Risk‐adapted autologous stem cell transplantation with adjuvant dexamethasone ± thalidomide for systemic light‐chain amyloidosis: results of a phase II trial

Abstract

Summary High‐dose melphalan (MEL) with autologous stem cell transplant (SCT) is an effective therapy for systemic AL amyloidosis (AL), but treatment‐related mortality (TRM) has historically been high. We performed a phase II trial of risk‐adapted SCT followed by adjuvant dexamethasone (dex) and thalidomide (thal) in an attempt to reduce TRM and improve response rates. Patients (n = 45) with newly diagnosed AL involving ≤2 organ systems were assigned to MEL 100, 140, or 200 mg/m2 with SCT, based on age, renal function and cardiac involvement. Patients with persistent clonal plasma cell disease 3 months post‐SCT received 9 months of adjuvant thal/dex (or dex if there was a history of deep vein thrombosis or neuropathy). Organ involvement was kidney (67%), heart (24%), liver/GI (22%) and peripheral nervous system (18%), with 31% having two organs involved. TRM was 4·4%. Thirty‐one patients began adjuvant therapy, with 16 (52%) completing 9 months of treatment and 13 (42%) achieving an improvement in haematological response. By intention‐to‐treat, overall haematological response rate was 71% (36% complete response), with 44% having organ responses. With a median follow‐up of 31 months, 2‐year survival was 84% (95% confidence interval: 73%, 94%). Risk‐adapted SCT with adjuvant thal/dex is feasible and results in low TRM and high haematological and organ response rates in AL patients.

Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis

“…51 Adjuvant therapy with 9 months of thalidomide and dexamethasone following riskadapted SCT in patients who did not achieve CR resulted in hematologic responses in 71% of patients including 36% who achieved CR at 12 months post SCT. 52 In a similar trial, investigators used bortezomib and dexamethasone for six cycles following SCT, reporting an overall response rate of 96% with CR in 65% of patients. 53 Novel agents following initial therapy or SCT appear effective for AL, but uniform definitions of 'consolidation' and 'maintenance' are needed to design clinical trials and to develop standard practice guidelines.…”

Current status of hematopoietic cell transplantation in the treatment of systemic amyloid light-chain amyloidosis

“…They applied thalidomide (thal) and dex as adjuvant treatment after risk adapted HDM within a phase II trial. 48 Forty-five newly diagnosed patients were included. Thirty-one patients with persistent clonal disease 3 months after HDM received thal/ dex, or dex alone.…”

Light-chain amyloidosis: SCT, novel agents and beyond

“…The low TRM (4 and 10% respectively) in both trials suggests that this approach is safe. With thalidomide-based consolidation, the overall response rate at 12 months was 71% (including 36% CR); 44 and was 97% (77% CR) when bortezomibbased therapy was used. 49 Organ improvement was noted in 44% and 69% of patients with thalidomide and bortezomib-based treatment, respectively.…”

“…40 Although cardiac staging has helped to identify patients at risk for TRM during HDM/SCT, [41][42][43] advanced cardiac disease as defined by clinical criteria (New York Heart Association 42, symptomatic arrhythmias and cardiac syncope) has also been used to exclude patients from SCT. 44 Older age and impaired renal function have been associated with early death in patients with AL undergoing SCT 37 and risk adapted melphalan dosing 44 has reduced this risk. Supportive strategies including continuous telemetry monitoring, 40 routine fecal occult blood testing with platelet support and lymphedema therapy contribute to patient safety during SCT.…”

“…In order to compensate for modified-dosing, which may impact efficacy, 47 consolidation with novel agents following HDM/SCT has been investigated. 44,48 In a series of trials, patients with newly diagnosed AL were treated with melphalan 100, 140 or 200 mg/m 2 based on age, renal function and cardiac involvement. Patients with persistent clonal disease following SCT received further therapy with thalidomide and dexamethasone and in a subsequent study, bortezomib and dexamethasone.…”