Efficacy of Risk Adapted Cyclophosphamide, Thalidomide and Dexamethasone in Systemic AL Amyloidosis.

Abstract

The prognosis for advanced AL amyloidosis (AL) with conventional treatment remains very poor and stem cell transplantation has unacceptably high mortality (TRM). Single agent thalidomide in standard doses is poorly toleranated and has low response rates in AL (Dispenzieri et al, Amyloid 10:247; 2003) and few data on the role of thalidomide based combination chemotherapy in AL are available. We report experience with a risk adapted thalidomide based combination using cyclophosphamide and dexamethasone (CTD) in 43 patients with AL amyloidosis at the National Amyloidosis Centre, UK. The regime (adapted from the UK MRC Myeloma IX trial) consisted of a 21-day cycle oral cyclophosphamide 500mg once weekly, thalidomide 200mg/day (starting dose 100mg/day, increased after 4 weeks if tolerated) continuously and dexamethasone 40mg days 1–4 and 9–12. This was risk attenuated (CTDa) in the elderly (>70yrs), heart failure >NYHA grade II or significant fluid overload to a 28-day cycle of cyclophosphamide 500mg days 1, 8 and 15, thalidomide 200mg/day (starting dose 50mg/day, 4–weekly 50mg increments as tolerated), and dexamethasone 20mg day 1–4 and 15–18. A total on 43 patients (22M:21F, median age 61yrs, range 43–79) were treated; 35 received CTD and 8 received CTDa. Median number of organs involved was 2 (1–4), including renal in 62% of patients, cardiac in 60%, hepatic in 39%. Median follow-up from treatment initiation was 7mo (0.4–35) and from diagnosis 16.5mo (0.6–69). Patients received a median of 4 cycles of treatment (1–7). The number of previous treatments was none in 39%, one in 39%, two in 14% and three in 6%. Toxicities were seen in 17 (39%) of patients (CTDa 3; CDT 14) necessitating dose reduction in 11 (25%), dexamethasone omission in 6 (14%), thalidomide omission in 1 (2%) and complete regime discontinuation in 4 (9%). The main side effects were: worsening heart failure 20%, neuropathy 11%, infections 11%, sleepiness 2%, and neutropenia, renal impairment, constipation and fatigue − 4% each with no thrombotic complications or TRM. Survival data was evaluable in all patients while response was evaluable in 35 (81%).Haematologic response was defined as follows: complete response (CR) - sustained normalisation of sFLC (serum free light chains) ratio, partial response (PR) - sustained ≥50% reduction in pre-treatment clonal isotype. There was a haematologic response in 26 (74%). 12 (34%) has a CR, 14 (40%) had a PR, 9 (25%) had no response. sFLC assays were available after every cycle in 27pts; a reduction in the clonal class of ≥25% was evident within 30days in 59% and in another 33% by day 60. An appreciable regression of amyloid was evident in 15% of the responders by SAP scintigraphy. The median survival for the cohort has not been reached at 36 months. This preliminary study shows excellent efficacy of CTD in patients with advanced AL with response rates superior to conventional intermediate dose chemotherapy. The regime appears to be safe with no treatment related mortality and tolerance appears to be better than than standard dose thalidomide alone (Dispenzieri et al, Amyloid 10:247; 2003) or with dexamethasone (Pallidini et al, Blood 105:7; 2005). However, a quarter of the patients needed dose reduction and more stringent use of risk adaptation may improve the tolerability of this regime. Risk adapted CTD may be an alternative to standard therapies as front line treatment in AL amyloidosis.