A Prospective Study of Treatment Outcomes in 179 Patients with Advanced Cardiac Stage STAGE IIIb Amyloidosis
Authors: Sevillano Belen , Wechalekar Ashutosh , Foard Darren , Whelan Carol , Fontana Marianna , Quarta Cristina , Mahmood Shameem , Lachmann Helen , Gillmore Julian D , Hawkins Philip N 
Published: October 2019

Abstract
A PROSPECTIVE STUDY OF TREATMENT OUTCOMES IN 179 PATIENTS WITH ADVANCED CARDIAC STAGE IIIB AMYLOIDOSIS
Authors: Belen Sevillano, Darren Foard, Carol Whelan, Mariana Fontana, Critina Quarta, Shameem Mahmood, Helen Lachmann, Julian Gillmore, Philip Hawkins and Ashutosh Wechalekar
INTRODUCTION
The prognosis of systemic light chain amyloidosis is determined by extent of cardiac involvement. The Mayo cardiac staging system (Dispenzieri et al JCO 2004) is widely used for prognosis and we defined a particularly poor prognostic subgroup within Mayo stage III patients (Wechalekar et al Blood, 121(17), 2013) characterized by NT-proBNP >8500 ng/L with a median survival of 4 months-stage IIIb disease. All such patients are excluded from clinical trials and treatment outcomes of this group are not known. We report the treatment outcomes of a cohort of stage IIIb cardiac AL patients prospectively followed up in the ALChemy study
PATIENTS AND METHODS.
All patients from the ALChemy study (a prospective observational study of all patients with AL amyloidosis undergoing chemotherapy) at the UK National Amyloidosis Centre (identified from first 1000 patients recruited into the study from 2009 to Jan 2015) with Mayo stage IIIb cardiac AL (defined as NT-proBNP >8500 ng/L and cardiac troponin T >0.035 μg/L) were included. All were treated according to nationally agreed protocols. Organ involvement and hematologic/amyloidotic organ responses were assessed according to 2010 amyloidosis consensus criteria. The primary outcome measure was overall survival (OS) and impact of hematological response on survival. Statistical analysis was undertaken using SPSS software package. Survival was assessed by the Kaplan-Meier method and compared by log-rank test.
RESULTS
A total of 179 patients were included. The median age was 65 yrs, 77 (43 %) were female and 102 (57 %) male. All patients had cardiac involvement, renal involvement was seen in 131 (73.2 %) and liver involvement in 28 (15.6 %). The median NT-proBNP was 19056 ng/L (range 8500 - 70084 ng/L). The median left ventricular (LV) wall thickness was 14.2 mm (range 11-22 mm) and median ejection fraction (EF) was 48.7 % (23-75 %). 34 % had dyspnea ≥ NYHA grade 3 and 16.8 % had ECOG performance status ≥3. Only 68 (38 %) patients managed a 6 min walk test and median distance was 130.5 m.
30 (17 %) patients died prior to treatment initiation. Initial treatment regimens were: Bortezomib combinations - 48 % (87); Thalidomide or Lenalidomide combinations in 28 % (51), alkylators based regimens - 5 % (9) and rituximab based in 1 %. The hematological best responses on an intention to treat basis were: complete response (CR) - 35w (20%), very good partial response (VGPR) 25 (13%), partial response (PR) 32 (18%) and no response (NR) 87 (47%) (NR included patients who died before treatment).
The median OS for the cohort was 6 months (mo). Univariate and ROC analysis identified LVEF >55%, dFLC <400 mg/L and SBP >110 mm of Hg predictors of OS. The median OS was significantly better for patients with LVEF>55% (13 mo); for dFLC < 400 mg/L was 7 mo (vs. 3 mo for dFLC >400 mg/L); and for those with SBP > 110 mmHg was 10 mo (vs. 5 mo in those with lower SBP). Median OS for patients achieving a CR/VGPR at day 30 was 26 mo compared to 5 mo for patients with <VGPR at that time. The median OS for patients who finally achieved CR/VGPR was 38 mo, PR 7 mo and NR was 2.6 mo (log rank p<0.0001) (Fig 1). In a multivariate model, achieving a hematological CR/VGPR (HR 5.3), LVEF <55% (HR1.5), dFLC >400 mg/L (HR 1.3) and SBP <110 mm of Hg (HR 1.5) were independent predictors of outcomes.
CONCLUSIONS:
The survival of stage IIIb AL remains poor but has improved compared with historical reported series. The survival of patients who achieve a CR or VGPR is over 3 years. Early achievement of ≥VGPR, as early as end of cycle 1, seems to predict for a better survival challenging the practice of treating stage III patients with "low" dose chemotherapy which often leads to slower clonal responses. This study confirms that, even in this advanced group of patients, a rapid hematological response will translate into improved outcomes. Since most non-responders to the first 1 or 2 cycles succumb to progressive disease, prospective studies are urgently needed to design rapidly effective well tolerated regimes possibly with combination of anti-amyloid therapy.

Disclosures
No relevant conflicts of interest to declare.