Patients suffering from non-IgM light chain (AL) amyloidosis with severe cardiac dysfunction have a poor prognosis. A deep hematologic response can translate into a cardiac response and improve the survival of these patients. The Cyclophosphamide Bortezomib Dexamethasone (CyBorD) regimen is widely used as the first-line regimen, but therapeutic options are limited in relapsed/refractory patients. Recently, Daratumumab has emerged as an attractive option in this indication and has been evaluated in several prospective trials (NCT02841033, NCT02816476, NCT03201965, NCT03283917). Patients with severe heart failure (stage IIIb) have been excluded from these studies and data regarding the use of Daratumumab in patients with severe cardiac involvement are lacking.
Evaluate the safety and efficacity of daratumumab in patients with cardiac stage III AL amyloidosis.
Consecutive patients with cardiac stage III AL amyloidosis treated with Daratumumab were included in this monocentric retrospective study. The diagnosis of AL amyloidosis, evaluation of organ involvement and response were established according to consensus criteria. The cardiac stage was determined by the Mayo Stage 2004 with European modification wich distinguish stage IIIa (NT-proBNP < 8500 ng/L) and stage IIIb (NT-proBNP > 8500 ng/L).
Ten patients (4 with stage IIIa and 6 with stage IIIb) have been treated between June 2017 and July 2018. Median age was 77,5 years (62–83), the median number of organs impairment was 2 (1–5) and 6 patients had renal impairment. All patients except one received previous treatment with CyBorD and the median number of previous lines was 1 (0–4). Six patients were refractory to their previous treatment, 2 had non-optimal response and one patient relapsed after reaching VGPR. At Daratumumab initiation, the median value of dFLC was 116,95 mg/dL (37,6–480,9), median value of NT-proBNP was 12104 ng/L (1329–62759) and median value of Troponin-T was 148 ng/L (83–287). The median NYHA score was 3 (2–4). Patients received a median of 2 cycles (0,25–11) of daratumumab in association with dexamethasone for 7 of them. Lenalidomide was associated with Daratumumab after 3 cycles in one patient with an unsatisfactory response. Grade 1–2 infusion reactions occurred in 2 patients (20%), but no grade 3 or 4 reactions was observed. Two patients were not evaluable for haematological response, one because of dFLC<50 mg/L at daratumumab initiation and one because of early death 8 days after starting the treatment, thus 8 patients were evaluable for hematological response. After a median follow up of 12,1 months, 6 patients (75%) had a response including 1 CR, 2 VGPR and 3 partial response. One patient had a stable disease and 1 had progressive disease. Median time to first response was 1 month and the median time to best response was 2,5 months. No cardiac response was observed, but 4 patients had stable disease, 4 had progressive disease and 2 were not evaluable. One patient received heart transplantation in partial response after 2 cycles. Four patients died from cardiac events, 2 of infection and 1 because of suicide. Overall survival was 7,2 months (not reach in IIIa and 3,65 months in IIIb groups).
Daratumumab is safe and can result in rapid haematological responses in patients with cardiac stage III AL amyloidosis, most of them being refractory to bortezomib based therapy. However, cardiac response remains absent and survival short in these patients, stressing the need to develop new therapies aiming at improving the cardiac function.