months, the median NT-proBNP had increased significantly to a median 3258ng/L (p<0.0001). At 12 months, there was a significant decrease in the NT-proBNP to a median of 2097 pMol/L (p=0.014). There was a discordance in NT-proBNP response at 6 and 12 months in 42 (44%) of patients (Figure 1). At six months, 52 (25%) patients had achieved NT-proBNP response and at 12 months 94 patients (46%) achieved an NT-proBNP response. When NT-proBNP at the 6 month time point was used as a baseline for response assessment, at 12 months, 106 (52%) patients met the criteria for a cardiac response. There was no significant difference in the median six minute walk test at baseline, 6 m and 12 months was 390m, 370m and 400 m. The six minute walk distance improved by greater than 10% over baseline at 6 and 12 months in 12% and 20% patients, worsened by more than 10% in 32% and 27% patients with change of less than 10% in the remainder. The median survival for this cohort has not been reached at 5 years with 60% survival at 7 years. Contrary to published data, NT-proBNP response at six months had a non-significant impact on survival whilst the NT-proBNP response at 12 months significantly impacted survival (median not reached for responders vs. 67 months for the non-responders; p<0.0001). CONCLUSIONS This study shows the median NT-proBNP increased at six months over the baseline. There was a marked discrepancy in NT-proBNP at 6 months and 12 months Ð with a clear mis-classification of nearly half of all eventual cardiac responders. Consequently, the NTproBNP measurements at six months did not have a significant impact on survival whilst there was a marked impact at 12 months. NT-proBNP, as a primary end point, measure too early has potential for giving false negative results as a trial end point. This study highlights the critical importance of the timing of NT-proBNP measurements in response assessment for AL amyloidosis for clinical trials to avoid false negative results. FIgure 1 FIgure 1. Disclosures Wechalekar: Janssen: Honoraria; Celgene: Honoraria; Glaxo Smith Kline: Honoraria; Takeda: Honoraria.

Download Full-text

FOLFIRINOX in locally advanced or metastatic pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.313 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 313-313 ◽

Cited By ~ 4

Author(s):

Jason Edward Faris ◽

Theodore S. Hong ◽

Shaunagh McDermott ◽

Alexander R Guimaraes ◽

Dushyant Sahani ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Trial ◽

Advanced Disease ◽

Locally Advanced ◽

Phase Iii ◽

Metastatic Pancreatic Cancer ◽

Clinical Trial Setting ◽

Locally Advanced Disease ◽

Grade 3 ◽

Trial Setting

313 Background: The recently published Phase III trial of 5-FU, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) demonstrated improved survival compared to gemcitabine in good performance status (PS) patients with metastatic pancreatic cancer (Conroy et al, NEJM 2011). Less is known about the efficacy and tolerability with FOLFIRINOX in the non-clinical trial setting. In this retrospective analysis, we report our institutional experience with FOLFIRINOX. Methods: 29 patients with locally advanced or metastatic pancreatic cancer treated with FOLFIRINOX between July 2010 and April 2011 were used for this analysis. Clinical characteristics, and gradeable toxicities were tabulated, and formal radiographic review performed to determine best overall response rates (ORR). Results: 17 patients received FOLFIRINOX for metastatic disease and 12 patients for locally advanced disease. The median age of patients was 60 (range 39-76). 22/29 patients were men. 18/29 patients had received no prior chemotherapy. There was one patient with PS 2; all others had PS 0 or 1. 8/29 patients had biliary stents. Overall, 11 partial responses (PR) were observed (ORR 38%); 10/11 partial responses were in chemo-naïve patients, who had an ORR of 56%. In the metastatic setting, there were 6 PR, for an ORR of 35%, and 7 patients with stable disease (SD). In the locally advanced setting, there were 5 PR (ORR 42%), and 7 patients with SD. Following treatment with FOLFIRINOX, one patient with locally advanced disease has subsequently undergone R0 resection. The median number of cycles performed was 8 in both the locally advanced and metastatic settings. 12/29 patients required an ED visit or hospitalization during treatment. Grade 3/4 neutropenia was observed in 10 patients; 7/10 had not received prophylactic growth factor treatment from the start of FOLFIRINOX. 4 patients developed febrile neutropenia, 4 patients developed grade 3/4 thrombocytopenia, and 1 patient developed grade 4 anemia. Conclusions: In a non-clinical trial setting, FOLFIRINOX demonstrated activity in both the metastatic and locally-advanced settings. FOLFIRINOX appears to be associated with manageable, but significant toxicities, with over 40% of patients requiring hospitalization.

Download Full-text