Weekly Combination Chemotherapy with Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) for Newly Diagnosed Patients with Advanced Cardiac Disease Due to Systemic AL Amyloidosis

Abstract 5139

The treatment of systemic AL amyloidosis (AL) with advanced cardiac involvement (cardiac biomarker stage III) at diagnosis remains challenging and unsatisfactory. Median survival with melphalan and dexamethasone (MDex) in stage III patients is about 10 months from diagnosis with one quarter of patients dying within 3 months of starting therapy (BJH 2008;143:369; Blood 2010;116:522). Bortezomib has been shown to be the most active single agent in the treatment of AL (Blood 2011;118:865) and, when incorporated into CyBorD, clinical studies have shown a > 90% hematologic response rate in both myeloma and in AL (Blood 2010;115:3416; Leukemia 2009;23:1337; Amyloid 2010;17(S1):171a). In addition, bortezomib has been shown to have limited cardiac toxicity and no arrhythmogenicity in patients with AL and cardiac involvement (QJM 2011 published online July 13, 2011). Based on these data we have used CyBorD as initial standard therapy in patients with newly diagnosed systemic AL amyloidosis with advanced (stage III) cardiac involvement who are ineligible for stem cell transplant or clinical trials. We now retrospectively report the outcomes in the 11 consecutive stage III patients who have been treated thus far with CyBorD as initial standard therapy (6F, 5M). Patients were a median of 57 years old (range, 44–74) with median brain natriuretic peptide (BNP) of 709 (145–1490), troponin I of 0.29 (0.11–0.77), involved free light chains of 322mg/L (101–4325) and marrow plasma cells of 20% (4–41%). Median left ventricular (LV) ejection fraction and LV wall thickness (average of IVSd+LVPWd) by echocardiogram were 52% (35–70%) and 1.7cm (1.2–2.1) respectively. Patients received CyBorD on a 35-day cycle on days 1, 8, 15 and 22 with cyclophosphamide (300mg/m2) and dexamethasone (20 or 40mg flat dose) given orally or IV and bortezomib (1.3mg/m2) given IV or subcutaneously. Routine prophylactics included acyclovir, fluconazole and omeprazole. Patients have received a median of 4 cycles (1–8). Of the 11 patients, 2 died suddenly at 1 and 5 months, and 9 are alive with a median follow up of 8 months (3–15). Three patients experienced worsening congestive heart failure requiring hospitalization, medication adjustments and in 1 case pericardiocentesis. The gastrointestinal (GI) side-effects of bloating and constipation were common and usually manageable although 1 patient stopped therapy after 2 cycles because of lower GI bleeding. Of 10 patients evaluable for hematologic response, 8 responded (1 CR, 4 VGPR, 3 PR) (response criteria from Blood 2010;116:586a) and 2 had no response. Median time to response was 1 cycle (1–3). Thus far, there have been 4 patients (2 VGPR, 2 PR) who within months of starting therapy have had BNP reductions of 40% to 76% of baseline (median BNP reduction of 434pg/ml (282–712)). In conclusion, these retrospective data are encouraging and hopefully will spur the development of phase II and III trials in newly diagnosed patients with advanced cardiac involvement due to AL.