Carlson, Robert H.
NEW YORK—With combination treatments incorporating novel agents now standard for chronic lymphoid leukemia and multiple myeloma, highly sensitive polymerase chain reaction and flow-cytometry assays are showing that minimal residual disease can be eradicated (MRD-negativity) with or without transplantation. The clinical significance of MRD-negativity, though, in terms of informing therapy, continuing maintenance, and ultimately on patient outcome, has yet to be determined.
Patients who stay in remission longer tend to have longer survival; but it may be that MRD negativity is simply a marker for patients who will have inherently better prognosis.
Four speakers here at the Lymphoma & Myeloma International Congress were asked informally for their opinion of the importance of MRD negativity. (Note: MRD negativity is often called simply MRD.)
Neil E. Kay, MD, Professor of Medicine at the Mayo Clinic, said that “whatever treatment approaches are used, if CLL patients can get to MRD status using sensitive 4-color flow cytometry, they will very likely have a much longer duration of response.”
He said that four-color flow cytometry developed by the European Research Infrastructure Consortium (ERIC) and others convincingly shows that if a CLL patient's total tumor burden in the blood or marrow is less than 10-5 at the time of complete remission, then those patients are going to do much better than those who are in the same level of remission but still have detectable disease.
What's important now, he said, is to develop more convincing clinical trial data to convince the Food and Drug Administration that the use of MRD should be incorporated in CLL trials. The hope would be that this would be a surrogate for both progression-free survival and overall survival data that, for CLL patients, now takes a very long time to prove by clinical trials.
“Right now, we conventionally use clinical trial data for progression-free survival and overall survival estimates, but you'd have to be immortal to use those in routine trials. But if you could substitute MRD as a surrogate for progression-free or overall survival you could shorten clinical trials, test the promising new drugs more quickly, and then if they are effective, bring them to the patient in a reasonable time frame.”
Susan O'Brien, MD, Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, said that in the past complete response rates in CLL were so low that there wasn't any point in talking about MRD negativity. “But now that we are getting moderately good rates it becomes a more realistic target, and we're just starting to use it to identify patients who might benefit from further strategies such as consolidation or maintenance.”
Less sanguine about the value of MRD negativity was Richard R. Furman, MD, Director of the CLL Research Center at New York-Presbyterian Hospital/Weill Cornell Medical Center: “I have a bias that it is of no value,” he said. “What is the value of a prognostic factor after you've given the treatment?
“Knowing how someone did after they've gotten the treatment does not really help you with treatment planning. I think a lot of people intervene on it and that's not appropriate because we don't have the data to support that.”
Furman, who moderated a session here on CLL, said it is important to remember that the MRD data were generated using the FCR regimen, and by looking for it in peripheral blood. “But people are now applying that everywhere and I think that's a mistake, because it has been validated only for FCR, at two months after the completion of therapy. So looking at MRD status in someone a year out doesn't tell you anything, and looking at MRD status at the end of treatment doesn't tell you anything, because there is enough rituximab there to suppress the clone, and other factors that might give you a false positive or negative result.”
The new tyrosine kinase inhibitors cause preferential lymphocytosis by interfering with adhesion molecules that hold the cells in the lymph nodes and in the different niches, he continued. “If you take someone with a large amount of lymphadenopathy and a white count of 40,000 and give them ibrutinib, you can get the white count going up to 200,000, just because of the compartmental shift between the lymph node and the peripheral blood. I wouldn't be surprised if you took people who are MRD negative, give them the tyrosine kinase inhibitor, and they would become MRD positive.
“So I believe that MRD status will have lost its predictability and its importance when we deal with these tyrosine kinase inhibitors.”
The conference's Chairman, Morton Coleman, MD, Clinical Professor of Medicine and Director of the Center for Lymphoma and Myeloma at New York Presbyterian Hospital-Weill Cornell Medical Center, said that patients with chronic lymphocytic leukemia who reach MRD negativity stay in remission longer, sometimes for extended periods. “In fact, a molecular remission for hematologic malignancies is a prerequisite, but is by no means a guarantee, of cure, the elusive target we aim for in CLL but have yet to achieve for almost all patients.
“MDR, though, may simply be an expensive marker in CLL for people who would inherently have fared better regardless of our ability to achieve this goal. Until we show that the attempt to achieve MDR increases the survival of the group as a whole, we can't be absolutely sure. Nevertheless, I myself do consider it a worthy goal in my patients.”
Coleman said that with the advent of new agents, particularly the TKIs and IMiDs, either with or without chemotherapy and monoclonal antibody therapy, MDR will be achieved with increasing frequency.
“We are entering a whole new era in CLL treatment,” he said.