Safety Profile of Bortezomib Impacts Survival in Light Chain Amyloidosis
Authors: Van de Wyngaert Zoé , Vanoutryve Greg , Fouquet Guillemette , Guidez Stéphanie , Herbaux Charles , Demarquette Helene , Renaud Loic , Terriou Louis , Noel Marie Pierre , Petillon Marie Odile , Hivert Bénédicte , Wemeau Matthieu , Launay David , Lamblin Nicolas , Hachulla Eric , Facon Thierry , Leleu Xavier 
Published: October 2019

Background. Bortezomib has improved overall survival (OS) in light chain (AL) amyloidosis; however, data on its activity in severe cardiac AL are sparse. Furthermore, the impact of the safety profile of Bortezomib on overall survival in severe cardiac AL amyloidosis remains unknown given the fragile population. We sought to outline the activity and safety profile of Bortezomib in severe cardiac AL amyloidosis.

Methods. Twenty-seven patients diagnosed with AL amyloidosis and treated with Bortezomib were included, mean age was 63 years (36-85), with a sex ratio of 18/9. Eighteen patients had cardiac involvement, among which all had Mayo-Clinic stage III staging but 3, and 9 had kidney involvement only. Seventy percent of patients received Bortezomib as a 1st-line therapy, once (19%) or twice weekly (81%), given IV at the starting dose of 1.3g/m2 in combination to Dexamethasone. Thirteen (48%) patients also received an alkylating agent.

Results. Overall hematological response rate was 75% in patients who received at least 1 cycle of Bortezomib, and 83% and 62.5% in patients with and without cardiac involvement, respectively. Complete response was obtained in 45%, and 42% and 50% in the 2 groups, respectively. 44% patients with cardiac involvement had an organ response.

An hematological toxicity occurred in 26% of patients, similarly in the 2 groups, consisting mainly of thrombocytopenia with no need for treatment modification. Non-hematological toxicity (grade ≥2) rate was 62% in patients with cardiac involvement and 38% in patients with kidney involvement (p=ns), consisting mostly of fatigue, peripheral neuropathy, infection and gastro-intestinal adverse effects, and leading to 25% of dose reduction, and 33% of Bortezomib interruption before cycle 4, similarly in both groups.

The median follow-up was 41 months from start of Bortezomib. Seven patients died during the first cycle of treatment, all of them but one had severe stage III cardiac involvement with LVEF <40%. Importantly, the patients with cardiac involvement who were treated past the first cycle had an estimated 3-year OS similar to those with kidney involvement only (50 vs. 62%, p=ns). All patients with cardiac AL who completed at least 3 cycles of treatment and survived beyond 3 months remained alive at follow-up date. In univariate analysis for the cohort as a whole, occurrence of non-hematological toxicity grade ≥2 was associated with a lower OS (20% if present vs. 67% when absent; p=0.001), as for the consequence of Bortezomib dose reduction (54% vs. 71%, respectively; p=0.036), and decrease of the total dose received to less than 50% of the initial dose (12% vs. 92% respectively, p=0.009). Bortezomib interruption (36% vs. 78%, respectively; p=0.004), or inability to receive at least 3 cycles of Bortezomib also impacted OS (36% vs. 78%, respectively; p=0,004). The impact on OS appeared even more dramatic in patients with cardiac involvement.

In multivariate analysis, independent variables that were associated with poor OS were the number of Bortezomib cycles (inability to receive at least 3 cycles) (OR=34.7; p=0.001), occurrence of a non-hematological toxicity (OR=5.1; p=0.011), and absence of hematological response (OR=3.6; p=0.05).

Conclusion. Bortezomib is an effective treatment of AL amyloidosis, and significantly improves the most adverse patients characterized with severe cardiac presentation. However, the safety profile is of particular concern in severe cardiac AL, particularly the non hematological ≥grade 2 incidence rate; patients often characterized with dose reduction or interruption, inability to receive sufficient dose concentration or number of cycles. This study confirms that alteration of the safety profile of Bortezomib may hamper the benefits seen particularly in severe cardiac AL, questioning on the use of weekly and sub-cutaneous Bortezomib for very fragile AL, as optimized in fragile patients with Myeloma.

Disclosures

No relevant conflicts of interest to declare.