Improvement in Global Longitudinal Strain (GLS) correlates with NT-proBNP response in Patients with Cardiac Amyloidosis Treated on a Phase 1b Study of Anti- Amyloid mAb CAEL-101 Divaya Bhutani MD, Sofia Shames, MD, Jeff Goldsmith, PhD, Siyang Leng MD, Mathew S. Maurer, MD, Andrew Eisenberger MD, Suzanne Lentzsch, MD, PhD Columbia University Medical Center New York, NY
Disclosures • Divaya Bhutani: No conflict of Interest • Sofia Shames: No conflict of Interest • Jeff Goldsmith: No conflict of Interest • Siyang Leng: No conflict of Interest • Mathew S. Maurer: Pfizer: Personal fees and Research Funding. Eidos: Personal fees and Research Funding. Alnylam: Research Funding. Glaxo Smith Kline: Personal Fees. Prothena: Research Funding. Akcea: Personal fees. Ionis: Personal fees and Research Funding • Andrew Eisenberger: No conflict of Interest • Suzanne Lentzsch: Janssen: consultancy. Caelum Biosciences: consultancy, Shareholder for Caelum Biosiences, recused herself as an investigator from the Phase 1a/b trial testing CAEL-101 in 11/2017. Bayer: consultancy. BMS: Consultancy
AL Amyloidosis • Primary AL Amyloidosis is a disorder characterized by presence of a Monoclonal Plasma cell population in the Bone Marrow leading to production and extracellular deposition of abnormal monoclonal Immunoglobulin Light chains in one or more organs • Overall Incidence 8 per million per year • Heart and Kidney are the most commonly affected organs (70%) • The deposition of the Monoclonal immunoglobulin can lead to organ dysfunction manifested diastolic dysfunction and Heart failure with cardiac involvement and Proteinuria and renal failure with renal involvement
Cardiac AL Amyloidosis-Prognosis • Degree of Cardiac dysfunction remains the main prognostic factor for survival in patients with systemic Amyloidosis • Revised Mayo clinic staging system consists of the following factors: 1. NT-Pro- BNP ≥1800pg/ml 2. Troponin T ≥ 0.025 ng/ml 3. Free light chain difference ≥ 18mg/dl Kumar S et al. Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements. J Clin Oncol 30:989-995.
Fibril directed therapy for AL Amyloidosis mu11-1F4 • mu 11-1F4 mAb is a monoclonal IgG1 antibody that binds to a conformational epitope present on both human kappa and lambda light-chain amyloid fibrils • The 11-1F4 mAb leads to dissolution of human AL λ and κ amyloidomas in mice Untreated Treated Wall, JS et al, Tijdschr Nucl Geneeskd. 2011 Dec;33(4):807-814
mu 11-1F4: localization to the amyloid tissue Jonathan Wall et al. Blood. 2010;116(13): 2241-2244 Wells K. J Nucl Med 2011 vol 52 supplement: 1;1090
Global Longitudinal Strain • Longitudinal strain is an Echocardiographic measurement of base to apical shortening of the left Ventricle during each cardiac cycle • It can be reported by each cardiac region or as a global average called Global Longitudinal Strain (GLS) • Sensitive and specific marker for diagnosis as well as prognosis of Cardiac Amyloidosis • As a diagnostic tool apical sparing has been shown to be a specific marker of Cardiac Amyloidosis Agha Ali et al. Role of cardiovascular imaging for the diagnosis and prognosis of cardiac amyloidosis. Open Heart 2018: 26;5(2):e000881.
GLS: A prognostic marker for Cardiac AL- Amyloidosis Salinaro F et al. European Heart Journal - Cardiovascular Imaging (2017) 18, 1057 – 1064. Pun Shawn et al. J Am Soc Echocardiogr 2018;31:64-70.
Salinaro F et al. European Heart Journal - Cardiovascular Imaging (2017) 18, 1057 – 1064
Phase 1a/b Study of ch 11-1F4 (CAEL-101) in Patients with AL Amyloidosis • GMP-grade amyloid fibril-reactive chimerized IgG1 11-1F4 mAb was produced by NCI’s Biological Resource Branch • Secondary outcome of GLS in patients enrolled in Open-label, dose-escalation phase 1b study of Ch IgG1 11-1F4 mAb (CAEL- 101) • Patients who received anti-plasma cell directed therapy in the past but with persistent organ dysfunction. https://clinicaltrials.gov/ct2/show/NCT02245867
Eligibility • Confirmed diagnosis of AL amyloidosis KEY • Age > 21 years INCLUSION • ECOG performance status ≤ 3 • Received prior systemic therapy CRITERIA • Does not require plasma cell targeted therapy • EF < 40% KEY • Intraventricular Septum > 25mm • Creatinine clearance < 30 cc/min EXCLUSION • Alkaline phosphatase > 3 times institutional CRITERIA upper limit of normal • Bilirubin > 3.0 mg/dL https://clinicaltrials.gov/ct2/show/NCT02245867
Phase 1b Dose Escalation Dose Level Weeks weeks (mg/m 2 ) -2 0.125 0 1 2 3 4 5 8 12 -1 0.25 1 0.5* Ch 11-1F4 mAb (CAEL-101) infusion 2 5 Clinical Evaluation 3 10 • 11-1F4 mAb (CAEL-101) infusion once per week for 4 weeks 4 50 • Starting again at Dose Level 1 • Once tolerated, successive patients each received 5 100 progressively higher doses of 11-1F4 mAb (CAEL-101) 6 250 • 6 additional patients enrolled at Dose level 6 • 6 additional patients enrolled at Dose level 7 7 500 https://clinicaltrials.gov/ct2/show/NCT02245867
Study Design • Phase 1b study of patients with systemic AL amyloidosis (N=19) • All patients underwent transthoracic echocardiograms at screening and 12 weeks post therapy • GLS was measured using speckle-tracking (TomTec-Arena 1.2, Germany) and calculated as an average of 4-, 2-, and 3- chamber based measurements • Paired student’s t -test was used to compare echocardiographic variables at screening and 12 weeks after therapy start with CAEL- 101. GLS was correlated with NT-proBNP using Pearson correlation coefficient
Patient Characteristics (Phase 1b) characteristic Median Age (N=19) 63 (Range Gender Male N=13 (68%) Female N=6 (32%) Light chain type Lambda N= 9 (47%) Kappa N=10 (53%) Revised Mayo Stage II (I-IV) Organ Involvement Median=2 (range 1-4) Cardiac N=10 Renal N=7 GI N=3 Liver N=2 Soft tissue N=4 MSK N=2 Neurological N=4 Prior Anti-Plasma cell chemotherapy 2 (range 1-4) Proteasome Inhibitor N=15(78%) Immunomodulator: N=6 (30%) Auto-SCT N=8 (42%) Hematologic disease status at enrollment CR N=10 (52%) Active disease N=9 (48%) Baseline NT-proBNP (cardiac involvement 1186 (699-3964) only) Baseline Proteinuria (renal involvement 3272 mg/24h (1078-7260mg/24h) only)
Results-Organ Response (phase 1b) • 10 patients had cardiac involvement but 8 were considered evaluable for NT-proBNP response • 6/8 (75%) evaluable patients with Cardiac involvement met cardiac response criteria with ≥ 30% decrease in NT -proBNP • 4/7 (57%) patients with Renal involvement met Renal response criteria with ≥ 50% decrease in 24 hour urine proteinuria • Median time to organ response was 3 weeks • Overall 17/19 patients were alive at a median follow up of 19 months • No difference in organ response rates in patients with and without active hematologic disease Edwards, V. et al, Blood Abstract, 2017 130:509
Global Longitudinal Strain (GLS) • Mean GLS at screening was -15.58 -4.14% in patients with cardiac Amyloidosis vs -22.77 -3.12% in patients without cardiac Amyloidosis • Mean GLS improved significantly in 9/10 patients with cardiac involvement from -15.58 -4.14% at screening to -17.37 -3.53% at week 12, p = 0.004 • Pearson correlation coefficient between NT-proBNP response and GLS response (in 8 cardiac evaluable patients) was 0.345 • No changes in GLS in patients without cardiac involvement (Mean GLS -22.77 - 3.12% at screening and -22.36 -3.02% at end of treatment)
Change in GLS D= 1.79
GLS response by Light chain type Patient (N) Baseline Follow-up P-value GLS Mean 6 (Kappa) -16.6 (4.10) -18.16 (3.48) 0.074 4(Lambda) -14.3 (4.38) -16.17 (3.74) 0.022
Conclusion 1. Monoclonal antibody CAEL-101 is able to induce rapid organ responses in patients with AL Amyloidosis 2. Improvement in Global Longitudinal Strain correlates with improvement in NT-proBNP in in patients with cardiac AL Amyloidosis treated with CAEL-101 3. Global Longitudinal Strain should be further evaluated as a marker of early Cardiac Response in patients with Cardiac AL Amyloidosis
Acknowledgements • Columbia Amyloidosis Multidisciplinary Program (CAMP), Columbia University, New York ➢ Multiple Myeloma and Amyloidosis Program : Suzanne Lentzsch ➢ Advanced Heart Failure Group: Matthew Maurer ➢ Nephrology: Jai Radhakrishnan ➢ Bone Marrow Transplant: Markus Mapara ➢ Renal Pathology: Glen Markowitz ➢ Cardiac Pathology: Chuck Marboe • Funding ➢ NCI Experimental Therapeutics (NExT) Grant ➢ R01 FD005110-01 PI ➢ Columbia Technology Ventures ➢ Caelum Biosciences
Recommend
More recommend
