Safety Profile Of Bortezomib Impacts Survival Of Cardiac AL Amyloidosis
Authors: Van de Wyngaert Zoé , Vanoutryve Greg , Herbaux Charles , Fouquet Guillemette , Demarquette Helene , Bonnet Sarah , Beauvais David , Guidez Stéphanie , Lamblin Nicolas , Hachulla Eric , Launay David , Terriou Louis , Hivert Bénédicte , Wemeau Mathieu , Leleu Xavier 
Published: October 2019

Abstract

Background
Light chain amyloidosis (AL) is characterized by a median overall survival (OS) from diagnosis of approximately 3 years, but with clinically overt cardiac involvement this is reduced to 1 year. Bortezomib (B) has shown great promise in the treatment of AL, especially of cardiac involvement. However, efficacy might be hampered by severe safety issues with use of B, primarily of neuropathy type. We sought to study the prognostic impact of the safety profile of B in AL with attention to cardiac involvement.

Method
This study has included 27 patients with AL, of these 18 had cardiac and 9 kidney but no cardiac involvement. AL was diagnosed as outline in international consensus criteria, as to the hematologic and organ responses. B was given IV twice weekly at the starting dose of 1.3 mg/m², in combination to weekly cyclophosphamide in 13 patients (52%).

Results
The median age was 63, sex ratio was 18/9, all cardiac AL had Mayo Cardiac Stage III but 3, and none in patients with no cardiac AL. 70% were at diagnostic. Seven patients died during the first month, all of them but one had cardiac AL. We then looked at the safety profile of B in the studied population, and found that 25% and 75% experienced some degree of hematotoxicity in cardiac and in no cardiac AL (p=NS). The non hematology toxicity rate was 62% and 38%, respectively (p=NS). 26% of patients needed dose reduction of B and 33% dose interruption of B in the study before cycle 4, all related to non hematological toxicity of neuropathy, fatigue and GI AEs; and was similar in cardiac as compared to no cardiac AL.
The overall hematologic response rate (ORR) was 56% and at least VGPR (with >90% decrease in difference between involved/uninvolved light chain) 41%. The responses were 56% and 39% in cardiac AL, similar to patients with no cardiac involvement (56% and 44%), respectively. The median duration of response was 13 months overall, 10 and 20 months in cardiac and in no cardiac AL, respectively (p=NS). Non hematological toxicity did not impact the response rate or the duration of response.
With a median follow-up of 41 months from start of B, 70% relapsed and 59% died in the study as a whole, and 67% and 67% in the cardiac group, respectively. The median time to progression was 20 (95CI 4;35.5) months as a whole, and 13 (9;17) months and 20 (0;43) months in cardiac and in no cardiac AL (p=NS). The median OS was not reached in the cohort as a whole and in patients with no cardiac involvement, but was 5 months in cardiac AL (p=NS); the estimated 4-year OS was 55%, 62% and 50%, respectively. Interestingly, all cardiac AL that survived beyond 6 months remain alive at F-up date. Several variables negatively impacted survival in univariate analysis in the group with cardiac AL, including decreased LVEF (p=0.025), NYHA greater than 2 (p=0.007),Mayo Cardiac Stage III (p=0.028), no hematological (p=0.002) and no organ responses (p=0.05), occurrence of non hematological toxicity (p=0.002) with the consequence of dose reduction of B (p=0.09) and dose interruption of B (p=0.04).
In multivariate analysis, independent variables that impacted survival were hematological response (OR = 5.1, 95%CI = 1.5-18; p = 0.011) and non hematological toxicity (OR = 3.6, 95%CI = 0.8-14; p = 0.05).

Conclusion
Bortezomib is a very rapid and effective therapy for AL particularly of cardiac involvement. However, patients may develop severe side effects with Bortezomib that preclude efficacy of Bortezomib given IV, and consequently impact negatively survival. This data favours use of sub cutaneous Bortezomib in AL although not validated in this indication yet.

Disclosures:
Leleu: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Leopharma: Consultancy, Honoraria; Millennium : Honoraria; Amgen: Honoraria; Novartis: Honoraria.