First Line Therapy With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) In Patients With AL Amyloidosis and Potentially Reversible Contraindications To Autologous Stem Cell Transplant
Authors: Palladini Giovanni , Milani Paolo , Rosin Marta Vidus , Foli Andrea , Merlini Giampaolo 
Published: October 2019

Abstract
Two recent reports by the Mayo Clinic and UK groups showed that the combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) grants a high rate of complete response (CR) and very good partial response (VGPR) in AL amyloidosis. In the two papers a total of 30 patients who received CyBorD upfront were reported, 63% of whom achieved CR. This combination has the further advantage of sparing stem cells, allowing second-line autologous stem cell transplant (ASCT).
In the present study we treated with frontline CyBorD 56 consecutive newly diagnosed patients with AL amyloidosis, diagnosed between 2010 and 2012, who were transplant candidates and refused the procedure frontline or had potentially reversible contraindications to ASCT. Main exclusion criteria from the present study were age ≥70 years, NT-proBNP >8500 ng/L, systolic blood pressure <100 mmHg, and glomerular filtration rate (eGFR) <15 mL/min. The patients received weekly cyclophosphamide 300 mg/m2, bortezomib 1.3 mg/m2, and dexamethasone (40 mg). The dose of dexamethasone was reduced to 20 mg in 13 patients (23%) who were cardiac stage 3. Starting in September 2012, bortezomib was administered subcutaneously. Hematologic response was assessed every 2 cycles. Median age was 55 years. The kidney was involved in 41 patients (73%), the heart in 39 (70%), and the liver in 5 (9%). Cardiac stage was I in 17 patients (30%), II in 26 (46%), and III in 13 (33%). Five subjects (9%) had eGFR <30 mL/min. Eleven patients (20%) experienced severe adverse events, namely fluid retention and worsening heart failure (4, 7%), cytopenia (4, 7%), worsening renal failure (2, 4%), and deep venous thrombosis (1, 2%). Additionally, 4 patients (7%) died on treatment due to progressive cardiac amyloidosis, before the first evaluation of response. Overall, 63% of patients responded (95%CI: 49-75%). Best hematologic response by intent-to-treat, was CR in 16 patients (29%), VGPR in 8 (14%), and partial response (PR) in 11 (19%). All responders achieved at least PR by cycle 2, and best response was reached by cycle 6 in all cases. Cardiac response was achieved in 13/39 subjects (33%) and in 3/41 (7%) there was a renal response. So far, 10 patients, 6 non-responders, 3 attaining PR, and 1 in VGPR with progressing proteinuria were transplanted. Response data are available for 4 of these subjects, 3 of whom responded to ASCT (1 CR, 1 VGPR, 1 PR). With a median follow-up of living patients of 15 months, 11 patients (20%) died. Median survival was not reached and 78% of patients are projected to be alive at 1 year. The main baseline determinant of patients’ outcome was cardiac stage, with 100% 1-year survival in stage I, and 70% in stage II and III patients.
This is the largest study on frontline CyBorD in AL amyloidosis reported so far. In this homogeneous patient population including low/intermediate-risk subjects with potentially reversible contraindication to ASCT, 43% of patients achieved CR/VGPR and cardiac dysfunction improved in one third of cases. Second-line ASCT was feasible in subjects with suboptimal responses. Though good, the response rate to CyBorD observed in the present study was lower than that reported in the 2 previously published studies, indicating that randomized clinical trials are needed to assess the efficacy of this combination in AL amyloidosis.

Disclosures:
Off Label Use: Bortezomib in AL amyloidosis. Merlini:Millennium-Takeda: Honoraria; Pfizer: Honoraria.