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

August 21, 2020 updated by: Tufts Medical Center
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.

Study Overview

Status

Completed

Conditions

Detailed Description

This protocol will assess AL amyloidosis patients who achieve a CR or VGPR to first-line therapy for evidence of MRD by Q-PCR, NGS, and plasma protein analysis by mass spectrometry using marrow cells obtained annually at times of standard clinical evaluations.

A bone marrow aspirate sample from diagnosis will be used to create a baseline profile of each patient's disease. This sample will allow the investigators to create the primer-probe sets required for MRD testing by Q-PCR, which will be conducted after the patient has achieved a CR or VGPR. A baseline bone marrow biopsy sample will either be taken at the time of consent or can be taken from storage if the patient has previously consented to have their marrow cells banked for research purposes. An extra 15 mL of aspirate will be taken from their diagnostic bone marrow biopsy, which is routinely conducted on newly diagnosed patients for clinical purposes. Annual bone marrow aspirates will not be taken for research purposes until after the patient has responded. Patients will remain on protocol, but only begin MRD testing after achieving a CR or VGPR to first-line therapy at which point annual marrow collections for MRD testing will begin. In the event the patient does not reach a CR or VGPR to first-line therapy, the baseline bone marrow aspirate from diagnosis will be discarded.

Patients who choose to allow their marrow to be used in this study will sign a consent form specifically for this study. At the time of consent, three green top tubes of peripheral blood will be obtained for WGS of non-tumor cells. No further blood samples will be required for this study. After achieving a CR or VGPR, patients will be completely re-staged as is standard of care at annual intervals. Samples to test for the presence of MRD in their marrows will be obtained at these times of clinical re-staging for up to 3 years after their response to therapy. Both blood and bone marrow samples for this study will be immediately taken to an on-site laboratory where they will be briefly stored before testing. This will ensure no study samples interfere with routine clinical care.

In order to test for the presence of MRD, three techniques will be used: Q-PCR, WGS, and plasma protein analysis by mass spectrometry. Both Q-PCR and WGS will use genomic DNA from marrow aspirate samples. To make primer-probe sets for Q-PCR, bone marrow samples from baseline will be used to create individualized primer-probe sets that can recognize the genetically unique LC gene that causes each patient's disease. To perform WGS, genomic DNA will be supplied to the core genetics laboratory for creation of a library and multiplex next generation sequencing. To perform plasma protein analysis, plasma will be isolated from a portion of each subject's peripheral blood and bone marrow aspirate samples in an on-site laboratory. Each subject's de-identified LC gene sequence and their de-identified plasma samples will then be sent to Memorial Sloan-Kettering Cancer Center (MSKCC) for mass spectrometry to look for fragmentary protein sequences associated with the culprit LC gene of each subject.

After reaching a CR or VGPR, at annual evaluations for up to 3 years, the genomic DNA from the research sample of bone marrow collected during standard of care clinical procedures will be used to confirm maintenance of response by testing for the presence of MRD with each of the 3 methods (Q-PCR, WGS, and plasma protein analysis) noted above. Marrow material collected for the purposes of this study will not be stored after analysis, and primer-probe set design will be conducted entirely within Tufts Medical Center. Any marrow samples not fully consumed during analysis will be destroyed.

By using these three methods this protocol will determine whether one method is superior to the others and whether the three methods produce results that correlate with each other. The decision to discontinue participation in MRD testing will be made by the patient and the physician on an individual basis. Patients who have relapse or hematologic progression of disease during the three year period by standard blood and urine tests will no longer have testing for MRD.

Study Type

Observational

Enrollment (Actual)

56

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02111
        • Tufts Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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.

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Minimal Residual Disease Testing by Q-PCR, NGS, and mass spectrometry
Time Frame: 3 years
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tufts Medical Center

Investigators

  • Principal Investigator: Raymond Comenzo, MD, Tufts Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2015

Primary Completion (Actual)

August 1, 2020

Study Completion (Actual)

August 1, 2020

Study Registration Dates

First Submitted

September 16, 2015

First Submitted That Met QC Criteria

September 21, 2015

First Posted (Estimate)

September 22, 2015

Study Record Updates

Last Update Posted (Actual)

August 24, 2020

Last Update Submitted That Met QC Criteria

August 21, 2020

Last Verified

August 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11829 (DAIDS ES Registry Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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