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.


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.

#amyloidosisJC 12/1/2015: A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis.

This is the 5th and final pre-symposium installment of #amyloidosisJC, with the following summary by travel grant awardee and article author Paolo Milani. Dr. Milani is from the esteemed Pavia Amyloidosis group, and is currently spending some time at Mayo Clinic. Needless to say, he’ll be bringing a high level of knowledge to this journal club. Starting in January, 2016, #amyloidosisJC will be a monthly online journal club activity.

The article:

Giovanni Palladini1, Ute Hegenbart3, Paolo Milani1, Christoph Kimmich3, Andrea Foli1, Anthony D. Ho3, Marta Vidus Rosini1, Riccardo Albertini2,3, Remigio Moratti5, Giampaolo Merlini1,2,3 and Stefan Schönland3

  1. Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;
  2. Department of Molecular Medicine, University of Pavia, Pavia, Italy;
  3. Amyloidosis Center, Division of Hematology, Oncology, and Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; and
  4. Clinical Chemistry Laboratory, and 5Scientific Direction, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy


Immunoglobulin light-chain (AL) amyloidosis is caused by a usually small plasma cell clone synthesizing light chains undergoing conformational changes that lead to their aggregation and deposition in tissues. The kidney is involved in 70% of patients, but little is known on progression or reversibility of renal involvement. Renal involvement results in significant morbidity, and renal failure limits the therapeutic options. Previously, criteria defining renal response and progression were based on the International Society of Amyloidosis (ISA) consensus criteria of 2005 but the clinical significance of each have never been validated. The goal of this study was to identify and validate criteria by assessing the risk of dialysis in 732 consecutive, previously untreated patients with AL amyloidosis with renal involvement evaluated at 2 European referral centers: the Pavia Amyloidosis Research and Treatment Centre and the Heidelberg Amyloidosis Centre.


The databases of the Pavia Amyloidosis Research and Treatment Centre and of the Heidelberg Amyloidosis Centre were systematically searched for subjects with renal involvement diagnosed between 2004 and 2012. Baseline evaluation at each center included a complete physical examination, assessment of amyloid organ involvement, echocardiography, cardiac biomarkers measurement of serum creatinine concentration and of 24-hour urinary protein excretion, serum and urine immunofixation electrophoresis, and quantitation of free light chain (FLC).

The study end point was renal survival, defined as the time from diagnosis to dialysis initiation. The authors assessed the impact of baseline variables and of their changes with therapy on renal survival . The Italian cohort was used as the testing population and the German series as the validating cohort.

Cox models were fitted to compute hazard ratios and 95% confidence intervals for progression to dialysis, identifying baseline variables predicting renal survival. Receiver operating characteristic (ROC) analyses based on progression to dialysis at 2 years identified the thresholds of baseline variables best predicting renal survival.


Patient Characteristics:

A total of 71 (15%) patients required dialysis in the Italian group and 84 (31%) in the German series.

Patients’ survival from dialysis initiation was not significantly different in the 2 cohorts [median survival was 39 months in the Pavia cohort and 24 months in the Heidelberg cohort (P=0.102)]. Hemodialysis was chosen in most cases, and only 11 patients underwent peritoneal dialysis (9% of the 155 subjects requiring dialysis), 8 in the Italian cohort and 3 in the German cohort.

Factors predicting renal survival:
Renal survival was influenced by proteinuria, eGFR, and, to a lesser extent, by serum albumin. The thresholds best discriminating patients who progressed were 5 g/24 h for urinary protein loss and 50 mL/min per 1.73 m2 for eGFR. Based on these cutoffs, it was possible to design a staging system sharply discriminating 3 groups with significantly different risk of progression to dialysis, with none (renal stage I), 1 (renal stage II), or both (renal stage III) risk factors, respectively (Figure 1A). These results were validated in the Heidelberg cohort (Figure 1B).

Criteria for renal resposne and progression:
For the identification of response and progression criteria, the authors performed a landmark analysis on 472 patients (64%), 301 in the Italian cohort and 171 in the German cohort, who were evaluated for response 6 months after treatment initiation. A ROC analysis based on progression to dialysis at 2 years from the landmark date performed in the testing cohort (Italian series) showed that changes in proteinuria, eGFR, and dFLC (difference between involved [amyloidogenic] and uninvolved free light chain) were able to discriminate subjects progressing to dialysis. The cutoff that identify renal response was a 30% decrease in proteinuria. A 25% decrease in eGFR identified a renal progression. Obtaining a very good partial response (dFLC <40 mg/L) or complete response (negative serum and urine immunofixation and normal FLC ratio) was able to improve renal outcome not only in renal stage II but also in renal stage III patients, indicating that successful treatment can improve renal outcome also in high-risk subjects.  

Finally, they tested the applicability of the novel renal response and progression criteria, related to renal survival, in patients who had response assessment data at an even earlier time point (3 months), 133 in the Italian cohort and 69 in the German cohort, in a 3-month landmark analysis. Given the relatively small number of cases, they performed this analysis in the overall study population of 202 evaluable patients. We found that the proposed response and progression criteria retained their prognostic significance.

Authors’ conclusions:

The progression of renal dysfunction is accurately predicted by baseline proteinuria and eGFR. These 2 variables identify low-risk patients who are unlikely to require dialysis and subjects who are at very high risk of renal failure. Secondly, early changes in eGFR and proteinuria should be used to assess treatment efficacy, in addition to the currently recognized hematologic and cardiac response criteria.

Our comments:

The renal staging system formulated by Palladini and colleagues significantly divided the population of patients with renal AL amayloidosis in low-, intermediate- and high-risk of progression to dialysis. This staging could be a useful tool for the routine patients’ management and could be added in the stratification of patients enrolled in clinical trials.
The identification and validation of renal response and progression criteria that can be assessed at 3 and 6 months is an other important implication of this work. However, it is important to note that the morbidity of renal involvement is not restricted to the minority of patients who develop end stage renal disease.

Finally, we think that it will be important to confirm these data in a prospective setting. Ongoing randomized trials would be the ideal setting.

#amyloidosisJC 11/11/15 @ 9 pm EST: targeting the amyloid fibril with anti-SAP therapy

The first two #amyloidosisJC chats were a huge success, and with this installment we hope to build on that. The second journal club, in particular, was fantastic. With Raymond Comenzo (Tufts), Vaishali Sanchorawala (Boston University), and Brendan Weiss & Adam Cohen (both from Penn) participating, it felt like we had the Eastern Conference All-Star team playing. Not to mention over a dozen other engaged participants. This week, with an extremely interesting article on anti-fibrillar therapy being discussed, maybe we can tempt the Western All-Stars into joining…? Mayo? MDACC? Stanford? I’ll pester them. Whoever suits up this week, I am certain Drs. Adam Waxman and Brendan Weiss (same Brendan Weiss) will co-moderate a thoughtful and educational discussion.

[special thanks to Dr Waxman for his hard work preparing the original draft of this summary!]

The Article: 

“Therapeutic Clearance of Amyloid by Antibodies to SerumAmyloid P Component.” Richards et. al. NEJM,2015; 373(12):1106-14.


The systemic amyloidoses are rare diseases characterized by protein misfolding, leading to insoluble amyloid fibril tissue deposition and consequent organ dysfunction. It is the organ deposition, particularly cardiac, that leads to morbidity and mortality. There are over 20 subtypes of systemic amyloidosis. Immunoglobulin light chain (AL) amyloidosis is the most common subtype and is characterized by clonal plasma cell or B-cell expansion and production of misfolded immunoglobulin light chains (LC) that form amyloid and also are directly toxic to organs. Commonly affected tissues and organs include the kidney, liver, heart, and spleen. Currently, the treatment of AL amyloidosis focuses primarily on prevention of light chain production through the use of anti-plasma cell therapy. In other systemic amyloidoses, there are no non-experimental methods to reduce the precursor protein that forms toxic amyloid fibrils. A fundamental problem in the management of the systemic amyloidoses is the development of a treatment to address amyloid that is already deposited in the tissues. A fibril constituent common to all subtypes of amyloidosis is serum amyloid P (SAP). This study explores an early but promising therapy that targets SAP with a monoclonal antibody to stimulate macrophage-mediated clearance of deposited amyloid, which has been previously shown to be effective in a murine model (Bodin, et al. Nature 2010).

The authors (Richards, et al.) performed a phase I clinical trial of a combination of a small molecule CPHPC ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid) that has been shown to deplete circulating SAP (serum amyloid P component) followed by administration of a humanized monoclonal anti-SAP antibody that has been shown in preclinical models to stimulate macrophage driven destruction of SAP-containing amyloid deposits. This study describes the first-in-human experience using these agents, including serial assessment of deposited amyloid load in tissues.


This is a prospective, single center (National Amyloidosis Center in the United Kingdom), open-label phase I dose escalation study of 16 patients. All patients had biopsy proven systemic amyloidosis; different types of amyloidosis were included. Patients with clinical evidence of cardiac involvement were excluded, as were potentially child bearing women.

CPHPC was administered for 3 days until SAP concentration decreased to below 2.0 mg/L. Patients then received escalating doses of anti-SAP antibody. The last 7 patients received a tailored dose based on the pretreatment SAP load as determined by SAP scintigraphy.

Changes in tissue amyloid content were assessed by whole-body I-SAP scintigraphy at baseline and 42 days post-treatment. Patients were also assessed for retention of tracer at 24 hours by CT. Equilibrium MRI of the heart, liver, and spleen as well as transient elastography (to measure liver stiffness) were performed on days 6, 14, 21, and 42). 42 days was chosen as this was the length of time for SAP to reach equilibrium between the plasma and amyloid components.


Patient characteristics and response data are shown in Table 1, below. Eight patients had AL amyloidosis, 4 had AFib amyloidosis, 2 had AA amyloidosis, and one had AApoA1. Four of the first 6 patients had small amounts of amyloid in the kidney and spleen. Patient 3 was removed from the study due to poor venous access. Patients 7 – 16 all had moderate to large amounts of amyloid deposition.

Adverse events were mild and included headache and nausea during infusion of CPHPC. Symptoms of transient warmth, flushing, headache, transient changes in heart rate, diarrhea, nausea, and abdominal discomfort during infusion of the anti-SAP antibody were reportedly mitigated with changes in infusion rate. 

There were no changes in serial echocardiography and there were no significant changes in serum troponin T or NT-proBNP concentration.

Rapid depletion of circulating SAP was achieved. Depletion was greater in patients with small or moderate load than in those with a high pre-treatment amyloid load. The half-life of the anti-SAP antibody was found to be around 16 hours in patients with small amyloid load and closer to 4 hours for patients with a large load, consistent with a rapid sequestration.

Correlative studies of immune markers showed that the 9 patients receiving >200 mg of antibody had a transient increase in IL-6, IL-8, CRP, and serum amyloid A protein. Patients receiving >1 mg/kg had a prolonged decrease in complement C3 levels for about a week.

Table 1:

Patient information (amyloid type and response to therapy)

Patients were assessed for amyloid elimination at 42 days after treatment. 6 of 8 patients with liver involvement receiving >200 mg of antibody had a significant decrease in liver stiffness. 5 of these same 8 patients had an overall improvement on their SAP scintigraphy corresponding to decreased amyloid load at 42 days. MRI showed normalization of extracellular volume in 3 patients. Figure 1 shows representative decrease in C3 level and changes in SAP-scintigraphy in patients 8 and 13.

Figure 1:

Response details for two patients 

Author’s Conclusions:

·       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

Our Comments:

·      This small, phase 1 study demonstrates first-in-human data showing a potential decrease in amyloid load among nine out of sixteen enrolled patients with minimal adverse events.

·      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.

#amyloidosisJC 11/4/15 @ 9 pm EST: examining the prognostic and predictive relevance of cytogenetics in AL amyloidosis



Light chain (AL) amyloidosis is a rare plasma cell dyscrasia which causes morbidity and mortality through deposition of toxic amyloid fibrils. Although the prognostic significance of specific cytogenetic aberrations in the plasma cell malignancy multiple myeloma is established, the relevance of cytogenetics in AL amyloidosis is still being defined. Several recent retrospective studies including this study by Bochtler et al., have attempted to characterize the significance of chromosome aberrations in AL amyloidosis. This paper seeks to establish translocation t(11;14), as a predictive marker of poor response to bortezomib. This is important because bortezomib-based regimens (such as Vel/Dex) are often used as front-line treatment for AL amyloidosis. In this disease where patients often have progressive multi-organ damage, selection of an efficacious regimen to rapidly establish disease control is crucial. This paper raises the question of whether cytogenetic studies could guide treatment of AL amyloidosis.

·      Retrospective, single-center study of 101 consecutive transplant ineligible AL amyloidosis patients who received Vel/Dex as first-line therapy. These patients had high-risk clinical features such as severe cardiac or kidney involvement. Patients with concurrent stage II/III MM or IgM paraprotein were excluded.

·      Outcomes assessed included hematologic response after 3 cycles (by consensus criteria for PR, VGPR), hemEFS (hematologic relapse, hematologic progression, start of a second-line therapy, death) and OS. Early deaths counted as remission failures on intent-to-treat basis.

·       High-risk aberrations were defined as t(4;14), t(14;16) and deletion 17p13.

·      After backward variable selection, validation and calibration of the final multivariable model was done using a CyBorD-treated cohort (32 patients).


Patient Characteristics 

Most patients in Vel/Dex and CyBorD cohorts had cardiac involvement (91% vs 88%) and around half had renal involvement in both cohorts


·      Median hemEFS 4.7 mo with median F/U of 24.0 months and hematologic events in 84/101 patients. The t(11;14)-positive group had inferior hemEFS (median hemEFS 3.4 monthsvs 8.8 months in t(11;14)-negative group; p=.002). Median hemEFS in high-risk group was 10.3 monthsvs 3.9 months in patients without high-risk aberrations (P=.15).

Overall Survival (OS)

·      Median OS was 15.7 mo with median F/U time of 24.1 months and 53 observed deaths. t(11;14) predicted for shorter OS with median OS 8.7 monthsvs 40.7 months in t(11;14)-negative group (P=.05). High risk aberrations conferred favorable prognosis (median OS = NR for high-risk v 10.6 months for absence of high-risk aberrations; P=.04).

Remission Rates

·      95/101 (94%) pt had initial dFLC >50mg/L and thus evaluable for ≥VGPR

·      30 (32%) achieved ≥VGPR after 3 cycles, 24 (25%) attained PR and 21 (22%) did not achieve remission, 20 (21%) had early death before remission assessment. ≥VGPR rates worse in t(11;14)-positive patients compared with t(11;14)-negativepatients [14/61 (23%) versus 16/34 (47%) patients, P=.02].  High-risk aberrations had favorable remission rates compared to those without [8/12 (67%) versus 21/80 (26%), P=.008]

Multivariable testing in Vel/Dex Cohort with Clinical and Cytogenetic Factors

·      By Cox regression, t(11;14) and dFLC were the only two statistically significant prognostic markers for both OS and hemEFS. NT-pro-BNP reached statistical signification for OS. Thus t(11;14) is an independent negative risk factor in the Vel/Dex treated cohort. 

    A final model developed: hemEFS, t(11;14), sex, dFLC, NT-proBNP and dose reduction. For OS, t(11;14), dFLC and NT-proBNP. For outcome remission ≥VGPR, t(11;14) and age.

External validation using CyBorD cohort

·      ≥VGPR rate after 3 cycles, 24% (4/17) in t(11;14)-positive compared with 80% (8/10) int(11;14)-negative patients. Median hemEFS 5.7 months in all 32 patients, 4.0 months in t(11;14)-positiveand NRint(11;14)-negative patients (P=.01). Median OS for both groups NR. Median F/U was 7.5 months. Calibration analysis of final models performed which showed that all trained predictors had a trend for better prediction of the outcome in the CyBorD validation cohort.
Authors’ Conclusions

  • 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.

Our Comments

  • 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. 

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