On the Lookout for Minimal Residual Disease in CML

When Michael Ray went to his doctor for an annual checkup two years ago, he felt fine. But the bloodwork results of the Boston-area native now living in Naples, Florida, told a different tale.

“My white blood cell count was a little high,” says Ray, now 48. “And just through testing, my doctor eventually said, ‘I think we should test you for leukemia.’ I was shocked. I had no idea. I didn’t even really know what leukemia was at the time.”

A bone marrow biopsy later confirmed that Ray had chronic myeloid leukemia (CML).

“The first three months were difficult, very difficult,” Ray says. “I mean, you just have a lot of questions: ‘Why me?’ ‘How did this happen?’ ‘How could this be true?’

“I think (it’s) pretty much what most people probably go through when they get a cancer diagnosis.”

“And then, after the first three months, when you have your first big test — the BCR-ABL test (which quantifies the amount of residual leukemia remaining) — and you see that the medication’s working, you start to feel better,” Ray says. “You start to realize that it’s not a death sentence.”

Ray is a patient of Sylvester Comprehensive Cancer Center, part of UHealth, University of Miami Health System, where the chief of the division of hematology, Dr. Mikkael A. Sekeres, explains that the BCR-ABL test that gave Ray some peace of mind has been established for decades as the standard means of determining minimal residual disease status in patients with CML.

Minimal residual disease, also referred to as measurable residual disease or MRD, is an assessment of malignant cells remaining in the patient’s body following treatment.

“When we do a bone marrow biopsy on somebody for leukemia, we give that bone marrow sample to a pathologist who then looks at it under a microscope … and leukemia cells can be apparent to the eye or they can become more apparent when a pathologist adds markers, dyes, to the bone marrow,” Sekeres explained. “So, they’re looking in a field in a microscope for abnormal cells.

“But what if you can look for cells that may look on the outside as normal, but inside they actually have the abnormality that’s going to cause cancer? And that’s when we start to look (at) the genetics of those cells for minimal residual disease. Or, instead of relying on a pathologist’s eyes to look at a bone marrow sample, we’re putting the blood through a machine called flow cytometry and we’re allowing the machine to detect very small amounts of those cells that are still left over, that may not be apparent to a pathologist looking at a bone marrow sample or a blood sample.”

CML has long been a target of MRD due to its specific genetic abnormality, commonly referred to as the Philadelphia chromosome, two chromosome pieces fused together forming the BCR-ABL mutation, which drives the development of CML.

“When the drugs that we now use as standard procedure were introduced into CML and the first of those drugs, Gleevec (imatinib), was approved in 2001, soon after people realized that a decrease in the amount of BCR-ABL that was detected was associated with people who had better responses to the drug and were less likely to have their disease get worse,” Sekeres said. “So, we’ve been using BCR-ABL as a minimal residual disease (indicator) now for 20 years.”

Ray, who describes Gleevec as “a miracle drug,” says his time between BCR-ABL tests is still stressful.

“About a week out before the testing, I start to get really nervous, (I have a) hard time sleeping, I just start to get really scared that the other shoe is going to drop, let’s say. You’re going along good, you feel good and everything, but you don’t know if the numbers are going to be good or not,” Ray says.

Increased Chance of Cure?

Although MRD assessments have been more developed for some types of cancers than others over the past couple of decades, experts are optimistic regarding further advancements.

“These are really the future for guiding the very best therapies,” says Dr. Michael Pulsipher, division chief of pediatric hematology at Intermountain Primary Children’s Hospital and Oncology, director of the Children’s and Adolescent Cancer Initiative at Huntsman Cancer Institute and a presidential chair in pediatric oncology and hematology at the University of Utah. “Over and over again, we’ve seen examples of how MRD is the best predictor for outcome and (how) it can help us know when to increase or decrease therapies.

“So, in the future, I see this, as our testing gets more sophisticated, (as) being really the best way to … tailor what needs to be given to a given patient. So, in the future, more and more diseases will be having these type of minimal residual disease responses or cell-free DNA assessments to see whether we’re treating (patients) the way we should.”

By studying blood or bone marrow cells via tests such as flow cytometry and next-generation sequencing, MRD assessments for types of leukemia and lymphoma can “detect one leukemia cell among 10,000 to 1 million normal cells,” according to Dr. William Wierda, section chief for chronic lymphocytic leukemia in the department of leukemia, division of cancer medicine at The University of Texas MD Anderson Cancer Center in Houston.

Wierda, also the coauthor of the 2021 chronic lymphocytic leukemia recommendations published in Nature, explained via email that MRD “is a way to assess or measure the depth of remission achieved with treatment. If the number of leukemia cells is below the limit of detection, patients are said to have achieved undetectable MRD status. Undetectable MRD status is correlated with longer remission and survival following treatment.”

MRD results can be of great help to patients whether they are positive or negative, Pulsipher explains.

“It won’t necessarily ease (the patient’s) mind, but it will increase their chance of cure,” Pulsipher says.

Patients with acute lymphoblastic leukemia (ALL), Pulsipher says, who display an “exceptional response” to treatment and are MRD negative after a month of treatment, “have such a good prognosis that it’s predicted that 98% of the time, they will be cured. … It doesn’t mean you don’t have to take your two years of therapy, because you do. What it does mean is that your chance of cure is exceptionally high.”

Patients who are MRD-positive, on the other hand, are categorized as high risk.

“Is your outcome terribly worse? No, but your treatment is more intense,” Pulsipher says. “But the patient shouldn’t feel terrible about that. They should feel relieved that, ‘Oh, good, they know that I have to have this extra therapy, but my chance of survival with the extra therapy is still really good.’ ”

A “worst-case scenario,” according to Pulsipher, is when a patient considered MRD positive and high risk is still showing a high MRD value following a second month of treatment.

“There’s just no getting around it; that’s going to be bad news to a patient. They’re going to feel like they failed. But in reality, they haven’t failed,” Pulsipher says. “They … may never have gotten into good remission and may never have gotten curative therapy, but now that we know that they are (in) the 5% that are very high risk, and we get them to either transplant or CAR-T (cell therapy) or both early, that improves their chance of cure.

“So, if someone can have Zen and can say, ‘It’s OK if I get news from my MRD that I need more intensive therapy because it’s maximizing my chance of cure,’ then you’ll be OK.”

‘Give MRD Time’

Dr. Andy Rawstron, clinical scientist at the Hematological Malignancy Diagnostic Service in Leeds, England, stated in June at the European Hematology Association (EHA) 2023 Congress that MRD is “one of the strongest predictors of what’s likely to happen in the next few years” for patients with chronic lymphocytic leukemia, but it is not without its predictive limitations.

“You’ve got to give MRD time,” Rawstron said. “It’s not an early predictor of outcome unless you look just at the very high levels. You’re using MRD to say what’s going to happen five, 10 years ahead.”

Appearing at EHA, Rawstron’s final slide made his position clear: “Is MRD assessment necessary? Not in routine clinical practice yet, but MRD is likely to play a central role in developing the treatment of the future.”

Association with Remission and Survival

An investigation into the association of MRD with survival outcomes among patients with acute myeloid leukemia (AML) published in JAMA Oncology found that, in a review of 81 publications studying more than 11,000 patients, the estimated five-year disease-free survival rate (the time following treatment that a patient lives without signs of cancer) was 64% for patients who were MRD negative — more than double that of the 25% rate for MRD-positive patients. Likewise, the estimated overall survival rate (the time that a patient is still alive following treatment) was 68% for MRD-negative patients and 34% for those who were MRD positive.

According to Wierda, there is no debate regarding the association between undetectable MRD status following treatment and longer remission and survival.

“There is no trial that has shown that treatment should be continued until undetectable MRD status is achieved, so community providers do not use it for this purpose but can use MRD assessment at end of treatment to understand the depth of remission for a patient and if a long remission duration can be expected based on this test result,” Wierda says.

The Nature paper co-written by a team including Wierda and Rawstron stated that, at the time, there was “no clear role for MRD assessment” in routine practice. In the past two years, that has changed — to a point.

“The current data for MRD (support) doing the test at the end of fixed-duration treatment, which would be (Venclexta [venetoclax])- based or chemoimmunotherapy-based treatment, to assess the depth of remission,” Wierda says. “There (are) no data to use this information to support extending the treatment to achieve undetectable MRD status. So, (the data are) not used to make any treatment decisions, only to understand depth of remission.”

‘There Isn’t Standardization’

Wierda says that there are several ongoing trials evaluating the use of MRD in treatment, related to topics such as duration of treatment and changes to treatment if undetectable MRD status is not achieved. MRD, Wierda says, “is also an important test when evaluating new treatments for curative potential, since undetectable MRD status must be achieved if we are aiming at developing curative treatments.”

However, some debate remains in the field — particularly, according to Sekeres, regarding the best way of assessing MRD, and standardization of that assessment.

“One lab assessing minimal residual disease may disagree with another lab that’s looking for the same abnormality,” Sekeres says. “And that’s the trick with it — that there isn’t standardization across labs of how they measure minimal residual disease and how they define that.”

A team of researchers in a study in the journal Frontiers in Oncology said MRD assessment has been “transformational in the landscape of CLL clinical trial design and reporting. With an increasing number of MRD-directed end points, the next challenge is how MRD assessment will be integrated into routine clinical practice, which will also require evaluation from both patient benefit and health economic perspectives.”

However, the researchers also noted that it “remains to be demonstrated that deeper MRD necessarily predicts a better clinical outcome in all clinical situations. At present, MRD has been linked to disease prognosis and used to tailor treatment duration, but it remains to be demonstrated whether MRD-driven therapeutic decisions will always be clinically beneficial or sufficient to challenge the traditional CLL treatment paradigms.”

‘I Have to Put Faith in That’

Sue D’Agostino, a two-time breast cancer survivor, was caught off guard when, in 2020, the discovery of enlarged lymph nodes during her annual mammogram led to her receiving a diagnosis of CLL.

Sue D’Agostino has her bloodwork checked every three months and trusts her MRD test results. “I have to put faith in that,” she says.

Photo credit: Andrew Jordan

“Of course, I first turned to Dr. Google, who told me I was dying,” D’Agostino, a 63-year-old native of Akron, Ohio, says. “And so, I don’t recommend that for anybody.”

D’Agostino then joined a Facebook support group for patients with CLL where, she says, she “got a little bit more confidence that it’s not curable, but it’s manageable. So, I thought, ‘I can do this.’ ”

Following the advice of the Facebook group, she connected with a CLL specialist who discovered via biopsy that D’Agostino had CLL in 90% of her bone marrow and then referred her to a clinical trial.

During the trial, D’Agostino received three rounds of infusions of the chemotherapy bendamustine and the monoclonal antibody Rituxan (rituximab), after which her CLL had plummeted to 2% of her bone marrow in just three months. She then moved on to the next phase of the trial: targeted treatment with Venclexta (venetoclax), along with six additional treatments of Rituxan, with a blood sample sent to the Mayo Clinic for MRD testing.

“My first one came back and (it) was April of (2021), and they said I was MRD negative,” D’Agostino says. “So, they test one in 10,000 and 100,000 cells and I was in complete remission in my blood.” A September 2021 biopsy found that she was also in remission in her bone marrow.

D’Agostino still has her bloodwork checked every three months and trusts her MRD results.

“I have to put faith in that, because that’s all I have,” she says. “And I haven’t seen anywhere that anybody has said that the MRD is not like the gold standard to tell you where your cell count is. “So, at this point, because that is to me the gold standard, I don’t doubt it. I firmly believe in it. I mean, we don’t have anything else.”

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