Abstract
Background: Survival of patients with AL amyloidosis has improved over the last decade due to availability of novel agent based therapy. Bortezomib combination regimes, such as CyBorD, give unprecedented response rates in early stage disease but cannot overcome poor prognosis in patients with advanced AL amyloidosis (Venner et al and Palladini et al Leukemia 2014); which has remained poor and essentially unchanged over the last 25 years. Heart failure occurs in AL amyloidosis not only due to mechanical impairment of cardiac function from physical amyloid deposition but also due to direct cardiomyocyte light chain toxicity as shown in animal models by groups from Pavia and Boston. Doxycycline appeard to reduce light chains muscle toxicity in a C.Elegans model and hence may have a potential role to improve outcomes in cardiac AL.
Methods: We report here the outcomes of a cohort of patients with advanced cardiac amyloidosis treated with addition of doxycycline (as an off-label indication) to chemotherapy compared to matched group of similarly treated control patients without doxycycline, identified from the ALChemy study database of the UK National Amyloidosis centre. ALChemy is a prospective observational study of patients with AL amyloidosis undergoing treatment and has currently recruited just over 800 patients. All patients who received doxycycline with their front line chemotherapy regime were identified These patients were matched with controls based on updated Mayo disease stage, age, SBP >100 mm of Hg, dFLC and NT-proBNP levels. Since all but one patient in the doxycycline cohort received a velcade triplet regime, only patients treated with a velcade triplet regime were included in the matching cohort.
Patients and results: A total of 16 patients and 22 controls were identified. The median age was 60 yrs (range 40-81 yrs), all patients had cardiac involvement, 35 patients had Mayo stage 4 disease, 3 had Mayo stage 3 disease. The median NT-proBNP was 5621 pMol/L (range 1211-17365), high sensitivity troponin 0.1 mcg/L (range 0.022-0.58), eGFR 60 ml/min (range 15-100) and dFLC 490 mg/L (range 54-5825). Two patients from each group had NT-proBNP >8500 ng/L. There was no significant difference at baseline between the treated and control groups in terms of length of follow up, body mass index, supine systolic BP, LV wall thickness, ejection fraction, NT-proBNP, Hs-TNT, proteinuria or dFLC. 34 (89%) started with CyBorD, 1 each with Bor-MelDex, Vel-Rev-Dex and IV intermediate dose melphalan. 4 patient (3 in the doxycycline and one in the control group) switched due to lack of clonal response at cycle 2 or 3. 14 patients received doxycycline 100 mg daily and two patients received 200 mg daily. Three patients had to discontinue doxycycline early (2 months each) due to photosensitive rash in 2 and nausea in one patient. Overall 60% achieved a complete haematological response (CR), 8 % VGPR and 13% PR. In the doxycycline group 56% achieved a CR (89% CR+VGPR) compared to 63% CR (no VGPR's) in the control group. The median follow up of the whole cohort is 13 months and there were a total of 10 deaths – 9 deaths in the control group (median 3.5 months) and one in the doxycycline treated group (at 2.3 months). The 3, 6 and 12 month survival in the doxycycline treated group was 94% and in the control group was 86%, 68% and 55% respectively; median not reached in either group (log rank p =0.04; Figure 1). On an intent to treat basis, 57% of the doxycycline group and 36% of the control group achieved cardiac responses by NT-proBNP criteria.
Conclusions: Treatment with doxycycline in combination with a bortezomib triplet regime significantly reduces early mortality (with only one death in the doxycycline treated group over one year median follow up) in patients with advanced cardiac AL amyloidosis which translated into a higher CR/VGPR rate compared to controls and greater cardiac responses. This is one of the first interventions to have a significant impact on early mortality in AL. Larger studies are urgently needed to confirm the findings of this simple intervention to substantially improve outcomes in cardiac AL amyloidosis.
Off Label Use: Doxycycline for reducing early cardiac mortality.
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