Continued Refinement of the Treatment for Light-Chain Cardiac Amyloidosis
2021; Lippincott Williams & Wilkins; Volume: 145; Issue: 1 Linguagem: Inglês
10.1161/circulationaha.121.057538
ISSN1524-4539
AutoresJustin L. Grodin, Larry D. Anderson, Ankit Kansagra,
Tópico(s)Parathyroid Disorders and Treatments
ResumoHomeCirculationVol. 145, No. 1Continued Refinement of the Treatment for Light-Chain Cardiac Amyloidosis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBContinued Refinement of the Treatment for Light-Chain Cardiac Amyloidosis Justin L. Grodin, MD, MPH, Larry D. Anderson Jr, MD, PhD and Ankit Kansagra, MD Justin L. GrodinJustin L. Grodin Correspondence to: Justin L. Grodin, MD, MPH, 5323 Harry Hines Boulevard, Dallas, TX 75390. Email E-mail Address: [email protected] https://orcid.org/0000-0003-2400-3196 Divisions of Cardiology (J.L.G.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas. , Larry D. Anderson JrLarry D. Anderson Jr https://orcid.org/0000-0002-6531-9595 Hematology and Oncology (L.D.A., A.K.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas. and Ankit KansagraAnkit Kansagra Hematology and Oncology (L.D.A., A.K.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas. Originally published29 Dec 2021https://doi.org/10.1161/CIRCULATIONAHA.121.057538Circulation. 2022;145:18–20This article is a commentary on the followingDoxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled TrialLight chain cardiac amyloidosis (AL-CA) is a devastating disease caused by a buildup of abnormal, misfolded light chain aggregates in the myocardium. When untreated, AL-CA leads to progressive heart failure and premature death. The long-term prognosis of AL-CA is dependent on the disease stage at diagnosis and then the response to treatment. Median survival of advanced stage AL-CA at diagnosis may approximate 6 months.1 These sobering metrics have served to motivate the detection of AL-CA in earlier stages and the continued advancements of treatment for AL-CA.Article, see p 8There has been continued improvement of amyloid light chain (AL) prognosis resulting from significant advancements in treatment strategies.2 Recent clinical trial data show that among patients with AL amyloidosis (≈71% with cardiac involvement), the addition of daratumumab (a CD-38–targeting antibody toward plasma cells) to conventional therapy led to a dramatic improvement in hematologic and end-organ response compared with conventional therapy alone.3 The added use of daratumumab was associated with nearly a 3-fold greater likelihood of complete hematologic response (normalization of the abnormal light chain concentration and negative serum and urine immunofixation) and a 2-fold greater likelihood of a cardiac response (defined as >30% and >300 ng/L decrease in patients with baseline NT-proBNP [N-terminal pro–B-type natriuretic peptide] ≥650 ng/L or ≥2 class decrease in patients with baseline New York Heart Association class III or IV) by 6 months.All contemporary therapeutic strategies for AL-CA rely on therapies that target plasma cells to halt or slow the source of the AL production. Despite these advancements, there remains a crucial unmet need to address the residual risk attributed to already-deposited amyloid fibrils. One repurposed therapy that may inhibit amyloid fibril formation and clear deposited fibrils is doxycycline—a commonly used, inexpensive tetracycline-based antibiotic therapy. In a study of transgenic mice that exhibit a light-chain amyloidosis phenotype, doxycycline had a dose-dependent inhibitory effect on recombinant AL aggregation in vitro and reduced the quantity of AL fibrils ex vivo.4 The mechanism of this benefit is thought to be related to its inhibitory effects on matrix metalloproteinase pathways, which are elevated in patients with AL-CA.5 Observational data from a single-center cohort (n=103) of patients with AL-CA suggest that doxycycline use in addition to bortezomib-based treatment may be associated with improved survival and greater cardiac response (defined as a larger decrease in aminoterminal NT-proBNP).6 Until now, clinical trial data testing the efficacy of doxycycline as a treatment for AL-CA have been lacking.In this issue of Circulation, Shen and colleagues7 present an open-label randomized trial that aimed to test the effect of oral doxycycline administered at a dose of 100 mg twice daily added to a standard regimen of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) on 2-year progression-free survival (PFS) in patients with biopsy-proven AL-CA. PFS was defined as a prespecified composite time-to-event end point of death, hematologic progression (a resurgence in the abnormal free-light chain), or organ progression (an abnormal rise in NT-proBNP for cardiac progression, alkaline phosphatase for liver progression, or a decrease in estimated glomerular filtration rate for kidney progression). In an exploratory analysis, these investigators also tested whether doxycycline reduced incident cardiac PFS, defined as cardiac progression (>30% and 300 pg/mL increase in NT-proBNP, ≥33% increase in cardiac troponin, or ≥10% decrease in left ventricular ejection fraction8) or death.This study had four main findings. First, 140 patients were randomly assigned to either doxycycline plus CyBorD or CyBorD alone. After a median follow-up of 24.4 months, there was no difference in PFS, cardiac PFS, or overall survival between the 2 groups. Second, there were no differences in the rates of cardiac response, kidney response, or liver response, all of which are outcomes that would have been consistent with the posited mechanism of benefit of doxycycline for light-chain amyloidosis. Third, no demonstrable differences were found in the rates of hematologic responses—outcomes that are not consistent with the mechanism of benefit of doxycycline for light-chain amyloidosis because it does not target the abnormal plasma cell burden. Fourth, nausea and vomiting–related adverse events were more common in the doxycycline group in comparison with the control group. Overall, these observations highlight the potential for a lack of usefulness for doxycycline and underscore the potential for its use to increase the risk of excess nausea and vomiting for individuals with AL-CA.The primary limitation of this trial is that it was unblinded to the investigators, participants, and treating clinicians. Although this limitation could lead to differential bias in favor of the doxycycline arm, the numbers of participants who completed treatment, who died, and who had disease progression were comparable between groups, and there was consistent lack of benefit of doxycycline for any of the prespecified outcomes of this study. Furthermore, the median number of cycles of chemotherapy completed was higher in the doxycycline group in comparison with the control group (9 versus 7.5, respectively), a finding that would have biased these results toward a favorable effect of doxycycline. In total, these data support the validity of this trial's observations.Before the present study, the effects of doxycycline as an adjunct therapy to standard of care for AL-CA have not been supported by trial data. Its use has been endorsed largely by findings from observational data to this point.6 Whether a blinded, more rigorous study design powered for a smaller effect size may have yielded different results is unknown. Observations from future clinical trials will clarify findings from the current study and one such study is enrolling (A Trial of Doxycycline vs. Standard Supportive Therapy in Newly-Diagnosed Cardiac AL Amyloidosis Patients Undergoing Bortezomib-Based Therapy: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03474458).With the availability of novel compounds, the treatment landscape of AL-CA is changing rapidly. Daratumumab-based quadruplet therapy is now considered standard of care in many parts of the world.3 In the recent ANDROMEDA trial (A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With CyBorD Compared to CyBorD Alone in Newly Diagnosed Systemic AL Amyloidosis), the concomitant use of daratumumab with CyBorD in comparison with CyBorD alone was associated with a 42% reduction in the risk for major organ deterioration, hematologic progression, or death.3 These data bring attention to an important question: If hematologic response is achieved more quickly, leading to less mortality, can agents such as doxycycline given over a longer period have a potentially greater effect on cardiac outcomes? It is unknown whether a longer exposure to doxycycline or higher doses would demonstrate benefit in AL-CA. Furthermore, NT-proBNP levels are influenced by kidney function and are an indirect metric of myocardial amyloid infiltration. Whether a more directly measured assessment of myocardial amyloid load such as contrast-enhanced cardiac magnetic resonance imaging with parametric mapping would more accurately highlight phenotypic response to doxycycline is unknown.9Beyond doxycycline, the development of agents that inhibit AL fibril formation and clear deposited AL aggregates is continuing to evolve. The monoclonal antibody birtamimab (NEOD001) is a humanized immunoglobulin G1 engineered to target misfolded light chains promoting phagocytic clearance of AL deposits.10 Its clinical benefit has not been demonstrated clearly, and a recent phase III study (VITAL [A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, 2-Arm, Efficacy and Safety Study of NEOD001 Plus Standard of Care Versus Placebo Plus Standard of Care in Subjects With AL Amyloidosis]) testing the added effect of birtamimab for AL-CA in addition to usual care was terminated early for lack of benefit. It remains to be seen whether birtamimab is beneficial for patients with more advanced forms of AL-CA and this hypothesis is being tested in an enrolling phase III clinical trial (AFFIRM-AL [A Study to Evaluate the Efficacy and Safety of Birtamimab in Mayo Stage IV Patients With AL Amyloidosis]). Another agent, CAEL-101, is an amyloid fibril–reactive chimeric immunoglobulin G1k monoclonal antibody currently under development. When bound to misfolded light chains, CAEL-101 activates neutrophils and launches a proteolytic cascade against AL fibrils. Results from a recent phase 1a/b study of CAEL-101 in patients with relapsed or refractory AL-CA support the hypothesis that it improved target organ function through improved left ventricular global longitudinal strain and lower NT-proBNP after 12 weeks of therapy.11 Data from phase III trials testing the effect of CAEL-101 on clinical outcomes for newly diagnosed AL-CA cases are forthcoming (A Study to Evaluate the Safety and Tolerability of CAEL-101 in Patients With AL Amyloidosis [URL: https://www.clinicaltrials.gov; Unique identifier: NCT04304144]; A Study to Evaluate the Effectiveness and Safety of CAEL-101 in Patients With Mayo Stage IIIa AL Amyloidosis [URL: https://www.clinicaltrials.gov; Unique identifier: NCT04512235]; A Study to Evaluate the Effectiveness and Safety of CAEL-101 in Patients With Mayo Stage IIIb AL Amyloidosis [URL: https://www.clinicaltrials.gov; Unique identifier: NCT04504825]).In this context, the report by Shen et al7 argues against the role of doxycycline among other therapies for AL that target amyloid fibril formation and clearance in comparison with therapies that target plasma cells. These observations highlight a lack of usefulness of doxycycline as an adjunct for AL-CA treatment. Recent studies testing the efficacy of therapies designed to clear amyloid fibrils and amyloid deposits have been mixed, but more data are on the horizon that will further inform their usefulness. Nevertheless, there is a clear unmet need to develop therapies that promote accelerated cardiac improvement in this disease beyond plasma cell–targeting therapies. The understanding of optimal therapeutic strategies to inhibit light chain formation and promote amyloid clearance will continue to be a critical part of the refinement of the treatment for AL-CA.Article InformationSources of FundingDr Grodin has grant support from the Texas Health Resources Clinical Scholarship, Eidos/BridgeBio, and Salubris. Dr Kansagra has grant support from the Eugene P. Frenkel Scholarship, the Cancer Prevention and Research Institute of Texas, National Institutes of Health, Leukemia Lymphoma Society, and GlaxoSmithKline.Nonstandard Abbreviations and AcronymsALamyloid light chainAL-CAlight chain cardiac amyloidosisCyBorDcyclophosphamide, bortezomib, and dexamethasoneNT-proBNPN-terminal pro–B-type natriuretic peptidePFSprogression-free survivalDisclosures Dr Grodin has received consulting income from Pfizer, Eidos/BridgeBio, Alnylam, and Sarepta. Dr Kansagra has received consulting income from Alnylam, Bristol Myers Squibb, Cota Health, GlaxoSmithKline, Janssen, Oncopeptides, and Takeda. Dr Anderson has received consulting income from BMS, Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Karyopharm, Amgen, and Prothena.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 20.Correspondence to: Justin L. Grodin, MD, MPH, 5323 Harry Hines Boulevard, Dallas, TX 75390. Email justin.[email protected]eduReferences1. Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Colby C, Laumann K, Zeldenrust SR, Leung N, Dingli D, et al.. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements.J Clin Oncol. 2012; 30:989–995. doi: 10.1200/JCO.2011.38.5724CrossrefMedlineGoogle Scholar2. Muchtar E, Gertz MA, Kumar SK, Lacy MQ, Dingli D, Buadi FK, Grogan M, Hayman SR, Kapoor P, Leung N, et al.. Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.Blood. 2017; 129:2111–2119. doi: 10.1182/blood-2016-11-751628CrossrefMedlineGoogle Scholar3. Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, et al.; ANDROMEDA Trial Investigators. 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Circulation. 2022;145:8-17 January 4, 2022Vol 145, Issue 1Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.057538PMID: 34965166 Originally publishedDecember 29, 2021 KeywordstherapeuticsdoxycyclineamyloidosisEditorialsPDF download Advertisement SubjectsCardiomyopathyHeart Failure
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