#amyloidosisjc 12-1-19: MRD and AL #amyloidosis

Here is a synopsis of the article we will be discussing in the December 1st, 2019 session of #amyloidosisJC, an online journal club focusing on all things amyloidosis.  The synopsis was prepared by two recipients of the Don Brockman ASH 2019 Trainee Travel Grants supported by the Amyloidosis Foundation, Dr Suresh Balasubramanian (@malignantheme, Karmanos Cancer Institute) and Dr Holly Lee (@holly_dldumls, University of Calgary), with the help of Dr Naresh Bumma (@NB191186, Ohio State University), the faculty co-moderator for the session. 


In this round of #AmyloidosisJC, we will be discussing a clinical paper that discusses the role of minimal (measurable) residual disease (MRD) in the management of AL amyloidosis.

In this retrospective observation study, the authors presented updated results with extended follow up of the AL amyloidosis patients who underwent end of treatment (EOT) MRD assessment by multiparametric flow cytometry (MFC)  described in a previous publication in 2017.

Study objective: 

To establish whether clearance of clonal plasma cells at EOT using sensitive and uniform MFC is associated with improved OS

Patient population: 

Of the original 173 patients with newly diagnosed AL amyloidosis patients (from their 2017 study), 82 patients who had MRD testing at EOT using sensitive and uniform MFC
 were included in this follow up publication.

84% of the patients underwent autologous stem cell transplant as first line therapy (relevance: consider inherent selection bias to include primarily transplant eligible patients who are generally fit and do not have extensive baseline organ involvement


For MFC testing, reported sensitivity was 1×10-4 to 2×10-5, depending on the number of analyzed events, phenotype and DNA index

A total of 500,000 live cellular events were set as a target per exam (median gated events achieved 489,922, 25–75% IQR 469,765–493,662)


MRD and hematologic response: 29% (24) had negative MRD, and 71% (58) had positive MRD at EOT. 19.5% (16) had CR, 46.3% (38) had VGPR, and 28 (34.1%) had less than VGPR

Patient outcomes (median 4.6 year follow up)

Among VGPR patients, MRD- was associated with improved PFS compared to patients with MRD+ (3-year PFS 88% vs. 46%, p=0.003), particularly among patients who achieved a complete response (3-year PFS 100% vs. 33%, p=0.001). In contrast, this difference in PFS advantage in VGPR/MRD- compared to those who achieved VGPR/MRD+ did not reach statistical significance (p=0.14)

OS difference was not seen between MRD- and MRD+ groups (3-year OS 96% vs. 84%, p=0.17)

MRD- compared with MRD+ among deep responders was associated with lower level of involved light chain (involved free light chain, median 1.1 vs. 1.7mg/dL; p=0.02) and higher frequency of renal response (100% vs. 68%; p=0.005)
. When assessing independent organ function, this difference was not evident in cardiac response


  • Conclusion 1. Despite the retrospective nature of this study with the inherent selection bias to include primarily transplant eligible patients, this work aims at offering novel, robust surrogate endpoint for the design of clinical trials, as well as for optimizing individual patients’ treatment
  • Conclusion 2. There may be value in bone marrow biopsy/aspirate at end of therapy in AL amyloidosis patients who achieve VGPR/CR. Presence of MRD is associated with reduced PFS in this group of patients.
  • Conclusion 3. The sensitivity of the current standard assay for serum free light chain detection does not discern between MRD positive vs negative among VGPR/CR patients.
  • Conclusion 4. This study is notable for presenting one of the largest patient cohorts for end of treatment MRD assessment and applying uniform flow cytometric techniques.


MRD assessment in AL amyloidosis is not yet standardized. Of interest, a study using next generation flow for MRD assessment found that 5 out of 12 MRD positive cases had very low residual tumor burden (<3×10-5), which would have not been detected with lower sensitivity assays (Kastritis et al. 2018). This paper assessed 20 AL patients with hemCR. 8 out of 20 patients were MRD(-).   2 out of 8 patients who had ASCT as primary therapy achieved MRD(-) status, versus 6/12 (50%) patients who did not have ASCT as primary therapy (p = 0.264). In two cases aberrant cells were detected at levels between 10−5 and 10−6  Their reported median sensitivity level of next gen flow was 2.3 x 10−6 (range: 2 × 10−6–3.1 × 10-6)

This is not surprising, as in the myeloma literature, 25% of MRD neg cases by conventional MFC were found to be MRD positive by next gen flow (Flores-Monteroet al. 2017)

We do not have studies that inform us how best to manage/ monitor patients deep hematological response based on their MRD status

  • How does MRD status guide frequency of follow up of patients after therapy?
  • If a patient initially achieves MRD neg CR but then progresses to MRD positive CR on repeat follow up, does this indicate progression/ requirement for treatment?
  • What is the role of transplant in achieving MRD negative status? The impact of daratumumab in achieving MRD negative status? As per our discussion from last week, looking forward to upcoming ISA abstract from @vsanchorawala regarding role of transplant in this topic!
  • Does time to MRD achievement matter and if so, what is the optimal time to assess MRD in AL amyloidosis? Interesting report by Muchtar et al. 2019 in Leukemiajournal, looked at not only the depth of response (in this case nadir iFLC <2mg/dL) but also the impact of time to nadir iFLC on patient outcomes. Patients whose nadir iFLC occurred after 12 months from EOT had significantly longer PFS and OS compared to patients who reached nadir before 12 months. This raises the question as to whether there a role for MRD assessment not only at EOT but also further out from EOT.

Obviously, there are many questions related to the utility and usage of MRD testing in AL amyloidosis – looking forward to the journal club where we can explore this further! -J.Zonder,MD

UPDATE 12/1/19 @ 10:19 pm: link to transcript of tonight’s twitter discussion CLICK HERE

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#amyloidosisJC 6/19/19: light chain stabilization and AL #amyloidosis

In this round of #AmyloidosisJC, we will be discussing a basic science paper that describes small molecules that stabilize light chain proteins in vitro. The following summary was written by Gareth Morgan (@wittyremarkhere), the first author. He will lead the discussion for this session of #amyloidosisJC.

Here is a link to the original paper: 
This work was carried out at Scripps Research by the group of Dr. Jeff Kelly. 

Dr. Kelly’s group invented tafamidis, a molecule that stabilizes transthyretin that was recently FDA approved (link: https://www.pfizer.com/news/press-release/press-release-detail/u_s_fda_approves_vyndaqel_and_vyndamax_for_use_in_patients_with_transthyretin_amyloid_cardiomyopathy_a_rare_and_fatal_disease) for treatment of ATTR amyloidosis. 

Amyloidosis is caused by aggregation of normally-soluble proteins. In inherited diseases such as familial ATTR amyloidosis, aggregation is linked to destabilization of the precursor protein by mutation. In AL amyloidosis this connection is less well understood, because each patient has a unique amyloid-forming antibody light chain, secreted by monoclonal plasma cells. However, several lines of evidence show that unstable light chains are associated with amyloidosis:

Since stabilization of precursor proteins has been shown to have clinical benefit for ATTR patients, the authors looked for stabilizers of light chains.

Key points from the paper:

1. The authors developed a method to measure light chain stability by high throughput screening. This was important because light chains do not have any known natural ligands that could be modified to make a drug. Instead, screening a large number of molecules was required.

2. From a starting set of 650,000 molecules, 16 molecules in four chemical classes could stabilize light chains when tested in several assays.

3. The paper focuses on one compound, which is a commercially available dye called “coumarin 1”. This molecule becomes fluorescent when it binds to light chains, which makes it useful as a tool for other experiments.

4. The crystal structure of coumarin 1 bound to light chains shows that the small molecule binds between the two variable domains in the dimer, at an interface that is made up of highly conserved residues (Figure D in the image seen at this link: F3.large.jpg). This site is likely to be present in most patient’s involved light chains. However, the molecules do not bind to the normal antibody heavy chain:light chain dimer interface.

5. The authors intend to develop molecules that bind more tightly and more specifically to light chains. These molecules could become drug candidates.

Clinical points for discussion:
1. These molecules are not drugs. There is a lot of work to be done before they can be tested in patients.

2. Stabilization may be most effective in when combined with anti plasma-cell therapies. One potentially promising use would be in maintenance for patients who have a hematological response to therapy but are at risk of relapse. Another would be for patients who are too sick to tolerate cytotoxic drugs.

3. Doxycycline, which has shown some efficacy for AL in Phase 2 trials, does not stabilize light chains in this assay – whatever it’s doing is probably different. https://www.ncbi.nlm.nih.gov/pubmed/28338670
4. Tafamidis is beneficial in ATTR patients. Would a light chain stabilizer have similar properties? We don’t know what the consequences of stabilizing light chains in patients will be. Many individuals with other plasma cell dycrasias (e.g., MGUS, smoldering myeloma, multiple myeloma) tolerate elevated levels of a monoclonal light chain without direct organ damage. However, light chains are cleared by the kidneys and several renal syndromes other than amyloidosis are associated with light chains. Altering light chain metabolism may cause problems in the kidney or elsewhere.

5. if stabilizers alter light chain clearance, they may interfere with free light chain measurements, currently considered key in the management and monitoring of AL amyloidosis.

6. It may be possible to measure the inherent stability of light chains in blood, thereby potentially identifying patients who might benefit from light chains  stabilization by small molecules.
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#AmyloidosisJC 5/8/19: ASCT in AL patients with impaired renal function

In this installment of #amyloidosisJC we will be discussing outcomes of Autologous Stem Cell Transplant (ASCT) in AL amyloidosis patients who have impaired renal function, written by Dr. M. Hasib Sadiqi and colleagues at the Mayo Clinic’s Amyloidosis Program. 

Here is a link to the article: https://www.nature.com/articles/s41409-019-0524-2
For those of you who either do not have access to the full article or didn’t have time to read it (or couldn’t make the live journal club discussion taking place at 9 pm EST on 5/8/19), here is a synopsis of the paper, including key findings:

  • This is a retrospective review of all patients with AL amyloidosis transplanted at Mayo between May 1999 and September 2017. Of 696 pts, 41 were excluded for various reasons (including ALREADY BEING ON DIALYSIS AT TIME OF ASCT IN 29 PATIENTS).  The remaining 655 pts were divided into “Normal Renal Function” (NRF; eGFR >45 mL/min; n=568) and “Impaired Renal Function” (IRF; eGFR <45 mL/min; n=87)
  • Since this wasn’t a randomized prospective study, the groups were predictably not balanced for all clinical characteristics. The NRF grp was less likely to have gotten pre-ASCT chemotherapy (41% vs 53%) and more likely to have been treated with a full dose of melphalan as ASCT conditioning (79% vs 29%). Also, the IRF grp had higher cardiac biomarkers (though no statistical difference in Mayo Cardiac Stage distribution) and more patients with advanced Amyloid Renal Stage (0% renal stage 1, compared with 63% in the NRF grp).  Cardiac and Renal staging have both been covered in previous #amyloidosisJC sessions.
  • 100-day mortality was greater in the IRF grp (14% vs 5%). Risk of progression to ESRD and hemodialysis was also higher in the IRF grp (16% vs 6%). These differences did not have to do with differences in control of the underlying amyloidosis, as the hematologic response rates (88-89%) and complete hematologic response (CR) rates (42-44%) were essentially identical in each grp, though NRF pts who got less than 200 mg/m2 of melphalan had lower CR rates than other patient subsets. There was a higher rate of hospitalizations, a longer duration of hospitalizations, and a higher incidence of culture-confirmed episodes of bacteremia in the IRF group, though causes of death within the first 100 days post-ASCT were not elaborated upon in the article. 
  • Median Overall Survival (140 mos) and Progression Free Survival (49 mos) were not statistically different between the NRF and IRF gaps. 
  • The authors provided a thoughtful discussion regarding the limitations and quirks of the trial. 
    • The period over which patients were treated was long, and eligibility criteria for ASCT evolved over that time. A disproportionate number of pts in the IRF grp were treated in the earlier part of the analyzed period. 
    • It was difficult to determine whether any of the differences in survival were due to an imbalance of cardiac involvement, because cardiac markers (used to assign Cardiac Stage) are affected by renal clearance
    • The definition of “NRF” was not really “N” (that is, a significant number of patients had an eGFR of less than 60 mL/min, though it is not clear exactly how many. The definition of “Renal Stage I” assures us that at least 63% of the NRF pts had an eGFR of at least 50 mL/min). 
Looking forward to a lively discussion at #amyloidosisJC! 
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#amyloidosisJC 3/27/19: BU Cardiac Staging System for AL Using BNP

This week we will be discussing cardiac staging of AL (light chain) amyloidosis. As mentioned in this post from February 4th, 2018, we are used to the idea of staging AL amyloidosis on the basis of baseline cardiac biomarker measurements. The most widely used system is the European modification of the original 3-stage Mayo 2004 system which uses Troponin T or I and NT-pro-BNP to divide patients into Stages 1, 2, 3a and 3b. The Mayo 2012 system, which incorporates serum free light chain levels, is another 4-stage variation on this theme. Finally, there is a British cardiac staging system for transthyretin (ATTR) amyloidosis which was the subject of a prior #amyloidosisJC discussion. What all of these publications have in common is the use of NT-pro-BNP as a key cardiac biomarker. What all medical centers don’t have in common is the ability to order this test without having to send out a blood sample. Many centers use BNP as an alternative. In this installment of #amyloidosisJC, we examine a new 4-stage cardiac staging system for AL amyloidosis devised by researchers at Boston University which incorporates BNP rather than NT-pro-BNP (and we will be lucky enough to have them lead the Twitter discussion!)

Here is a Visual Abstract from the journal Blood summarizing the article:

Visual Abstract for Lilleness B, et al

Key Details of the article we will be reviewing: 
  • A 250-patient derivation cohort from 2016 was used to establish an optimal BNP cut-off to identify cardiac involvement by amyloidosis and also to establish the optimal BNP value to incorporate into a prognostic staging system that corresponded well with the Mayo 2004 system. All the patients in this cohort (except 1) had both BNP and NT-pro-BNP measured. The authors then validated the new staging system with a 1073-patient validation cohort (patients seen between 2004 and 2014, of whom 592 had both BNP and TnI measured at baseline). A Receiver Operating Characteristic (ROC) analysis of 1-yr survival was done to establish a BNP cut-off for BU Cardiac Stage 3b (corresponding to European Cardiac Stage 3b).
  • The presence of cardiac involvement was determined by the following criteria, in order of preference: endomyocardial biopsy or cardiac MRI consistent with cardiac amyloidosis, intraventricular septal end-diastole (IVSd) thickness of at least 12 mm obtained on transthoracic echocardiography without other cause of wall thickening (consistent with established consensus criteria), and IVSd at least 11 mm in men or at least 10 mm in women with no history of hypertension or valvular disease (consistent with current reference ranges, as established by the American Society of Echocardiography).
  • Based on the ECHO/MRI criteria outlined above, 47% of pts in the derivation cohort had cardiac involvement. Only 22 out of the 116 pts identified as having cardiac involvement (19%) had an endomyocardial biopsy confirming cardiac amyloidosis. 
  • In deriving the new cardiac staging system, the authors elected to use the same Troponin I (TnI) cut-off of 0.1 ng/mL used in the Mayo 2004 system, and then determine the best BNP cut-off to use with that. The value they found was 81 pg/mL (𝛋 = 0.854 with Mayo 2004 system). 81 pg/mL also turned out to be an optimal value for predicting the presence of cardiac amyloidosis (except for pts with advanced Chronic Kidney Disease, defined as eGFR <30, in whom the BNP and NT-pro-BNP cut-offs were higher). 
Concordance between he BU and Mayo AL cardiac staging systems
  • Of 592 patients with both BNP and TnI levels measured in the validation cohort, 151 patients (25.5%) were assigned to stage I, 259 patients (43.6%) were assigned to stage II, and 182 patients (30.7%) were assigned to stage III. To create a stage IIIb, a BNP threshold of 700 pg/mL was derived by ROC analysis for survival at 1 yr among the 182 pts with stage III disease (AUC, 0.73; 95% CI, 0.66-0.81). 
  • The median OS from the time of diagnosis was 1.0 year for stage IIIb, 4.3 years for stage III, 9.4 years for stage II, and not reached for stage I patients (Figure 3; HR, 2.6; 95% CI, 1.7-3.9; P , .001). 43.6% of patients with stage IIIb disease died within 6 months.

  • The authors comment on the fact that about half of cardiac stage 3 patients die within the first year, after which time the survival curve for this group flattens out. This is similar to what has been noted previously by the Mayo investigators, and it remains a major challenge in the management of AL amyloidosis. 
  • A BNP-based staging system was hypothesized to be superior to the NT-pro-BNP-based one (since NT-pro-BNP is affected by renal clearance) but this was not confirmed in this work.
Please join us at 9 pm on Wednesday, March 27th, 2019 on Twitter (find us at #amyloidosisJC) for a full and spirited discussion of this article, as well as the other AL cardiac staging papers cited above! 
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#amyloidosisJC 1/23/19: LECT2 Amyloidosis

#amyloidosisJC resumes this week on a new night: Wednesday night (Jan 23, 2019 at 8 pm EST). 

Short notice and a short but important article describing a series of patients with a relatively recently recognized subtype of amyloidosis: ALect2. 

Here is a link to the full text of the article: 


For anyone unable to access the article via that link, email me at zonderj@gmail.com and I can send you the pdf. 

The article we are reviewing this week discusses a series of 130 patients with hepatic #amyloidosis analyzed with tandem mass spectrometry at the Mayo Clinic. 

Key Points:

  • The most common form of hepatic amyloidosis was AL (light chain) subtype. Alect2 also commonly affects the kidneys. 
  • Leukocyte cell-derived chemotaxin 2 associated amyloidosis (ALect2) was next most common (25% of analyzed cases).
  • No definite amyloid-associated LECT2 gene mutation has been identified, but 10 of 10 sequenced patients in another report were homozygous for the G nucleotide in a non-synonymous SNP amongst people of Mexican heritage. 

We’ll talk about Alect2 and other forms of hepatic and renal amyloidosis this Wednesday – join us! 

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#amyloidosisJC 11/18/18: Tafamidis for ATTR amyloidosis!

The following is a GUEST-POST composed by Dr. Sascha Tuchman, a friend and colleague from the University of North Carolina in Chapel Hill, NC. Dr Tuchman will be co-moderating the final pre-ASH 2018 #amyloidosis journal club (#amyloidosisJC) with Untangling Amyloidosis 208 Trainee Travel Grant Awardee Dr. Sam Rubinstein
Dr Tuchman


Dr Rubinstein


For basic information on transthyretin (TTR) and how it forms amyloidosis, please refer to the background information in recent blog post dated 10/28/18, which summarized the APOLLO study of patisiranin hereditary transthyretin polyneuropathy.  Drugs like patisian work to suppress TTR synthesis by the liver (“A” in the below diagram). Another area of research interest has been in TTR stabilizers. If we refer to the image below, we see that TTR circulates in blood as a tetramer, meaning a single molecule made up of four pieces of TTR joined together. The TTR tetramer dissociates, resulting in single TTR pieces (monomers).  Those monomers can deposit in organs and form amyloid.  The theory behind TTR stabilizers is that making it harder for the tetramers to dissociate means there are fewer TTR monomers available to form amyloidosis (“B” in the below diagram). The “B” approach was first successfully tested using the drug diflunisal in patients with TTR neuropathy (Berk J et al., JAMA 2013).  The current “ATTR-ACT” study examined the oral TTR stabilizer tafamidis in patients with TTR amyloid cardiomyopathy.


Phase 3, international study of 441 patients with biopsy-proven TTR cardiac amyloidosis. Placebo-controlled and double-blinded.  Patients had to have clinical evidence of active heart failure, but less severe than symptomatic at rest (NYHA class <4).  Severe impairment of liver/kidney function or nutritional status precluded participation.  Patients were prohibited from receiving other TTR-directed agents such as diflunisal or doxycycline during study participation. 

Patients received either 80 or 20 mg of tafamidis daily orally or placebo (randomized in a 2:1:2 ratio). Stratified by TTR mutational status (wild-type vs mutated) and baseline NYHA class. Treatment was for 30 months and on completion, patients could opt to continue on to an extension study including open label tafamidis.

The primary endpoint was all-cause mortality followed by cardiovascular-related hospitalizations.  The planned sample size of 400 patients was 90% powered to detect a 30% reduction in mortality and in cardiovascular-related hospitalizations from 2.5 to 1.5 over the 30 months on study.


548 patients screened and 441 randomized. 264 patients received tafamidis and 177 placebo. ~24% in both groups had mutated TTR, with a similar frequency of specific TTR mutations in each group. Other baseline factors were similar, including NYHA class, NT-proBNP, and body mass index (BMI).

Both mortality and frequency of cardiovascular-related hospitalizations were improved with tafamidis. Specifically the hazard ratio for all-cause mortality was 0.7 (95% CI 0.51-0.96) and the relative risk for hospitalizations was 0.68 (0.56-0.81).  The mortality benefit appeared after approximately 18 months on study. Benefits were consistent across all subgroups except NYHA class 3 CHF, in which mortality was the same but rate of hospitalizations was higher for tafamidis.
Functional measures of the heart also showed a slower decline with tafamidis than placebo, such as distance walked in 6 minute walk test and patient-reported symptoms.

There were no significant adverse events for tafamidis, and discontinuation from study as a result of adverse events was more common for placebo-treated than tafalidis-treated patients.


Tafamidis reduced mortality and cardiovascular-related hospitalization in patients with cardiomyopathy resulting from either wild-type or mutated TTR.  Markers of heart function such as 6 minute walk test and NT-proBNP suggest that tafamidis doesn’t stop the disease, rather it slows its progression.


Tafamidis is clearly a game-changer in the sense that it’s the first medication that will likely be FDA-approved for TTR cardiomyopathy. However, the fact that the disease still progresses indicates that more needs to be done. In particular, combining tafamidis with drugs that perturb other aspects of TTR formation could be promising. (Recall in the diagram above that tafamidis is a “B” drug.  Other drugs such as patisiran and inotersen are “A” drugs.  Combining a B drug with an A drug and/or a C drug may improve the benefit overall to patients with these diseases by further slowing or even reversing damage caused to the heart by TTR.)

EDITOR’S ADDENDUM: looking forward to this week’s installment of #amyloidosisJC, at 8 pm EST on Sunday November 18, 2018. Remember to use the #amyloidosisJC hashtag when you log on! Also, hoping to see you in San Diego for the Untangling Amyloidosis 2018 Friday Satellite Symposium. Turns out Dr Tuchman is joining the faculty speaker roster! 
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#amyloidosisJC 11/4/18: Daratumumab as therapy for AL amyloidosis

We will be discussing this short, sweet, yet practice-changing article demonstrating the significant therapeutic efficacy of daratumumab in a series of patients with AL amyloidosis. Since this publication, there have been numerous other abstracts and a few publications expanding on these findings. We’ll discuss them all on Sunday night, 11/4/18, at 8 pm EST.

click HERE for a link to a similar series we just published with colleagues at the Cleveland Clinic, and HERE for an article by Dr Vaishali Sanchorawala (@vsanchorawala) summarizing other data on this topic presented last year at #ASH17
Tweet ya Sunday. I’ll be logging in from ALBANIA. Pix of Tirana and from the 13th Congress of the Albanian Association of Hematology to follow. 
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#amyloidosisJC 10/28/18: Patisiran vs Placebo for hATTR familial polyneuropathy

This installment of #amyloidosisJC focuses on the positive results of a randomized trial comparing the effects of Patisiran to placebo in ATTR amyloidosis patients with primarily amyloid-related neurological disease. Click HERE for a link to the actual article. 

The following is a nice summary of the article written by tonight’s co-moderator, Suresh Balasubramanian, @malignantheme, a hematology/oncology fellow at the Karmanos Cancer Institute
Background: Amyloidosis is a group of diseases characterized by extracellular deposition of fibrils comprised of misfolded proteins and other molecules such as glycosaminoglycans and SAP, resulting in end organ damage. Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominant, multi systemic, progressive, life-threatening disease caused by mutations in the gene encoding transthyretin (TTR). The liver is the primary source of circulating tetrameric transthyretin protein. In hATTR, fibrils containing both mutant and wild-type transthyretin deposit as amyloid in peripheral nerves and the heart, kidney, and gastrointestinal tract resulting in polyneuropathy and cardiomyopathy. If left untreated, death typically ensues within 10 years after the onset of symptoms. Historically, management was largely supportive, with the disease-modifying option of liver transplantation available to a select subset of patients.
Patisiran, a hepatically directed investigational RNAi therapeutic agent harnesses the endogenous mechanism that controls the expression of a specific gene, thereby reducing the production of mutant and wild-type transthyretin.
Phase 1 and 2 studies already showed sustained dose related reduction of wild type and mutant transthyretin levels. click HERE for a link to a previous #amyloidosisJC where we discussed this work.

This phase 3 study was designed to compare against the placebo exploring the benefits of lowering transthyretin levels in reducing the rate of progression of neuropathy including other secondary end points related to improvement in quality of life.
Trial Design: Multicenter, randomized, double-blinded, placebo-controlled comparison of patisiran to placebo (2:1 randomization)
19 countries, 44 sites, 225 patients were randomized in 2:1 ratio to receive patisiran (148) vs. placebo (77)  (12/1/2013-1/30/2016)
Key Inclusion criteria:
Male or female of 18 to 80 years of age with a diagnosis of FAP with documented TTR mutation
Have a NIS of 10 to 100
Key Exclusion criteria:
Patients with previous liver transplantation or who were planning to undergo liver transplantation during the trial period
NYHA class of III or IV
Have a serum creatinine >1.5 × ULN
Known primary (immunoglobulin) amyloidosis or leptomeningeal amyloidosis
Anticipated survival is less than 2 years, in the opinion of the Investigator

NIS 5 to 40 vs. 50 to 130
V30M vs. other pathogenic variants
Previous transthyretin stabilizer yes vs. no
Efficacy assessment:
Primary end point:
Change from baseline to 18 months in the modified Neuropathy Impairment Score+7 (mNIS+7)
The mNIS+7 includes the modified NIS (weakness and reflexes), NCS Σ5, QST, as well as autonomic assessment through postural blood pressure
Secondary end point:
Patient-reported QOL will be evaluated using the Norfolk QOL-DN and the EQ-5D.
Disability will be reported by patients using the R-ODS.
Gait speed (10-m walk test, with speed measured in meters per second)
Nutritional status (modified body mass index [BMI]
Patient-reported autonomic symptoms (Composite Autonomic Symptom Score 31; range, 0 to 100, with higher scores indicating more autonomic symptoms).
All efficacy end points were assessed at baseline and at 9 and 18 months, except modified BMI (at baseline and at weeks 12, 27, 51, 66, and 78).
Patient Allocation:

Treatment: Patisiran (0.3 mg per kilogram of body weight) or placebo intravenously over a period of approximately 80 minutes, once every 3 weeks for 18 months.
Notable Patient Characteristics:
Median age in both the groups is 62 yo. 75% in both groups were males. 72% of study populations were whites and only 2% were blacks. 38% of patisiran group and 52% of placebo group patients had V30M mutation. Previous use of tetramer stabilizer, FAP stage, polyneuropathy score and NYHA class were equally balanced between both the groups.
Primary composite endpoint:
The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group. At 18 months, the least squares mean (±SE) change in mNIS+7 from baseline was −6.0±1.7 with patisiran, as compared with 28.0±2.6 with placebo (least-squares mean difference, −34.0 points; 95% confidence interval [CI], −39.9 to −28.1; P<0.001)
74% in patisiran group vs. 14% in placebo group showed less than 10-point increase from baseline in the mNIS+7 at 18 months

Secondary end points: 
At 18 months, 51% of patisiran group vs. 10% of placebo group had an improvement (decrease from baseline at 18 months) in the Norfolk QOL-DN score.
Improvement relative to baseline was also seen in gait speed in the 10-m walk test (53% of the patisiran group patients vs. 13% placebo group) and motor strength (40% vs. 1%), as determined by the NIS-weakness test at 18 months.
Select Exploratory End Points:
Measures of neuropathy stage also favored patisiran, compared to placebo group.
In the cardiac subpopulation, the geometric mean baseline level of NT-proBNP in patisiran group was 726.9 pg per milliliter (coefficient of variation, 220.3) compared to 711.1 pg per milliliter (coefficient of variation, 190.8%) in the placebo group. At 18 months, the adjusted geometric mean ratio to baseline was 0.89 with patisiran and 1.97 with placebo (ratio, 0.45; P<0.001), representing a 55% difference in favor of patisiran.
Patisiran treatment was also associated with better cardiac structure and function than placebo, including significant differences in mean left ventricular wall thickness (P = 0.02) and longitudinal strain (P = 0.02) at 18 months.
Safety: Similar rates of AEs and SAEs between grps. No thrombocytopenia or renal failure as reported in the other RNAi therapy trial.
Our Analysis:
Sample size definitely substantial for the rare disease.
Response seems to be really promising. However, most endpoints in trial not used in routine clinical practice. So assessing individual patient response will be a challenge.

Relationship between the mNIS+7 response was analyzed with respect to relative serum transthyretin supression: clear correlation with patisiran. But association too loose to be clinically helpful. Further, there was NO association between TTR suppression and clinical response w inotersen…no way to measure misfoled vs normal TTR presently.
Extended follow-up of trials involving RNAi will be needed to fully understand the longer-term clinical benefits and risks of these drugs, as well as durability of such responses. Further, it remains to be determined the optimal use of RNAi therapy in a larger hATTR population, including patients with predominantly cardiac symptoms.
The significant costs associated with the use of these medications are also already being raised as an obstacle to use.

Nevertheless patisiran (and inotersen) should be viewed as a milestone in the management of hATTR amyloidosis, worthy of a spirited online journal club discussion. We also plan to discuss the results of another randomized trial comparing the antisense oligonucleotide inotersen versus placebo in a very similar group of patients, published in the same issue of the New England Journal of Medicine. 
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Two big announcements!


All are invited to attend the UNTANGLING AMYLOIDOSIS 2018 Friday Satellite Symposium (UA2018ASH) prior to the American Society of Hematology 2018 Annual Meeting, on Friday, November 30, 2018. 7:00 a.m. – 11:00 a.m. SDCC – Room 28 A-D. 

At our first Untangling Amyloidosis FSS in 2015, we reviewed principles of diagnosis, staging, and management of AL amyloidosis, and also discussed emerging anti-fibril and RNAi therapies for AL and ATTR amyloidosis. Now, at UA2018ASH we revisit these topics and more. We will examine advances and setbacks in the treatment of AL amyloidosis, including the use of monoclonal antibodies; the results of landmark trials in ATTR therapy which have already resulted in the first FDA approved therapy for ATTR amyloidosis (and likely two others in the near future!); adjunctive therapy for AL and ATTR cardiac amyloidosis; and clinical trial design in the current amyloidosis research landscape. 

Our esteemed speaker list includes: 

Giovanni Palladini, MD, PhD
Fondazione IRCCS Policlinico San Matteo
Pavia, Italy

Suzanne Lentzsch, MD, PhD
Columbia University
New York, NY, United States

Ashutosh Wechalekar, MBBS, DM
University College London Medical School Royal Free Campus
London, United Kingdom

Jeffrey Zonder, MD
Karmanos Cancer Institute
Detroit, MI, United States

Teresa Coelho, MD
Hospital Santo Ant?nio
Porto, Portugal

John Berk, MD
Boston University School of Medicine
Boston, MA, United States

This CME conference will be live streamed for those unable to attend the live event, and will also be archived for future online viewing and CME credits. Details on that to follow. 


Thanks to the generosity of the Amyloidosis Foundation, we are pleased to offer four travel grants related to UA2018ASH. 

Eligible applicants include medical students, residents, or fellows with an interest in amyloidosis, as well as individuals in the midst of completing a PhD in cancer biology or another field related to amyloidosis.  If the applicant is the first or last author on an abstract focusing on any topic directly related to amyloidosis submitted for presentation at the ASH 2018 Annual Mtg, s/he is encouraged to include that information with their application. 

Applicants must apply via email (zonderj@gmail.com) by 5 pm EST, Sunday, September 30th, 2018. The email must include the applicant’s full name, contact information (phone and email), current academic affiliation, training director/research supervisor contact information (phone and email), and a proposed article for an online amyloidosis journal club session. The applicant is strongly encouraged to explain why s/he feels the proposed article merits inclusion for the journal club. Applications will be reviewed by a selection committee (Andrew Kin, MD, Karmanos Cancer Institute; Vaishali Sanchorawala, MD, Boston University; Sascha Tuchman, MD, University of North Carolina). Four proposals will be selected based on the chosen article and rationale for selecting the article, with consideration of the applicant’s demonstrated interest in amyloidosis (related publications, research projects, lecture presentations, etc). Awardees will be announced by Sunday, October 7th, 2018. 

It is expected that selected awardees will co-moderate an online journal club session related to their article on one of the four following dates: October 28, November 4th, November 11th, and November 18th, 2018. Each session will be co-moderated by Dr. Jeffrey Zonder, one of the selection committee members, or another amyloidosis researcher TBD. The awardee will work with his/her co-moderator to develop the content for the journal club ahead of the actual online session. All awardees are encouraged to participate in each of the four online journal club sessions (though each will co-moderate only one session).  Additionally, each awardee is REQUIRED to attend the Untangling Amyloidosis 2018 FSS on Friday, November 20th, 2018. Grant awardees will be recognized at the symposium. Awardees will be asked to “tweet” or otherwise post online commentary/content related to the symposium in real time at the event. 

Awardees who complete the online journal club activity and attend the Untangling Amyloidosis 2018 FSS will be provided UP TO 5 (FIVE) NIGHTS HOTEL ACCOMMODATION AT THE CROWN PLAZA SAN DIEGO (THURSDAY, NOVEMBER 29th THROUGH TUESDAY, DECEMBER 4th) and will be reimbursed for ONE COACH CLASS AIRLINE TICKET and the REGISTRATION FEE FOR THE ASH 2018 MEETING

Please share this information widely! The application deadline is absolute, and the clock is ticking. This is a great opportunity for trainees interested in amyloidosis, and it is great pleasure for all of us involved in the symposium, the grant committee, and the journal club to meet and work with younger colleagues. 
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