Amyloid Planet

Time 2020-11-08 23:09:47

Web Name: Amyloid Planet

WebSite: http://www.amyloidplanet.com

ID:109454

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Amyloid,Planet,

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Here is a synopsis of the article we will be discussing in theDecember 1st, 2019 session of #amyloidosisJC, an online journal club focusing on all things amyloidosis. The synopsis was prepared by tworecipients of the DonBrockman ASH 2019 Trainee Travel Grants supported by the AmyloidosisFoundation, 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.Introduction:In this round of #AmyloidosisJC, we will bediscussing a clinical paper that discusses the role of minimal (measurable)residual disease (MRD) in the management of AL amyloidosis.Here is a link to the paper:Survival impact of achieving minimal residual negativity by multi-parametric flow cytometry in AL amyloidosis by Eli Muchtar et al. 2019 Amyloid.In this retrospective observation study, theauthors presented updated results with extended follow up of the ALamyloidosis patients who underwent end of treatment (EOT) MRD assessment bymultiparametric flow cytometry (MFC) described in a previous publication in 2017. Here is a linkto the 2017 paper: The prognostic value of multiparametric flow cytometry in ALamyloidosis at diagnosis and at the end of first-line treatment. Muchtar E et al.2017 Blood.Study objective:To establish whetherclearance of clonal plasma cells at EOT using sensitive and uniform MFCisassociated with improved OS Patient population:Of the original173patients with newly diagnosed AL amyloidosis patients (from their 2017study), 82 patients who had MRD testing at EOTusingsensitive and uniform MFC were included in this follow up publication.84% of the patients underwent autologous stem cell transplant as first line therapy (relevance: considerinherent selection bias to include primarily transplant eligible patients who are generally fit and do not have extensive baseline organ involvement )Methods:For MFC testing, reportedsensitivity was 1x10-4 to 2x10-5,depending on the number of analyzed events, phenotype and DNA index total of 500,000 live cellular events were set as a target per exam (mediangated events achieved 489,922, 25 75% IQR 469,765 493,662) Results:MRD and hematologic response: 29% (24) had negativeMRD, and 71% (58) had positive MRD at EOT. 19.5% (16) had CR, 46.3% (38) hadVGPR, 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 acomplete response (3-year PFS 100% vs. 33%, p=0.001).Incontrast, this difference in PFS advantage in VGPR/MRD- compared to those whoachieved VGPR/MRD+ did not reach statistical significance (p=0.14) difference was not seen between MRD- and MRD+ groups (3-year OS 96% vs. 84%,p=0.17) MRD- compared with MRD+ among deepresponders was associated with lower level of involved light chain (involvedfree light chain, median 1.1 vs. 1.7mg/dL;p=0.02)and higher frequency ofrenal response (100% vs. 68%; p=0.005) .When assessing independent organfunction, this difference was not evident in cardiac response Conclusions:Conclusion 1. Despite the retrospective nature ofthis study with the inherent selection bias to include primarily transplanteligible patients, this work aims at offering novel, robust surrogate endpointfor the design of clinical trials, as well as for optimizing individualpatients treatmentConclusion 2. There may be value in bone marrowbiopsy/aspirate at end of therapy in AL amyloidosis patients who achieveVGPR/CR. Presence of MRD is associated with reduced PFS in this group ofpatients.3. The sensitivityof the current standard assay for serum free light chain detection does notdiscern between MRD positive vs negative among VGPR/CR patients.Conclusion 4. This study is notable for presenting one of the largest patient cohorts forend of treatment MRD assessment andapplying uniform flow cytometrictechniques.Discussion:MRD assessment in AL amyloidosis isnot yet standardized. Of interest, a study using next generation flow for MRDassessment found that 5 out of 12 MRD positive cases had very low residualtumor burden ( 3x10-5), which would have not been detected withlower 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 between10 5and 10 6 Their reported median sensitivity levelof 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 byconventional MFC were found to be MRD positive by next gen flow (Flores-Monteroet al. 2017)We do not have studies that inform ushow best to manage/ monitor patients deep hematological response based on theirMRD statusIf a patient initially achieves MRD neg CR but thenprogresses to MRD positive CR on repeat follow up, does this indicateprogression/ requirement for treatment?What is the role of transplant inachieving MRD negative status? The impact of daratumumab in achieving MRDnegative status?As per our discussion from last week, looking forward toupcoming ISA abstract from @vsanchorawala regarding role of transplant in thistopic!Does time to MRD achievement matterand 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 EOThad significantly longer PFS and OS compared to patients who reached nadirbefore 12 months.This raises the question as to whetherthere a role for MRD assessment notonly 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,MDUPDATE 12/1/19 @ 10:19 pm: link to transcript of tonight's twitter discussion CLICK HERE.In this round of #AmyloidosisJC, we will be discussing abasic science paper that describes small molecules that stabilize light chainproteins 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:https://www.pnas.org/content/116/17/8360.longThis work was carried out at Scripps Research by the groupof Dr. Jeff Kelly.Dr. Kelly s group invented tafamidis, a molecule thatstabilizes 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.Background:Amyloidosis is caused by aggregation of normally-solubleproteins. In inherited diseases such as familial ATTR amyloidosis, aggregationis linked to destabilization of the precursor protein by mutation. In ALamyloidosis this connection is less well understood, because each patient has aunique amyloid-forming antibody light chain, secreted by monoclonal plasma cells. However,several lines of evidence show that unstable light chains are associated withamyloidosis:1. Hurle et al 1994 https://www.ncbi.nlm.nih.gov/pubmed/82025062. Blancas-Mejia et al, 2014 https://www.ncbi.nlm.nih.gov/pubmed/241574403. Morgan and Kelly 2016 https://www.ncbi.nlm.nih.gov/pubmed/275690454. Brumshtein et al 2015 https://www.ncbi.nlm.nih.gov/pubmed/26576950Since stabilization of precursor proteins has been shown tohave clinical benefit for ATTR patients, the authors looked for stabilizers oflight chains.Key points from thepaper:1. The authors developed a method to measure light chain stability by highthroughput screening. This was important because light chains do not have anyknown natural ligands that could be modified to make a drug. Instead, screeninga large number of molecules was required.2. From a starting set of 650,000 molecules, 16 molecules infour chemical classes could stabilize light chains when tested in severalassays.3. The paper focuses on one compound, which is a commerciallyavailable dye called coumarin 1 . This molecule becomes fluorescent when itbinds to light chains, which makes it useful as a tool for other experiments.4. The crystal structure of coumarin 1 bound to light chainsshows that the small molecule binds between the two variable domains in thedimer, 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 lightchains. However, the molecules do not bind to the normal antibody heavychain:light chain dimer interface.5. The authors intend to develop molecules that bind moretightly and more specifically to light chains. These molecules could becomedrug candidates.Clinical points fordiscussion:1. These molecules are not drugs. There is a lot of work to bedone before they can be tested in patients.2. Stabilization may be most effective in when combined withanti plasma-cell therapies. One potentially promising use would be inmaintenance for patients who have a hematological response to therapy but areat risk of relapse. Another would be for patients who are too sick to toleratecytotoxic drugs.3. Doxycycline, which has shown some efficacy for AL in Phase 2trials, does not stabilize light chains in this assay whatever it s doing isprobably different. https://www.ncbi.nlm.nih.gov/pubmed/283386704. Tafamidis is beneficial in ATTR patients. Would a lightchain stabilizer have similar properties?We don t know what the consequences of stabilizing lightchains in patients will be. Many individuals with other plasma celldycrasias (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 thanamyloidosis are associated with light chains. Altering light chain metabolismmay cause problems in thekidney or elsewhere.5. if stabilizers alter light chain clearance, theymay 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 chainsin blood, thereby potentially identifying patients who might benefit from light chains stabilization by smallmolecules.

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