Routine Monitoring for MRD in Leukemia? It's Coming

Megan Brooks

August 01, 2013

Results from a decade-long study "clearly" support the monitoring of minimal residual disease (MRD) in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), according to researchers from the University of Texas M.D. Anderson Cancer Center in Houston.

The study found that the detection of MRD with multiparameter flow cytometry and real-time quantitative polymerase chain reaction (qPCR) is an important predictor of outcome in this patient population.

These 2 techniques can be used to identify patients in first complete remission who would benefit from treatment intensification, the researchers say.

The study was published online July 9 in Blood.

Dr. Farhad Ravandi

Could MRD monitoring become standard? "Yes definitely," lead researcher Farhad Ravandi, MD, told Medscape Medical News.

"Many European centers already use MRD extensively to decide on intensification or alteration of therapy in patients with Ph-negative ALL," he said. "I think this will become even more important in Ph-positive ALL, because it can save some patients the potential toxicity of transplant, which is currently considered to be standard strategy in first remission."

Sparing Patients From Toxicity

One quarter to one third of adult patients with ALL have Ph-positive ALL, which is a rapidly progressing form of the disease caused by a reciprocal translocation between chromosomes 9 and 22, leading to the expression of the oncogenic protein BCR-ABL. After first complete remission, most patients undergo allogeneic stem cell transplantation, which has harsh adverse effects and is not always available.

With the introduction of tyrosine kinase inhibitors (TKI), which target BCR-ABL, the outcome of patients with Ph-positive ALL has improved significantly, leading some to question whether allogeneic stem cell transplantation is necessary in all patients, Dr. Ravandi and colleagues note.

The arrival of TKIs "marked the beginning of an exciting era in which we can begin considering alternative preventive cancer treatments and look to spare patients from the risk of toxicities that often accompany stem cell transplants," Dr. Ravandi added in a statement.

"Now that we know that these drugs are effective, we can take the next step and focus on studying lingering disease in Ph-positive ALL patients to guide more effective treatments and ultimately predict and manage possible relapse," he explained.

In their study, Dr. Ravandi and colleagues did just that. Between 2001 and 2011, they monitored 76 adults (average age, 54 years) with Ph-positive ALL who achieved complete remission with standard chemotherapy plus a TKI (dasatinib or imatinib) and received 2 years of TKI maintenance therapy.

None of the patients had undergone allogeneic stem cell transplantation, nor were they at an otherwise heightened risk for relapse. All patients were checked for MRD at the end of induction and at roughly 3-month intervals thereafter.

The researchers found that a major molecular response (BCR-ABL/ABL < 0.1%) and negative results on cytometry at 3 months and beyond were associated with a decreased likelihood of relapse and with longer overall survival.

When used together, cytometry and qPCR could effectively predict the majority of disease progression and patient outcomes in the cohort.

Of the 44 patients who had positive results for MRD with either of the techniques in the first year of therapy, 13 have relapsed. This includes 9 of the 22 high-risk patients who tested positive on cytometry or had less than a major molecular response at 3 months or beyond.

Only 13 of the 54 patients who remained negative on cytometry and had BCR-ABL of 0.1% or less at 3 months and beyond have relapsed. Of these 13 patients, 5 had molecular relapse 1 to 5 months before the morphologic relapse that occurred after 12 months, "further emphasizing the value of continued monitoring," the researchers note.

"Powerful Step Forward"

Peter Emanuel, MD, chair of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences in Little Rock, who wasn't involved in the study, agrees that MRD monitoring could become standard operating procedure.

"We don't want to have to do an allogeneic stem cell transplant on someone who is going to do okay without it because it's a very toxic treatment. Research like this is trying to identify [the subgroup] of patients who may be able to be cured without a transplant, which would be a major step forward," he told Medscape Medical News.

Dr. Emanuel, who is also chair of the communications committee at the American Society of Hematology, called the study a "powerful step forward," but said these techniques are "not necessarily ready to use as regular tools for all patients. More study is needed to see whether they can be part of the regular armamentarium for monitoring patients."

Dr. Emanuel noted that this is a single-center study, and the techniques "need to be applied across a multicenter protocol to see if the results can be reproduced."

Dr. Ravandi agrees. "Larger confirmatory studies are needed. Since Ph-positive ALL is a relatively uncommon disease, this would likely need an international effort. One issue of importance is the standardization of methods for detecting MRD, as was done for chronic myeloid leukemia," he told Medscape Medical News.

Another technique for detecting MRD in patients with ALL, known as LymphoSIGHT (lymphocyte sequencing of immunoglobulin and T-cell receptors), is also showing promise. A recent study found that LymphoSIGHT is comparable to more conventional but cumbersome methods of detecting MRD in ALL patients, as reported by Medscape Medical News.

The current study was supported by research funding from Bristol Myers Squibb. Dr. Ravandi reports receiving research funding and honoraria from Bristol Myers Squibb and honoraria from Novartis. Dr. Emanuel has disclosed no relevant financial relationships.

Blood. Published online July 9, 2013. Abstract

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