ALchemy - A Large Prospective ‘Real World' Study of Chemotherapy in AL Amyloidosis

There have been few prospective clinical trials in AL amyloidosis; existing prospective studies in this heterogeneous disease have been hampered by small patient numbers due to rarity of the condition, a lack of validated endpoints and high cost. More importantly, they have been subject to considerable bias due to almost complete exclusion of poor prognosis patients.

The aims of this prospective observational study, was to include all patients with systemic AL amyloidosis regardless of age or disease severity, in order to convey a ‘real-world' picture of the disease, its response to myeloma-type chemotherapy regimens, associated toxicity and outcomes in terms of amyloidotic organ function, quality of life (QoL) and survival.

All patients referred to the UK National Amyloidosis Centre (NAC) from 1^st September 2009 were screened for participation in the AL chemotherapy study (ALchemy). Patients were eligible if they were newly diagnosed with systemic AL amyloidosis and in need of chemotherapy. At each NAC evaluation (baseline, after completion of 3 cycles of chemotherapy and 6, 12, 18 and 24 months) the underlying clonal disease was assessed by sFLC assay and serum and urine electrophoresis; amyloidotic organ dysfunction/response was assessed according to the international consensus criteria. At baseline patients underwent bone marrow examination, assessment of whole-body amyloid load by ¹²³I-SAP scintigraphy, and completed a QoL questionnaire. Amyloid burden was monitored 6 monthly thereafter, and QoL after 3 cycles and yearly thereafter. Clonal disease assessments were undertaken monthly throughout the duration of the study and toxicity assessments during periods of chemotherapy. Patients received chemotherapy in local hematology centers and regimens and doses were at the discretion of treating physicians.

Two hundred and fifty patients were recruited in 2 years; 57% were male. Median age at presentation was 64 years (IQR 57 to 73). At baseline evaluation, which occurred a median of 1 month from diagnosis, 20% of patients had Mayo stage 1 disease, and 40% each had stage 2 and 3 disease. Renal (50%) and cardiac (31%) presentations predominated. At censor, 9 (4%) patients had died prior to starting chemotherapy and 217 (87%) patients had received at least one cycle and were thus considered ‘evaluable'. First-line treatment was with CTD in 168 (77%) cases, 89% of whom received dose attenuation. Nineteen (9%) patients received a melphalan- or bortezomib-based regimen first line. One third of those patients who commenced chemotherapy underwent a regimen change, usually (82%) to one containing bortezomib, either as monotherapy (9 patients) or in combination with dexamethasone and/or cyclophosphamide (47 patients). On an intention to treat basis, 20% patients died before reaching the 3 cycle timepoint and a further 9% were withdrawn or lost to follow up. Among the 154 remaining evaluable patients, the 3 cycle evaluation resulted in continuation of the same chemotherapy regimen in 42% cases, a switch of regimen in 21% cases, and cessation of chemotherapy altogether in 28% cases. At this timepoint, clonal CR, VGPR, PR and NR rates among evaluable patients were 35%, 9%, 30% and 26% respectively. Toxicity ≥grade 3 occurred in 49% of patients with a total of 359 episodes. The commonest severe toxicities were fluid overload (61%), lethargy (38%), infection (26%), hypotension (18%) and neuropathy (12%). Of 217 patients, 111 (51%) were admitted with a total of 148 hospitalizations, most commonly due to fluid overload or infection. After median follow-up of 7 months, 29% of patients had died. Mayo stage 3 disease, dominant cardiac presentation and inadequate clonal response after 3 cycles were independent risk factors for death. Achieving a dFLC response >65% after the first cycle of chemotherapy, appeared to overcome the poor prognosis associated with Mayo Stage 3 disease.

ALchemy is fast becoming the largest prospective study in AL amyloidosis and has provided a wealth of information on treatment, toxicity and outcome in a real-world clinical setting. The inclusion of most patients, regardless of disease severity, indicates a persistently poor prognosis among a substantial proportion of patients who are ineligible for randomized controlled trials, and highlights the unmet need for improved diagnosis and treatment.

No relevant conflicts of interest to declare.