【Introduction】There is ongoing unmet need for effective therapies in Mayo 2004 stage II-III amyloid light-chain (AL) amyloidosis patients, who undergo early death due to cardiac dysfunction. Lately, in vitro studies demonstrated that doxycycline could induce disruption of fibril formation in transgenic mouse model of AL amyloidosis. Matched case-control study of standard chemotherapy with or without doxycycline confirmed higher hematological response, cardiac responses and superior survival with doxycycline in AL patients. However, the possible advantage of doxycycline on lower early mortality and better long-term survival has not been evaluated in a randomized controlled clinical trial. We designed a randomized unblinded controlled study to investigate the efficacy and safety of co-administration of oral doxycycline with bortezomib-cyclophosphamide-dexamethasone (BCD) regimen in treatment-naïve AL amyloidosis patients with Mayo 2004 stage II-III disease.
【Methods】The randomized unblinded controlled study took place in 12 hospitals in China. Eligible participants were adults with a confirmed diagnosis of AL amyloidosis, whose Mayo 2004 stage were II or III. Enrolled patients were randomly allocated to receive either doxycycline combined with BCD or BCD alone as initial treatment. We chose stratified blocked randomization (block size of 4) to ensure Mayo stage II and III were evenly distributed between doxycycline group and control group. For both two groups, patients will receive 1.3mg/m2of subcutaneous bortezomib and 40mg of oral or intravenous dexamethasone on days 1, 8, 15 and 22, and 300mg/m2oral or intravenous cyclophosphamide on days 1, 8 and 15 of a 35-day cycle. This process was repeated for 9 cycles. Doxycycline was given orally 100mg twice daily for the experimental group. The primary endpoint is progression-free survival. Secondary endpoints include overall survival, adverse events, hematological response, organ response and safety of treatment. This trial has been registered with ClinicalTrials.gov (number NCT03401372) and recruitment and follow-up are ongoing. We planned to enroll a total of 140 participants.
【Results】Between April 21st, 2018 and June 30th, 2019, 111 patients were enrolled and randomly assigned to receive doxycycline plus BCD (n=56) or BCD alone (n=55) (Figure 1). The baseline characteristics were shown in Table 1. The median age was 61 (range, 41-78) years with a male: female ratio of 1.64:1. Mayo 2004 stage II disease was present in 28 patients in the control group and 29 patients in the doxycycline group. Mayo 2004 stage III disease was present in 27 patients in the control group and 27 patients in the doxycycline group. The median cTnI was 0.10 (range, 0-1.92) μg/L, NT-proBNP 3647 (range, 271-20507) pg/mL, and dFLC 205.30 (50.28-791.90) mg/L, with no significant difference between either group. Organ involvement included the heart (100%), kidney (61.3%), liver (14.4%), peripheral nerves (10.8%) and gastrointestinal tract (5.4%). The percentage of hepatic involvement and 24-hour urine protein were higher in the doxycycline group. The median duration of doxycycline was 5.9 months. Only one patient discontinued doxycycline due to toxicity (Grade 2 rash). Till now, the median follow-up time was 6.1 months and no patients were lost to follow-up. Fourteen patients have completed 9 cycles of chemotherapy. In total, 22 patients died and disease progression occurred in 3 patients. Two patients discontinued treatment due to withdrawal of consent and one of them proceeded to autologous stem cell transplantation. Three patients discontinued study drug owing to unacceptable diarrhea and received second-line treatment based on ixazomib or melphalan afterwards. The grade 3/4 adverse effects were developed in 8 patients (1 infection, 1 mucositis and 6 diarrhea) in the control group and 6 patients (1 infection, 1 arrhythmia, 1 kidney dysfunction and 3 diarrhea) in the doxycycline group.
【Conclusions】Our data suggested that addition of doxycycline to standard bortezomib-based chemotherapy was an tolerable regimen for treating patients with AL amyloidosis. If this protocol could significantly improve survival and organ response needs to be confirmed with further follow-up.
No relevant conflicts of interest to declare.
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