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 li…
#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.
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.
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.
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
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.
Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;
Department of Molecular Medicine, University of Pavia, Pavia, Italy;
Amyloidosis Center, Division of Hematology, Oncology, and Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; and
Clinical Chemistry Laboratory, and 5Scientific Direction, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
link to article: http://jco.ascopubs.org/content/33/32/3741.full.pdf+htmlBackground:The role of autologous stem cell transplantation (ASCT) in AL amyloidosis is controversial. Single center studies have reported durable, high hematologic response…
[special thanks to Dr Waxman for his hard work preparing the original draft of this summary!]
“Therapeutic Clearance of Amyloid by Antibodies to SerumAmyloid P Component.” Richards et. al. NEJM,2015; 373(12):1106-14.
There were no changes in serial echocardiography and there were no significant changes in serum troponin T or NT-proBNP concentration.
· Infusion of anti-SAP antibody after CPHPC infusion was safe in patients with systemic amyloidosis with relatively low, transient, infusional side-effects
· Anti-SAP antibody cleared faster in patients with large hepatic amyloid loads, consistent with rapid binding to their target
· 6/8 patients receiving >200 mg of antibody showed evidence of reduced amyloid load on imaging, even in patients who presumably had continued production of amyloidogenic precursors Including some patients with active AL amyloidosis)
· Correlative studies of immune markers are consistent with a proposed mechanism of phagocytosis of C3-opsonized complexes by macrophage infiltration as seen in preclinical models
· Patients with clinically significant cardiac and renal involvement will be included in the next phase of the trial
· Larger confirmatory studies are necessary as is a longer period of follow up to see if decrease in amyloid load at 42 days is a clinically meaningful endpoint
The optimal dosing and timing of CPHPC and anti-SAP need to be further studied.
· Patients receiving lower doses of anti-SAP disproportionally had non-AL amyloidosis compared to patients receiving >200 mg and having improvement in amyloid load who mostly (7/9) had AL amyloidosis, which could confound results.
· Response assessments used non-standard modalities (anti-SAP scintigraphy, liver elastography, extracellular volume by MRI), all of which will need further validation.
· Delivery of this agent to patients with cardiac disease will need to be done carefully, as the impact of macrophage phagocytosis in the heart on cardiac function is not yet known.
|CLICK HERE FOR A LINK TO THE FULL TEXT OF THE ARTICLE|
- Cytogenetic aberrations are important independent prognostic factors in AL.
- Bortezomib is less beneficial to patients with t(11;14)
- Bortezomib overcomes the poor prognosis of patients with high-risk aberrations.
- Study was of small sample size and would need confirmation with other studies, prospectively and multi-center ideally
- A potential criticism is the validation using a CyBord-treated cohort rather than additional Vel/Dex-treated patients. CyBorD cohort followup duration is a lot shorter than the Vel/Dex cohort. Despite this, results seen in the CyBord patients seem consistent with those described for the Vel-Dex cohort
- Paper suggests that cytogenetics may have predictive as well as prognostic significance.
Special thanks to Sandy Wong (@SandyWong02111) from Tufts University for her efforts preparing this summary. Looking forward to co-moderating this journal club discussion with her.
The ArticleClick HERE for link to FULL TEXT of NEJM articleBackground on transthyretin amyloidosis The amyloidoses are a heterogeneous group of disorders characterized by the production of misfolded proteins. These proteins form …
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