The Prognostic Importance of the 6-Minute Walk Test in AL Amyloidosis
Authors: Cohen Oliver C , Sathyanath Ananth , Ravichandran Sriram , Law Steven , Manwani Richa , Foard Darren , Sachchithanantham Sajitha , Mahmood Shameem , Martinez-Naharro Ana , Fontana Marianna , Whelan Carol , Hawkins Philip N , Lachmann Helen J , Gillmore Julian D , Wechalekar Ashutosh D. 
Published: November 2020

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&lt;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&lt;0.0001; Mayo IIIb HR 6.08 [3.63-10.12], p&lt;0.0001; 6MWT ≥300m HR 2.97 [2.38-3.72], p&lt;0.0001). Baseline 6MWT correlated strongly with other prognostic factors including Eastern Cooperative Oncology Group (ECOG) performance status (p&lt;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 &lt;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&lt;0.0001). Patients achieving ≥300m at any time point had a significantly better OS (at 6, 12, 24 and 36 months p&lt;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. &lt;300m: 4.0 [1.3-6.9] months vs. unable to walk: 1.0 [0.3-1.7] months, p&lt;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&lt;0.0001; NR: HR 5.61 [2.88-10.92], p&lt;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 &lt;300m but improved by ≥33m at 12 months, median OS was superior to those who improved by &lt;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&lt;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.