Minimal Residual Disease - Background: The Problem of Minimal Residual Disease (MRD)

Background: The Problem of Minimal Residual Disease (MRD)

Most research on MRD has been done on leukaemia, particularly two types: adult chronic myeloid leukemia, and childhood acute lymphoblastic leukemia (the commonest childhood cancer).

Leukemia is a cancer of white blood cells, and primarily affects bone marrow. For most human leukemias, the cause is not known. Risk factors can include chemicals and X-rays.

Leukemia involves a genetic abnormality that can begin in a single cell and then multiply rapidly, leading to a disruption in the proportion of cell types in the blood. When a bone marrow sample is drawn, leukemic cells can be viewed under a microscope. Leukemic cells look like normal immature blood cells, and healthy marrow is often 1–2% immature ('blast') cells. However, in leukaemia, there are abnormally high numbers of immature cells, making up 40–90% of marrow. Additional examination of the bone marrow by tests including flow cytometry and FISH is necessary to diagnose the specific malignancy.

Symptoms do not occur until the disease is advanced, and there are 1 kg or 1,000,000,000,000 leukemic cells in the body.

The initial five weeks of treatment kill most leukaemic cells, and the marrow begins to recover. Immature white blood cells may be present in the patient, although they are not necessarily malignant cells. In most cases, a few leukemic cells (approximately 0.001%) survive this treatment, and persist in the marrow for months or years. Cancerous cells can be identified by DNA-based or immunological tests, but they can not be identified as cancerous when viewed under a microscope.

About 30 years ago, leukemia was universally fatal. Patients were treated for a few weeks (rather than months or years as at present), producing remission, but nearly all patients relapsed after a few weeks or months. It is now known that minimal residual disease can regrow once treatment was stopped. Genetic tests can confirm the leukemic cells at relapse are descendants of those present when the disease first appeared.

Doctors aim to prevent relapse from occurring. Currently, most children do not relapse – the disease is "cured" at first attempt. If the disease relapses, it is usually more resistant to treatment than when first diagnosed. Patients who have relapsed once are at high risk of relapse in the future, and they may not respond as well to drugs they received in the past.

Tests which uncover minimal residual disease (one cancerous cell in a population of one million normal cells) are helpful for directing treatment and preventing relapse. A single remaining leukemic cell can be fatal, as malignant cells divide without control. Conditioning regimens can continue as long as the patient is healthy enough to sustain damage by cytotoxic treatments.

Most research on MRD was done on leukemia and lymphomas. Researchers hope that the discoveries made can be applied to understand and treat other cancers.

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