Evolution of Treatment for a Rare Type of Leukemia

Medical Author: Michael Lill, MD
Medical Editor: Leslie J. Schoenfield, MD, PhD
Medical Revising Editor: Melissa Conrad Stöppler, MD

One of my more vivid memories from the early days of my training in hematology (blood diseases) in Perth, Australia is of the tragedy of a young girl with acute promyelocytic leukemia (APL). This disease is a very serious, rare type of acute leukemia (cancer of the white blood cells). I admitted her to our oncology (cancer) floor in the hospital. A teenager, she had been completely well until one Sunday when she developed unusually heavy menstrual bleeding. She saw her doctor in her small country town on Monday, had a blood count done on Tuesday, and was flown up to us in Perth on Wednesday with a diagnosis of acute (rapid onset) leukemia. The next day, we performed a biopsy (removal of a tissue sample) of the bone marrow (where blood cells are made) that enabled us to confirm the diagnosis. We immediately started chemotherapy (medications that kill cancer cells) but that night she bled into her brain. Despite intensive medical efforts, including brain surgery, she died the next morning.

What a rapid course and horrible outcome! You can see why this patient has remained vivid in my memory for the past 15 years. Acute promyelocytic leukemia has always been one of the most feared of the acute leukemias. The reason for the fear is that a similar type of bleeding death often occurred during the initial (induction) chemotherapy of this leukemia. Remarkably, however, if these patients survived their induction therapy, many of them were cured by the chemotherapy.

Although its cause is not known, APL had been associated for many years with a specific chromosomal abnormality, referred to as a chromosomal translocation. Situated in the nucleus of all cells, the chromosomes carry the genes, which produce the proteins that determine an individual's characteristics. At the time that I was treating this poor girl, the significance of that chromosomal translocation was not known. Some years later, however, while I was doing additional training in hematology at UCLA and working in a molecular biology laboratory that focused on genes, I attended an international scientific convention. At that meeting, three different research groups from three different locations in the world reported simultaneously that they had identified the genes that were involved in that particular chromosomal translocation associated with acute promyelocytic leukemia.

One of these genes involved in the translocation was known to code for (that is, to determine) a receptor (cell binder) for retinoic acid, a compound related to vitamin A. This information was very interesting. You see, several years previously, a Chinese group of investigators had described in acute promyelocytic leukemia, a miraculously high rate of complete remission (disappearance of abnormalities) brought about by a compound called all-trans retinoic acid (ATRA). They used no chemotherapy, only the all-trans retinoic acid. The thing about this compound is that it binds to the receptor that is coded by the aforementioned gene and is more akin to vitamins than to classical chemotherapeutic agents. This discovery of the activity of ATRA in the treatment of acute promyelocytic leukemia has revolutionized the outcome for these patients. In fact, this disease is now excluded from most clinical trials of chemotherapy for leukemia because the results are so good with all-trans retinoic acid.

I also clearly remember the first patient that I treated with all-trans retinoic acid. This patient was a young woman who developed acute promyelocytic leukemia while pregnant. She soon lost her baby because of this disease. She received chemotherapy but failed to undergo a remission. When she was transferred to our care, she had an aggressive acute leukemia with no functioning white blood cells left. What's more, she had active infections in her abdomen and uterus, and progressive failure of her liver and lungs. We were unable to give her any more chemotherapy because that would worsen her infections. So, we treated her initially with all-trans retinoic acid.

Ultimately, in contrast to the first patient I described, after several months in the hospital, this young lady improved and was able to be discharged. Fortunately, she did not experience this drug's potentially life-threatening side effect involving the lungs, which can occur in up to 40% of patients. Subsequently, she received repeated cycles of chemotherapy (consolidation chemotherapy) and additional all-trans retinoic acid. The happy news is that, as a direct result of this revolution in the treatment of leukemia, this young lady is now cured of acute promyelocytic leukemia and has been able to get pregnant and have another child.

It turns out, however, that some people with APL, despite treatment with all-trans retinoic acid and chemotherapy resulting in a remission, subsequently experienced a relapse (return of the signs and symptoms) of the disease. The ways (mechanisms) by which the leukemia escapes from control by the ATRA remain unclear. Moreover, the treatment options for these relapsed patients had been grim. Once again, however, help came from Chinese medicine. This time, studies of ancient Chinese medicines led to the recognition of a new compound (rather, an old compound with a new look) that had striking activity in the treatment of acute promyelocytic leukemia.

This compound was arsenic trioxide, which, as you know, is associated in most people's minds with a poison. Actually, the way arsenic works in treating this leukemia is unclear but appears to be different from the way traditional chemotherapy works. Nevertheless, this drug was found to have remarkable activity in the treatment of relapsed acute promyelocytic leukemia that had been unresponsive (refractory) to all-trans retinoic acid. This effectiveness occurred with minimal toxicity, so that people tolerate the drug very well. Accordingly, today, most patients with relapsed promyelocytic leukemia can be brought to a complete remission by treatment with arsenic trioxide. In fact, a number of these patients can even be cured.

In conclusion, acute promyelocytic leukemia, which used to be such a feared disease, currently has two dramatically successful non-chemotherapeutic drugs for its treatment. As a matter of fact, the FDA recently has approved all-trans retinoic acid and arsenic trioxide for the treatment of acute promyelocytic leukemia. Besides that extraordinary benefit, the use of these drugs is informing us about the basic biology of this disease and about novel mechanisms for combating leukemia and other cancers. Additionally, these drugs are being actively investigated for the treatment of other malignancies (different types of cancers). Finally, the profound impact on treatment and the joining of modern molecular biology with ancient Chinese herbal medicine both make this an especially fascinating story that has had a major impact on me personally and on my practice.


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