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New Tests for Minimal Residual Disease Signal Growing Importance of Prognostic Tools in Leukemia

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This article has been updated with additional details about the ClonoSIGHT test and to clarify that Sequenta is in discussions with the FDA to transition the diagnostic from a lab test to a kit.

Increasingly sensitive diagnostics that can help researchers and healthcare providers track leukemia patients who have achieved remission and those who are relapsing after treatment are becoming an important tool in the treatment of these illnesses and the development of new drugs.

Recently, two entities announced efforts to incorporate novel diagnostics to determine minimal residual disease in patients participating in research. Minimal residual disease is the stage after treatment when patients have small amounts of leukemia cells or no evidence of cancer in their blood or bone marrow.

This week Sequenta announced that the Dana-Farber Cancer Institute/Acute Lymphoblastic Leukemia Consortium will use ClonoSIGHT, its sequencing-based test to gauge minimal residual disease in children with ALL. A few days before this announcement, Novartis said that it is working with MolecularMD to develop a quantitative real-time PCR-based research assay to identify Philadelphia-chromosome positive chronic myeloid leukemia patients who have achieved durable minimal residual disease status after treatment with its drug Tasigna (nilotinib).

"The measurement of minimal residual disease has proven over and over again to be the most important prognostic factor in patients being treated for lymphoid cancers, [or] … cancers of immune cells," Sequenta CEO Tom Willis told PGx Reporter.

Sequenta's ClonoSIGHT uses Illumina's MiSeq platform to sequence the immune cells in a leukemia patient's blood or bone marrow sample. The test can detect if any cancer-linked sequences are present and if they are present at very low levels (one cell per million). When immune cells encounter a foreign invader, they mutate their genome to confront it and produce the necessary antibodies. This antibody sequence is unique to the immune cell that makes it. "So, we're harnessing the power of next-generation sequencing to measure these very specific sequences, which are associated in the case of leukemias and lymphomas with cancer," Willis explained.

In adopting ClonoSIGHT, researchers at Dana-Farber and the ALL Consortium are moving to a faster and more sensitive platform for assessing relapse and remission in the children with ALL they treat. Currently they use allele-specific oligonucleotide PCR, which detects residual disease in one cell in 100,000, and takes several weeks to report results since an assay must be generated for each patient. Sequenta claims turnaround times of around a week.

"There are some kids that are not successfully monitored" using the PCR method, Willis said. "What we've shown in previous presentations with our data that we've generated with the Dana-Farber group is that with our technology we can get answers for minimal residual disease that their [standard] assay couldn't."

Formed in 1981, the Dana-Farber/ALL Consortium aims to research treatments for children with the disease. Through this consortium, clinicians have advanced standardized treatment protocols that have significantly improved the survival of children with ALL. The consortium decided to use ClonoSIGHT to improve researchers' ability to pinpoint which children have a higher risk of relapse based on their minimal residual disease levels. The higher the minimal residual disease level after initial treatment, the higher the child's risk of relapse, and the greater the need for more intense treatment compared to a child with low minimal residual disease.

"After induction therapy to try to cure their disease, one can assess using minimal residual disease detection methods whether those patients have achieved really deep remission or if they still have residual disease in the marrow," Willis said. "Based on that measurement, care is intensified for those children [who] have residual disease, because we know that the prognoses is much worse for minimal residual disease-positive patients." Children who respond well to therapy can often lead long, disease-free, healthy lives.

"The small part we're playing is to help make that minimal residual disease measurement a little better," Willis said. Researchers will use both Sequenta's ClonoSIGHT and the PCR test during a validation period, reflexing to ClonoSIGHT for cases that the PCR test fails to deliver results. Ultimately, the consortium will transition all minimal residual disease testing onto ClonoSIGHT, according to Sequenta.

In childhood ALL, approximately 20 percent of patients achieve minimal residual disease after their first round of treatment as measured by flow cytometry, and about the same proportion are identified by allele-specific oligonucleotide PCR. Approximately 50 percent of patients who relapse are deemed minimal residual disease-negative by flow cytometry. Sequenta is currently researching if the increased sensitivity of its test identifies more patients with minimal residual disease than standard technologies and if this leads to an improvement in outcomes.

While ClonoSIGHT addresses the management of patients with minimal residual disease with the majority of immune cell cancers, it is not intended for the subset of patients with Philadelphia chromosome-positive leukemias. The Philadelphia chromosome – a translocation between chromosomes 9 and 22 – characterizes 95 percent of CML, 25 percent of ALL, and in rare cases, some acute myeloid leukemia patients.

"The CML patients are descended from a different kind of immune cell than the [other] leukemias and lymphomas are, and so we cannot apply our technology to CML," Willis explained. "So, it's really a complementary technology. The BCR-ABL tests work really well in CML but not in the rest of the lymphoid cancers, and our test can assay the rest of the diseases, but not very well in CML."

In parallel to Sequenta's efforts, there are collaborations underway to improve methods of tracking minimal residual disease in patients with Ph-positive leukemias, particularly CML. "For CML, luckily enough for the purposes of measuring minimal residual disease, you have a very specific characteristic translocation," Willis said. "So, you can measure that one chromosomal change and measure the disease very sensitively and specifically. But that's only a few thousand patients a year that have CML. There are hundreds of thousands of patients that have other forms of immune cell cancers … and in those patients you don't have the characteristic single translocation."

The emergence of BCR-ABL testing following the launch of Novartis' Gleevec has laid the groundwork in terms of demonstrating the importance of standard, prognostic tools that can track which patients are relapsing and which are in remission.

Several years ago, noting the variability among labs in monitoring relapse and remission in Ph-positive CML patients receiving its blockbuster agent Gleevec, Novartis announced it would invest in standardizing BCR-ABL transcript monitoring by developing a test with Cepheid. The test, based on Cepheid's PCR-based GeneXpert system, would report results in line with the International Scale – a globally accepted set of guidelines for detecting and reporting BCR-ABL transcript levels. Standardization of BCR-ABL transcript monitoring, experts believe, will improve doctors' ability to manage patients, gauge when they become refractory to treatment, when they're relapsing, and when they're in remission.

Cepheid launched an updated version of its GeneXpert test for BCR-ABL monitoring in mid-2012, which reports results in two hours. The test is standardized to the International Scale. Novartis and Cepheid had previously said they would try to garner FDA approval for a standardized BCR-ABL monitoring test, but this hasn't happened yet. The status of this collaboration is currently unknown, as Cepheid did not respond to interview requests for this article.

Meanwhile, Novartis is continuing to explore diagnostics to improve management of leukemia patients who are receiving its drugs. Last week, it announced it would work with MolecularMD to develop a test that can gauge very low BCR-ABL levels and track whether patients remain in "deep remission" following Tasigna treatment or if they are relapsing. Tasigna is Novartis' next-generation Ph-positive CML treatment, slated to take Gleevec's place when it loses market exclusivity.

Novartis will use MolecularMD's PCR test in a single-arm trial investigating whether CML patients who are in so-called treatment-free remission – with minimal residual disease as defined by BCR-ABL levels less than or equal to 0.0032 percent – can stop taking Tasigna. Once patients are in remission and stop Tasigna therapy, they will be monitored in the trial by MolecularMD's assay to determine if they have remained in remission or if they relapsed and need therapy again.

"Stopping treatment is not a clinical recommendation and should only be attempted in the context of a well-conducted clinical study," MolecularMD said in a statement. A MolecularMD spokesperson noted that tracking minimal residual disease in CML patients requires a very sensitive assay that can pick up very low BCR-ABL transcripts levels, but would not comment further. Novartis declined to answer questions for this article.

Advances in prognostic tests in leukemia are coming as health regulators are considering minimal residual disease as a potential surrogate endpoint that can speed development of novel treatments. In recent years, the FDA has held a number of public workshops to explore the types of tools and standards that will be needed to use minimal residual disease measurements as a surrogate endpoint in drug development trials.

Following the approval of Gleevec in 2001 based on how well the drug improved patient outcomes, measurements of BCR-ABL transcript levels came to define response rates and the efficacy of follow-on drugs, such as Tasigna. "We think of [ClonoSIGHT] as lying at the center of a fundamental change in the clinical care paradigm … in the way that BCR-ABL has changed the paradigm for CML, in which patients can be monitored routinely at very sensitive levels, [and] different therapies can be applied at points of the patients' disease course at very low levels of disease that are more treatable than relapses," Willis said. "That kind of paradigm is what we're bringing to the rest of leukemias and lymphomas."

More sensitive tests for gauging minimal residual disease can also help drug developers run efficient drug trials for leukemia patients, he added. In many cases, leukemia patients live disease-free for many years on the standard of care before progressing and needing a new drug. "For a drug developer this is a challenge because to show superiority over the standard of care, if you want to see if patients will live longer progression-free, you have to wait quite a long time," Willis noted. "It becomes an expensive proposition to run a clinical trial for that long."

But with the help of more sensitive tests like ClonoSIGHT, which can measure more quickly whether patients' disease levels are being impacted by certain drugs, pharmaceutical firms can have clearer insights on how to advance new agents in studies, he added. "The hope is that by working with the FDA, these kinds of tests can be adopted as [tools to measure] surrogate endpoints and shorten the time to approval" for new drugs, Willis said.

Currently, there are no FDA-green lighted tests for measuring minimal residual disease in leukemia patients. While Sequenta is currently performing ClonoSIGHT as a lab developed test, the recent clearance of Illumina's MiSeqDx platform offers a clearer path for garnering the agency's nod for an NGS-based test, according to Willis.

"The kinds of analytes we are measuring are easier to imagine making into an FDA-approvable test given that we're measuring a digital readout of DNA sequencing, we're counting molecules, and the data can be interpreted without any user intervention and purely algorithmically to produce levels of minimal residual disease," he said.

Sequenta has begun discussions with the agency about transitioning ClonoSIGHT from a lab test to a kit. "If we were to sell the test as an IVD kit we would need to go through an approval process," Willis said. "We have discussed this with the FDA."

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