LymphoSIGHT Detects MRD Not Found With Conventional Methods

Becky McCall

June 28, 2013

STOCKHOLM — A novel investigational high-throughput sequencing technology, known as the LymphoSIGHT (lymphocyte sequencing of immunoglobulin and T-cell receptors) platform, is comparable to a more conventional but cumbersome method of detecting minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL).

However, the new screen found leukemia clones that the standard method did not, according to a study presented here at the 18th Congress of the European Hematology Association (EHA).

The 2 techniques generally measured the same amount of disease, said lead researcher Wendy Stock, MD, professor of medicine in the section of hematology/oncology at the Comprehensive Cancer Center, University of Chicago. However, "the LymphoSIGHT technique was a little more sensitive and found additional clones.... That may or may not have clinical relevance in the future," she told Medscape Medical News.

LymphoSIGHT, made by Sequenta, is a platform for counting and enumerating immune cells. It is marketed for use in ALL, chronic lymphocytic leukemia (CLL), and mantle cell lymphoma. Other presentations here at the EHA meeting showed data on its use in multiple myeloma and follicular lymphoma.

Effectively, it is a new version of flow cytometry with improved sensitivity and specificity. But unlike flow cytometry, LymphoSIGHT characterizes the immune cells by their DNA content, which is highly adaptable, and arms the cell to make antibodies on demand. "It's an engine of genetic diversity, with trillions of different combinations. These immune cells generate unique tags on their DNA, enabling immune cells in a sample to be characterized," said Tom Willis, PhD, chief executive officer of Sequenta.

Dr. Stock presented results from a head-to-head comparison of allele-specific oligonucleotide real-time quantitative polymerase chain reaction analysis (ASO-PCR) and LymphoSIGHT.

In 1 of the 37 patients, MRD was found with LymphoSIGHT but not with ASO-PCR. The novel technique detected that the patient had 2 other high-frequency clones, which existed at diagnosis. "These clones did not respond to treatment in the same way. We know there are subclones of disease that occur and that all leukemias arise from 1 or maybe 2 original mutated cells, but there's usually 1 dominant clone at diagnosis," she explained.

Study Design

In the study participants, who had ALL and came from the Intergroup C10403 trial, specific clones had already been identified with ASO-PCR. These clones were monitored for MRD with the conventional technique and with LymphoSIGHT.

Patient clone samples were taken before the start of treatment and after approximately 1 month of treatment. When LymphoSIGHT and ASO-PCR were compared, the quantitative concordance was 0.78. "We found that the 2 techniques generally measured the same amount of disease," although LymphoSIGHT was a little more sensitive, Dr. Stock reported.

"Patients who persistently show a positive reading on measurement of MRD have a very high risk of relapse and might need additional therapy," she noted. "The whole goal of measuring MRD is to try to avoid relapse by changing treatment course if a patient shows high levels of MRD."

Early relapse of disease, 3 months after induction, was seen in 1 patient as a result of the expansion of a treatment-resistant clone that was not monitored with ASO-PCR.

LymphoSIGHT identified 2 high-frequency clones present at diagnosis that did not respond to treatment. This suggests that ASO-PCR could have given the false impression that the patient was doing well, when the patient had actually suffered an early relapse. "We couldn't prove which clones contributed to that," Dr. Stock explained. This relapse might have been due to a resistant clone, although this was not shown definitively.

The LymphoSIGHT technique can delve deeper and can find smaller numbers, but Dr. Stock explained that it is important to demonstrate how clinically significant this is. "Maybe these tiny clones don't contribute to disease, but maybe they do. We need much more data on this to show if it is a better technique."

Identifying Patients at Risk for Relapse

Several hematologists at the meeting were asked by Medscape Medical News to comment on the findings.

Alessandro Rambaldi, MD, director of hematology and the bone marrow transplant unit at Azienda Hospital Giovanni XXIII in Bergamo, Italy, uses quantitative real-time PCR analysis in his laboratory. He is starting to work with LymphoSIGHT, and mentioned that he is keen to collaborate on trials using his institution's database of clinical and molecular biology. "LymphoSIGHT needs a set of clinical data validated prospectively to investigate its application," he explained.

"LymphoSIGHT looks promising, but at the moment I'm not sure that the sensitivity is as capable of detecting a minute amount of leukemic cells as quantitative real-time PCR, which is what we use," he noted. "The technology is amazing. It is more rapid and reproducible, but far more validation on clinical and laboratory data is needed."

Aaron Logan, MD, PhD, assistant professor at the University of California, San Francisco, noted that the novel technology has "enabled us to identify patients with lymphoid malignancies who are at risk of a relapse earlier than can be done with standard-of-care technologies. This is important because the earlier we can predict a relapse, the better chance we have of successfully treating a patient."

David Miklos, MD, assistant professor of bone marrow transplantation at the Stanford University School of Medicine in California, pointed out that with the LymphoSIGHT platform, it is not necessary to develop a unique assay for each patient. "That is the real power of this system. Also, compared with flow cytometry, which is expensive and laborious, this platform is bioinformatically driven. In addition, the cost is dropping because it is only limited by the availability of technology, which is changing by the hour," he said.

"This is the future. It is a question of how quickly we can validate it and get it in place," he explained.

Dr. Miklos briefly described a study his team conducted on cryopreserved blood samples, which had been collected from consenting patients with CLL in 2005 (Leukemia. Published online February 19, 2013). These samples had well-characterized clinical outcomes. "We applied the technology to these samples and then we analyzed the measurements with algorithms to determine the clinical utility."

The study involved 42 patients with CLL with samples collected prospectively up to 3 years after allogeneic hematopoietic cell transplantation (allo-HCT). Using the LymphoSIGHT technology, the team measured the relative number of cancer cells of a clone and of a range of clones in more than 400 samples. They then related these to clinical outcomes extending 4 years after allo-HCT. "One year after transplant, if there is any detectable CLL clone, then the patient will relapse. This provides a pre-emptive means of preventing relapse." These findings suggest that MRD could provide information on patient eligibility for transplantation, he noted.

Dr. Stock, Dr. Rambaldi, Dr. Miklos, and Dr. Logan have disclosed no relevant financial relationships.

18th Congress of the European Hematology Association (EHA): Abstract S537. Presented June 15, 2013.

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