Transcript from tonight's #amyloidosisJC (via Storify)

Here it is: 

https://storify.com/Amyloid_Planet/amyloidosisjc-vol-7-march-28th-2016#publicize 

A nice discussion about a very difficult topic. Grateful to have the lead author from the paper, Dr. Laura Dember from U Penn, join us! 

Paper and date for next installment will be announced soon! 

#amyloidosisJC 3/28/16 @ 9 pm EST: Eprodisate for the Treatment of Renal Disease in AA #amyloidosis

This installment of #amyloidosisJC examines the not-positive-enough results of a randomized trial comparing the effects of eprodisate to placebo in AA amyloidosis patients with amyloid-related renal disease. Click HERE for a link to the actual article. I'd like once again to thank Dr. Naresh Bumma (@NB191186) for his assistance preparing this post. 

Dember, Laura M., et al. "Eprodisate for thetreatment of renal disease in AA amyloidosis." New England Journal of Medicine 356.23 (2007): 2349-2360.  

Background: The amyloidoses are a group of diseases characterized by extracellular deposition of fibrils comprised of misfolded proteins and other molecules such as glycosaminoglycans and SAP. End organ damage may result from either the fibrillar deposits or toxic oligomers and/or protofilaments. AA amyloidosis is a rare entity, almost always seen in the setting of an underlying chronic inflammatory condition. The amyloid-forming protein is a proteolytic product of serum amyloid A protein (SAA), an acute phase reactant protein produced by the liver. The kidney is the most commonly affected organ, though the GI tract and other organs can also be involved.

AA Amyloidosis pathophysiology from T. Nakamura (click HERE for link to paper)

Eprodisate (Kiacta), a negatively charged molecule with structural similarities to heparin sulfate, inhibits fibrillogenesis (fibril formation) by interfering with the interaction between SAA and GAGs. The premise of this trial was that if Eprodisate could inhibit fibril formation, organ damage would be prevented. 

Trial Design: Multicenter, randomized, double-blind, placebo-controlled comparison of eprodisate to placebo (1:1 randomization)

13 countries, 27 centers, 261 patients screened and 183 enrolled (7/11/2001-2/14/2003)

Key Inclusion criteria : 

• Tissue diagnosed AA amyloidosis by histologic demonstration of Congo red staining and birefringence with the use of polarized microscopy and reactivity with anti-AA antibodies by IHC 
• Kidney involvement (24hr urine protein >1g x 2 OR CrCl <60ml/min x 2)

Key Exclusion criteria: 

• Kidney disease other than AA amyloidosis, 
• Severe renal disease: CrCl <20ml/min OR SCr >3, DM
• Abnormal liver function: LFTs or alk phos >5 xULN, t bili >1.5xULN
• Diabetes Mellitus

Stratification: 

• Nephrotic syndrome (Y/N)
• Treatment center

Patient Allocation: 

Treatment: 800-2400 mg (depending on renal function) eprodisate/placebo in two divided doses each day for 24 months. Alternating office visits and telephone follow-up calls every two months. 

Primary Endpoint: 

• Composite endpoint of worsening renal function (SCr >2x BL, CrCL <0.5 BL, or progression to dialysis-requiring ESRD) or death

Key Secondary Endpoints:

• Slope of decline in CrCl over time
• Change in proteinuria
• Change in amyloid quantitation in abdominal fat
• Resolution or development of chronic diarrhea

Noted Patient Characteristics: F>M, ~1/3 pts had "normal" SAA levels, eprodisate group had slightly better baseline SCr (1.1 vs 1.3) but no statistically significant difference in CrCl, ~40% had nephrotic syndrome. The chronic underlying inflammatory condition was usually RA in both groups, but the eprodisate grp had a higher incidence of chronic infection as an alternative condition. 

Results:

• Primary composite endpoint: 42% reduction in the risk of worsening renal function or death (HR 0.58 [95% CI 0.37 - 0.93; p=0.02]). Teasing this apart: renal function worsened in 27% of eprodisate-treated patients vs 40% placebo-treated pts (p=0.06). There was no difference in mortality (HR 0.95 [95% CI 0.27 - 3.29; p=0.94]).
• Secondary endpoints: Mean slope (+/- SE) of change in CrCl (in ml/min/1.73m2) was -10.9(+/-5.1) for the eprodisate grp versus -15.6(+/- 4.1) in the placebo grp (p=0.02), though no statistical difference in risk of progressing to ESRD (E: 7 pts, P: 13 pts, HR 0.54 ([95% CI 0.22 - 1.37; p=0.20]). Also, no difference in change in urine protein loss, change in abdominal fat amyloid content, or incidence of developing chronic diarrhea.
• Safety: Similar rates of AEs and SAEs between grps

Our Analysis: 

• "Sample size...substantial for the rare disease," but not large enough to be powered to assess differences in lower frequency events like progression to ESRD or death
• Finite versus indefinite therapy may have mattered
• PK analysis could have been informative, since more than half of eprodisate pts received modified doses of medication (authors posited that pts with less severe BL renal disease might have been more likely to benefit)
• Modest benefit may be in part due to mechanism of action: SAA oligomers and protofibril levels not reduced (predictably, since blocking SAA-GAG interaction should only affect mature AA fibril formation). Also, persisting albuminuria itself is nephrotoxic (as explained in an old post about kidney injury in AL amyloidosis) and therapy did not reduce proteinuria.

Have a great Easter (for those who celebrate) and hope a bunch of people can join us this coming Monday!

Leaping back into #amyloidosisJC on Monday 2/29/16 at 9 pm EST: ICD placement for cardiac #amyloidosis

#amyloidosisJC returns at 9 pm EST on Monday February 29th 2016 with a discussion focusing on the role of implanted cardiac defibrillators (ICDs) as a means of improving survival of patients with cardiac amyloidosis.  Thank you to Dr. Naresh Bumma (a Karmanos Cancer Institute hematology-oncology fellow, @NB191186 on Twitter) for his help preparing a summary of the following article from the Mayo Clinic:

Published in the Journal of Cardiovascular Electrophysiology, 2013: 24(7), 793-798.

Background:

Cardiac involvement with systemic amyloidosis by characterized by infiltration and/or deposition of amyloid chains in the myocardium leading to wall thickening and valvular damage.  The presence of cardiac involvement is usually associated with high mortality, in part due to a high risk of fatal arrhythmias. However, the benefit of implantable cardiac defibrillator (ICD) placement in this population remains controversial due to the lack of compelling evidence that it reduces mortality.

Methodology:

Retrospective chart review of all cardiac amyloidosis (CA) patients between 2000 and 2009 seen at a single institution (the Mayo Clinic). All cases of systemic amyloidosis were diagnosed by tissue biopsy and cardiac involvement was established by right ventricular biopsy or echocardiographic findings (left ventricular wall thickness >12 mm in the absence of other etiologies). Patients who underwent ICD implants were identified and characterized. Patients were staged according to the 2004 Mayo staging criteria using troponin T and NTproBNP measurements.

Results:

892 patients were found to have typical features of CA and out of these 53 underwent ICD placement. Of these 53 patients, 33 had AL, 10 had wild-type ATTR, 9 had familial and 1 had AA amyloidosis.
Forty-one patients (77%) underwent ICD placement for primary prevention (18 with unexplained syncope, 9 with left ventricular ejection fraction ≤ 35%, 6 with non-sustained VT, and 8 who were considered high risk for other reasons by their treating physican(s)).  Twelve patients (23%) underwent ICD placement for secondary prevention due to sustained ventricular arrhythmia or previous sudden cardiac arrest.

During follow-up (23.25 ± 21.45 months from ICD implantation), 15 patients received at least one appropriate ICD shock, with 12 out of 15 of these occurring in AL patients.

AL amyloidosis subgroup (n=33):

Twelve (36%) underwent successful autologous SCT (including one who underwent orthotopic heart transplantation prior to ASCT) and 21 (64%) were treated with nonmyeloablative chemotherapy.

Median surival was 7.5 months (similar to their historical cohort where median surivival was 10 months, p=0.31)

Familial, AA and wild-type ATTR amyloidosis:

Numbers were insufficient to draw any statistical comparisons

Conclusions:

Despite a high rate of appropriate ICD discharges, there has been no overall survival benefit seen in this cohort with ICD placement for CA compared to cotemporaneous patients without ICD placement.  Possible explanations for these findings are that cardiac deaths due to pump failure (rather than arrhythmias) may account for the observed poor survival in CA patients, or that patient selection for ICD placement needs refinement.