A European Collaborative Study of 230 Patients to Assess the Role of Cyclophosphamide, Bortezomib and Dexamethasone in Upfront Treatment of Patients with Systemic AL Amyloidosis

Background. Early small studies from our groups and others reported unprecedented response rates (up to 90%, with 65% complete remissions) in patients with AL amyloidosis treated with the combination of cyclophosphamide, bortezomib and dexamethasone (CyBorD). Based on these results CyBorD has become one of the most commonly prescribed frontline regimens in AL amyloidosis outside clinical trials. Subsequently, however, we have shown that this regimen is unable to overcome the poor prognosis of patients with advanced cardiac disease. There is the need of large studies to identify patients who benefit most from this highly effective regime in AL amyloidosis.

Patients and Methods. The prospectively maintained databases of the London National Amyloidosis Centre and of the Pavia Amyloidosis Research and Treatment Center were systematically searched for newly-diagnosed patients treated with CyBorD between 2006 and 2013.

Results. A total of 230 patients were identified. Median age was 60 years (range 38-85 years). Involved organs were heart (169, 73%), kidney (149, 65%), soft tissues (35, 15%), liver (25, 11%), and peripheral nervous system (6, 3%). Cardiac stage was I in 41 patients (18%), II in 77 (33%), and III in 112 (49%). N terminal pro natriuretic peptide type B (NT-proBNP) was >8500 ng/L in 51 patients (22%). Median estimated glomerular filtration rate was 82 mL/min (range 4 - >90 mL/min), being <30 mL/min in 17 patients (7%). Median bone marrow plasma cell infiltrate was 12% (range 2-50%) and difference between involved and non-involved free light chains (dFLC) was 248 mg/L (range 0-12650 mg/L). Cyclophosphamide was administered at a dosage of 300 mg/m² on days 1, 8, and 15. The dosage of bortezomib ranged from 1.0 mg/m² once weekly to 1.3 mg/m² twice weekly. The maximum dosages of 1.6 mg/m² weekly or 1.3 mg/m² twice weekly were used in 26% of patients. Most patients (148, 64%) received weekly dexamethasone, at the daily dosages of 10 (8 subjects), 20 (85), and 40 (55) mg. Other common dexamethasone schedules were twice weekly (32), and administration the day of bortezomib injection and the following day (10). Overall 69 patients (30%) received at least 160 mg/week of dexamethasone. The median number of cycles performed was 4 (range 1-8 cycles). A total of 201 patients had measurable disease, including 40 subjects who died before evaluation of response. The overall hematologic response rate by intent to treat was 62%, with 42 patients (21%) reaching complete response (CR), and 45 (22%) very good partial response (VGPR). In 30 evaluable stage I patients the ORR was 80% (P=0.044), with 33% CRs and 23% VGPR. The dosage of bortezomib and dexamethasone administered did not significantly affect the response rate and quality of response. On an ITT basis, cardiac and renal responses were noted in 17% and 25%, respectively. After a median follow-up of living patients of 25 months, 94 patients (41%) died. Median survival was 72 months. Projected survival at five years was 100% for stage I patients, 52% for stage II, and 27% (median 20 months) for stage III patients (P<0.001). Thirty-seven percent of patients with NT-proBNP >8500 achieved a response and 28% were alive at 12 months (85% of responders in this group with 69% CR/VGPR). Most common second-line treatments were autologous stem cell transplant (17 patients, 65% response rate, 47% CRs) and lenalidomide / dexamethasone (20 patients, 65% response rate, 10% CRs).

Conclusion. This is the largest study of CyBorD treatment in AL amyloidosis. This study confirms that CyBorD is remarkably effective in low risk patients with 56% CR/VGPR and no deaths observed in stage I patients. Unfortunately, outcomes in patients with advanced cardiac disease were poor, but 28% of advanced patients achieving a CR/VGPR had improved survival, showing importance of striving for a good response even in this poor risk group. The very high clonal response and excellent outcome in early stage AL with CyBorD confirm its place as a regime of choice for this group and raises a need for a randomized trial with ASCT for assessing the role of upfront ASCT in this era of novel agent based therapy in AL.