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Reprinted from St. Jude Rounds, a St. Jude newsletter for physicians.
Measurement of minimal residual disease is the key
Almost all children who are treated for acute lymphocytic leukemia (ALL) enter complete remission. However, nearly one fourth of these patients subsequently experience relapse and have a poor prognosis. Many relapses may be preventable if at-risk patients can be identified early and given more intensive therapy. St. Jude physician-researcher Dario Campana and his colleagues have developed a test that sensitively monitors each patient’s response to treatment and gauges the risk of impending relapse. St. Jude is the first institution to use the measurement of minimal residual disease to guide therapy on front-line leukemia protocols. We talked with Campana and with hematologist-oncologist Torrey Sandlund about this exciting advance in leukemia treatment.
Q: What is minimal residual disease?
A: It’s the presence of leukemic cells in numbers so small that they can’t be detected microscopically. Although microscopic examination of the bone marrow has traditionally been used to identify remission, it can’t detect levels of leukemic infiltration below 1%, or one leukemic cell in 100 normal bone marrow cells. Thus, patients may be in remission by traditional criteria but still have a tumor burden as large as 1010 malignant cells. These patients are said to have minimal residual disease, or MRD.
Q: Why is minimal residual disease important?
A: Until recently, the significance of residual leukemic cells was controversial. However, our research (published in Lancet, 21 Feb, 1998) showed that residual disease is a powerful indicator of the response to therapy and the risk of relapse.
Q: How are residual leukemic cells detected?
A: We use two methods for testing bone marrow samples. One is automated flow cytometry, which distinguishes leukemic cells from normal cells by their combination of cellular antigens. The other method, polymerase chain reaction (PCR), recognizes genetic sequences that are unique to the leukemic cells. Either method can detect a leukemic infiltration as small as 0.01%, or one malignant cell among 10,000 normal cells.
Q: How many patients whose disease is “in remission” have residual leukemia?
A: When we measured MRD at specific points during treatment for ALL, we discovered that almost one fourth of patients had residual disease when they entered clinical remission. The frequency of residual leukemia fell to 17% at week 14 of continuation therapy, then to 5% at week 32 and to zero at week 120, when therapy was complete.
Q: When is residual leukemia clinically significant?
A: In general, the presence of MRD at any point during remission is associated with an increased risk of subsequent relapse, regardless of other prognostic features. The higher the level of MRD, the greater the risk. For example, a high level of MRD at week 14 of continuation therapy has consistently predicted subsequent relapse, despite remission at the time of measurement. MRD that persists is also an ominous sign. Children who have residual leukemia that continues beyond month 6 of continuation therapy have an extremely poor prognosis.
Q: Can MRD studies indicate a good prognosis as well as a poor one?
A: Definitely. Patients who have no residual leukemia at the end of remission induction therapy have a 90% chance of survival without relapse, which is very good news. Even patients who do have MRD at that point have a good chance of staying in remission if the residual leukemia disappears with continued treatment. These patients need ongoing MRD surveillance as treatment progresses, to gauge how well their residual leukemia is responding to therapy.
Q: How is MRD testing being used to guide treatment?
A: At St. Jude, therapy is now being tailored to the risk of relapse predicted by MRD studies. For example, a child may have ALL that is classified as low-risk disease by its features at presentation. However, if the child has residual leukemia at the end of remission induction therapy, the disease is reclassified as higher-risk and a longer, much more intensive course of treatment is given. If residual disease persists after the third month of continuation therapy and there are other very high-risk features, alternative therapies such as bone marrow transplantation are then considered.
Q: Why has MRD testing not been used previously to guide therapy?
A: Although MRD testing has been technically feasible for years, there were two fundamental obstacles to its use in treatment protocols. First, its clinical significance had to be proved, and we have accomplished that. Second, it had to be applicable to all patients with ALL. Flow cytometry can be used for only about 75% of patients, and PCR methods work for about 85% of patients. Once we established that the two methods could be used in tandem to reliably test all patients, MRD assays were ready for clinical use.
Q: Will MRD testing help to improve the cure rate for children with ALL?
A: That is our expectation. The cure rate is now at an all-time high. We should be able to improve it further by using this new understanding of the relationship between residual disease and relapse to adjust therapy as needed and offset the risk of recurrence.
Other potential uses of minimal residual disease testing