Minimal Residual Disease as a Possible Predictive Factor for Relapse in Patients With AL Amyloidosis

NCT02555969 | Completed

• 1 other identifier: 11829
• Study Type: observational
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

This protocol will assess patients with AL amyloidosis who achieve a complete response (CR) or very good partial response (VGPR) to therapy for minimal residual disease (MRD). Three approaches to MRD testing will be used since there is no established method. The investigators will clone and sequence each patient's light chain (LC) gene and design patient-specific primers to evaluate genomic DNA from future marrow specimens. Whole genome sequencing (WGS) will be used to test baseline and follow-up marrow cell DNA, seeking copy number variations in chromosomes 1 and 2 or 22, and structural variations in chromosomes 11 and 14, consistent with the known genetic abnormalities in AL and with clonal LC gene use. Plasma protein analysis by mass spectrometry will also be used to look for fragmentary protein sequences associated with the culprit LC gene of each subject. The feasibility and predictive value of these three approaches in patients achieving CR or VGPR will be evaluated. This protocol will help provide insight into the ways that the disease changes and progresses. MRD testing is likely an important next step in AL management.

Conditions

Amyloidosis; Primary Amyloidosis

Outcome Measures

Primary Outcomes (1)

• Minimal Residual Disease Testing by Q-PCR, NGS, and mass spectrometry

  After achievement of a CR or VGPR, minimal residual disease testing (using Q-PCR, WGS, and plasma protein analysis by mass spectrometry) will be done annually for up to 3 years. These tests will show either the presence of absence of minimal residual disease. These findings will then be correlated with progression free survival as assessed through standard clinical tests for AL amyloidosis.

  3 years

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

This study will enroll AL amyloidosis patients at Tufts Medical Center who have baseline bone marrow cells available from the time of diagnosis, or from a time of therapy prior to achieving a response, and then subsequently achieve a CR or VGPR with first-line therapy. Up to 50 patients diagnosed with AL amyloidosis will be evaluated on this protocol.

You may qualify if:

• Patients with AL amyloidosis at Tufts Medical Center who have baseline bone marrow samples available and achieve a CR or VGPR to treatment. Patients may consent and register at diagnosis and have a baseline marrow collected at the time of consent; or patients may consent during therapy prior to achieving a response, if they have previously banked marrow cells for research.

You may not qualify if:

• Patients who do not have available baseline bone marrow samples.

Sponsors & Collaborators

• Tufts Medical Center: lead

Study Sites (1)

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Related Publications (15)

• Abraham RS, Geyer SM, Price-Troska TL, Allmer C, Kyle RA, Gertz MA, Fonseca R. Immunoglobulin light chain variable (V) region genes influence clinical presentation and outcome in light chain-associated amyloidosis (AL). Blood. 2003 May 15;101(10):3801-8. doi: 10.1182/blood-2002-09-2707. Epub 2002 Dec 19.

  PMID: 12515719 BACKGROUND

• Perfetti V, Casarini S, Palladini G, Vignarelli MC, Klersy C, Diegoli M, Ascari E, Merlini G. Analysis of V(lambda)-J(lambda) expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r (lambdaIII) as a new amyloid-associated germline gene segment. Blood. 2002 Aug 1;100(3):948-53. doi: 10.1182/blood-2002-01-0114.

  PMID: 12130507 BACKGROUND

• Bodi K, Prokaeva T, Spencer B, Eberhard M, Connors LH, Seldin DC. AL-Base: a visual platform analysis tool for the study of amyloidogenic immunoglobulin light chain sequences. Amyloid. 2009 Mar;16(1):1-8. doi: 10.1080/13506120802676781.

  PMID: 19291508 BACKGROUND

• Comenzo RL. Plasma cell neoplasms, their precursor States, and their prediction of organ damage. J Clin Oncol. 2014 Sep 1;32(25):2679-82. doi: 10.1200/JCO.2014.56.2892. Epub 2014 Jul 14. No abstract available.

  PMID: 25024079 BACKGROUND

• Comenzo RL, Wally J, Kica G, Murray J, Ericsson T, Skinner M, Zhang Y. Clonal immunoglobulin light chain variable region germline gene use in AL amyloidosis: association with dominant amyloid-related organ involvement and survival after stem cell transplantation. Br J Haematol. 1999 Sep;106(3):744-51. doi: 10.1046/j.1365-2141.1999.01591.x.

  PMID: 10468868 BACKGROUND

• Comenzo RL, Zhang Y, Martinez C, Osman K, Herrera GA. The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell burden. Blood. 2001 Aug 1;98(3):714-20. doi: 10.1182/blood.v98.3.714.

  PMID: 11468171 BACKGROUND

• Dasari S, Theis JD, Vrana JA, Meureta OM, Quint PS, Muppa P, Zenka RM, Tschumper RC, Jelinek DF, Davila JI, Sarangi V, Kurtin PJ, Dogan A. Proteomic detection of immunoglobulin light chain variable region peptides from amyloidosis patient biopsies. J Proteome Res. 2015 Apr 3;14(4):1957-67. doi: 10.1021/acs.jproteome.5b00015. Epub 2015 Mar 20.

  PMID: 25734799 BACKGROUND

• van der Velden VH, Cazzaniga G, Schrauder A, Hancock J, Bader P, Panzer-Grumayer ER, Flohr T, Sutton R, Cave H, Madsen HO, Cayuela JM, Trka J, Eckert C, Foroni L, Zur Stadt U, Beldjord K, Raff T, van der Schoot CE, van Dongen JJ; European Study Group on MRD detection in ALL (ESG-MRD-ALL). Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia. 2007 Apr;21(4):604-11. doi: 10.1038/sj.leu.2404586. Epub 2007 Feb 8.

  PMID: 17287850 BACKGROUND

• Wang Q, Xia J, Jia P, Pao W, Zhao Z. Application of next generation sequencing to human gene fusion detection: computational tools, features and perspectives. Brief Bioinform. 2013 Jul;14(4):506-19. doi: 10.1093/bib/bbs044. Epub 2012 Aug 9.

  PMID: 22877769 BACKGROUND

• Welschof M, Terness P, Kolbinger F, Zewe M, Dubel S, Dorsam H, Hain C, Finger M, Jung M, Moldenhauer G, et al. Amino acid sequence based PCR primers for amplification of rearranged human heavy and light chain immunoglobulin variable region genes. J Immunol Methods. 1995 Feb 27;179(2):203-14. doi: 10.1016/0022-1759(94)00286-6.

  PMID: 7876568 BACKGROUND

• Zhou P, Comenzo RL, Olshen AB, Bonvini E, Koenig S, Maslak PG, Fleisher M, Hoffman J, Jhanwar S, Young JW, Nimer SD, Boruchov AM. CD32B is highly expressed on clonal plasma cells from patients with systemic light-chain amyloidosis and provides a target for monoclonal antibody-based therapy. Blood. 2008 Apr 1;111(7):3403-6. doi: 10.1182/blood-2007-11-125526. Epub 2008 Jan 23.

  PMID: 18216299 BACKGROUND

• Zhou P, Hoffman J, Landau H, Hassoun H, Iyer L, Comenzo RL. Clonal plasma cell pathophysiology and clinical features of disease are linked to clonal plasma cell expression of cyclin D1 in systemic light-chain amyloidosis. Clin Lymphoma Myeloma Leuk. 2012 Feb;12(1):49-58. doi: 10.1016/j.clml.2011.09.217. Epub 2011 Nov 18.

  PMID: 22100494 BACKGROUND

• Zhou P, Ma X, Iyer L, Chaulagain C, Comenzo RL. One siRNA pool targeting the lambda constant region stops lambda light-chain production and causes terminal endoplasmic reticulum stress. Blood. 2014 May 29;123(22):3440-51. doi: 10.1182/blood-2013-10-535187. Epub 2014 Apr 10.

  PMID: 24723680 BACKGROUND

• Zhao M, Wang Q, Wang Q, Jia P, Zhao Z. Computational tools for copy number variation (CNV) detection using next-generation sequencing data: features and perspectives. BMC Bioinformatics. 2013;14 Suppl 11(Suppl 11):S1. doi: 10.1186/1471-2105-14-S11-S1. Epub 2013 Sep 13.

  PMID: 24564169 BACKGROUND

• Zhou P, Zhang Y, Martinez C, Kalakonda N, Nimer SD, Comenzo RL. Melphalan-mobilized blood stem cell components contain minimal clonotypic myeloma cell contamination. Blood. 2003 Jul 15;102(2):477-9. doi: 10.1182/blood-2002-12-3674. Epub 2003 Mar 20.

  PMID: 12649134 BACKGROUND

MeSH Terms

Conditions

Amyloidosis; Immunoglobulin Light-chain Amyloidosis

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias

Study Officials

• Raymond Comenzo, MD

  Tufts Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 16, 2015
• First Posted: September 22, 2015
• Study Start: August 1, 2015
• Primary Completion: August 1, 2020
• Study Completion: August 1, 2020
• Last Updated: August 24, 2020

Record last verified: 2020-08

Locations

US (1)