Long Term Follow up of Patients with Relapsed/Refractory Systemic Light Chain (AL) Amyloidosis Treated with Bendamustine and Dexamethasone in a Phase 2 Study

Background: Limited therapeutic options exist for patients with AL amyloidosis who have relapsed or refractory disease after initial treatment. Bendamustine, a bifunctional alkylating agent, has been promising in the treatment of multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, but has not been well studied in AL amyloidosis. In order to characterize the efficacy and safety of Bendamustine with dexamethasone (Ben/Dex) we conducted a phase II, multi-center trial of this combination in patients with previously treated AL amyloidosis. Here we report our final results with extended follow up.

Methods: Thirty one patients with persistent or progressive AL amyloidosis after at least 1 prior therapy were enrolled in this phase IIa trial. A two-stage Simon design approach was applied initially enrolling 13 patients followed by an additional 16 in the second stage once at least 3 patients experienced partial hematologic response (PR) in the first stage. The treatment was considered worthy of further development if 9 or more of the 29 patients experienced a PR. The primary objective was to define the PR rate. Secondary objectives included overall hematologic response rate, organ response rate, time to treatment failure, toxicity profile, and overall survival. Bendamustine was given on day 1 and 2 (100 mg/m² IV for CrCl≥60 mL/min, 90 mg/m² IV for CrCl 59-30 mL/min, 70 mg/m² IV for CrCl 15-30 mL/min) in 28-day cycles. Dexamethasone was dosed 20-40 mg weekly. Treatment continued until disease progression or up to 6 cycles after complete response. Evaluable response was defined as patients who completed at least 2 cycles of therapy.

Results: As of 3/1/2017 all 29 patients who had evaluable responses had completed treatment with a median follow up of 13.3 months (range 3.0-50.1). Median patient age was 64 (42-78) with a predominantly male population (72%). Primarily affected organs included heart (53%), kidney (36%), nerve (7%), and liver (4%) with 62% of patients having ≥ 2 organs involved. A median of 1.5 prior regimens (range 1-4) had been administered and 13 of the patients received a prior autologous stem cell transplant. With a median of 4 cycles of therapy (range 2-12), 45% of patients achieved a partial response or better (7% complete response, 14% very good partial response). Median time to best response was 3 cycles (range 1-8). Organ response was observed in 5 of 18 patients with renal involvement and 2 of the 17 patients with cardiac involvement. There were only 2 deaths while on treatment and both were attributed to underlying disease, not the Ben/Dex. Ten patients discontinued treatment due to an adverse event, although 5 were only grade 1-2 adverse events. Overall, the most common adverse events included gastrointestinal symptoms, myelosuppression, neurological symptoms, and fatigue. Median overall survival was 18.1 months (range 3.6-32.7) (Figure 1) and median progression free survival was 11.0 months (range 6.7-15.4) (Figure 2).

Conclusions: The final results of our study with extended follow up demonstrate that Ben/Dex is a viable treatment option for patients with pre-treated AL amyloidosis who have limited therapeutic options. The combination therapy was generally well tolerated and produced a substantial hematologic response with prolonged progression free survival in patients who have failed prior treatment.

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