NEW DRUGS, NEW ALTERNATIVES: UNDERSTANDING LEUKEMIA

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Otteau Christiansen of Minnetonka, Minnesota, was a 27-year-old television film producer and father of two when, like a bolt from the blue, he learned he had leukemia. His doctors told him he had 6 to 10 weeks left to live. Even with aggressive chemotherapy, they said, his chance of survival was 1 out of 5.

That was in 1983. Today, Christiansen is a successful independent film and video producer who swims, water skis, and goes wilderness camping with his children. He takes no medication and sees his doctor only for routine follow-up. He is cured.

Otteau Christiansen is one of the lucky ones. According to the National Cancer Institute (NCI) and the Leukemia Society of America, about 28,000 Americans will be diagnosed with leukemia in 1992. Fewer than 35 percent of them are likely to be alive in five years.

Survival is strongly linked to age at diagnosis. Physicians are now claiming cure rates of up to 80 percent for some types of childhood leukemia. Adults under 40 probably now have around a 40 to 50 percent chance of long-term survival. But leukemia is most common-and most likely to be fatal-in the elderly.

All forms of leukemia can be treated, and several new drugs have recently been approved by the Food and Drug Administration, while others are being tested in clinical trials. However, leukemia specialists say the best hope of a breakthrough that will significantly increase cure rates lies in understanding and controlling the aberrant molecular processes that lead to development of leukemia.
Not a Single Disease

Leukemia is not a single disease, but a group of malignancies in which the bone marrow and other blood-forming organs produce excessive numbers of white blood cells. The extra cells, which are usually immature or abnormal, suppress the production of normal white blood cells, the function of which is to protect the body against infection.

Malignant cells "take over" the bone marrow and prevent it from producing red blood cells, which transport oxygen around the body, and platelets, which help blood clot. They also invade other organs, such as the liver, spleen, lymph nodes, genitals, and brain.

Leukemias are classified by the type of white blood cell that is proliferating abnormally and by how fast the disease is progressing. Acute leukemia can be fatal in weeks or months without aggressive treatment. Chronic leukemia, progresses more slowly and may be "indolent"-producing no symptoms-for 20 years or longer.

A patient with leukemia may go to the doctor feeling extremely sick, complaining of recur-rent infections, bleeding, bruising, bone tenderness, fever, chills, sweats, weakness, fatigue, headaches, or swelling in the neck, armpits or groin.

On the other hand, the patient may have no symptoms at all and the disease may be discovered by chance from a routine blood test.

A normal blood smear contains many red cells and platelets and a few white cells. In leukemia, the blood usually contains many abnormal white cells and not enough red cells and platelets. Such an abnormal blood count is the physician's first clue that the patient may have leukemia, but it is not sufficient for a diagnosis.

The next step is a bone marrow aspiration and biopsy. Marrow is withdrawn from the body by suction, using a large needle and a syringe, and microscopically examined. This crucial diagnostic test is followed by more laboratory tests to identify what type of leukemia the patient has. A precise diagnosis is important because different types of disease respond to different therapies.

If the diagnosis is chronic leukemia and the patient has no symptoms, treatment may not be required for months or even years. "I have some patients in my clinic who have had chronic lymphocytic leukemia for well over 20 years," said Bruce Cheson, M.D., who heads the medicine section of NCI's cancer therapy evaluation program. "Two patients in particular only required therapy at 23 years and 22 years after diagnosis."

Patients with some types of chronic leukemia may be treated with splenectomy, or surgical removal of the spleen. This organ, located behind the stomach, sometimes becomes enlarged after leukemic cells invade it.
Acute Leukemia

A diagnosis of acute leukemia usually means immediate hospitalization. Patients are given antibiotics, or other appropriate therapy, for infections and other symptoms. Because leukemia patients need frequent transfusions of blood and blood products, they must be treated at medical centers with access to large quantities of such products.

Chemotherapy for acute leukemia involves two phases: an induction phase, in which the patient is aggressively treated with a combination of powerful drugs in an effort to kill all the leukemic cells, and a consolidation phase, using either the same or different drugs, which begins once the disease has gone into remission.

The two main types of acute leukemia are acute lymphocytic leukemia and acute myelogenous leukemia. Currently approved drugs to treat acute lymphocytic leukemia include vincristine (Oncovin), prednisone (Deltasone), asparaginase (Elspar), cyclophosphamide (Cytoxan, Neosar), and cytarabine (Cytosar). Approved drugs for acute myelogenous leukemia include daunorubicin, also called daunomycin (Cerubidine), and cytarabine (Cytosar).

These drugs are cytotoxic, which means they kill not only cancerous cells but also normal cells, particularly in the bone marrow. The patient's immune system-already malfunctioning because of the proliferation of leukemic cells-is completely knocked out, leaving the individual defenseless against bacterial and fungal infections.

"The major period of trouble runs three to five weeks, when the normal blood counts are markedly suppressed," said Peter Quesenberry, M.D., professor of hematology and oncology at the University of Virginia School of Medicine and a medical adviser to the Leukemia Society of America.

"The dominant problems are infections and bleeding. Patients get pneumonia, high fever, and mouth sores. You get a bacterial infection-we treat that. Then you get a fungal infection. Early on, vomiting is a problem, although we do much better at controlling that now."
Remission: Relapse or Cure?

About 50 to 80 percent of patients with acute leukemia achieve remission following an aggressive regimen of induction chemotherapy. Remission, however, is not cure.

"It's a period of stability and return to normal, short of cure," said Edward Henderson, M.D., a medical officer in the division of oncology at FDA's Center for Drug Evaluation and Research. Patients feel better, and their blood and marrow counts return to normal. But doctors know from experience that if treatment stops at this point, the disease will make a comeback in a matter of weeks or monthshence the need for remission maintenance therapy.

Remission maintenance therapy generally continues one to two years. After that, treatment stops. The patient still may not be cured, "but you know from experience that additional treatment is just going to add toxicity and it's not going to add therapeutic value," said Henderson. Sometimes remission maintenance therapy is given at higher doses for a shorter period.

Most patients do eventually relapse, usually within two years. One of the most frustrating aspects of treating leukemia, according to specialists like Cheson and Henderson, is the difficulty of predicting which patients will relapse and which ones won't.

"All cures go through a period of remission, but all remissions don't lead to cure," said Henderson. In leukemia, as in other forms of cancer, cure is usually defined as five or more years of disease-free survival.

There have been no major breakthroughs in chemotherapy for acute leukemia for about 20 years. "It's been an evolution, not a revolution, said Henderson. "The approach has shifted toward more aggressive treatment, backed up by bone marrow transplantation." (See accompanying article.)

Recently, however, some physicians and researchers have become excited about a new compound that appears to be extraordinarily effective at achieving remission in patients with a rare form of acute leukemia called acute promyelocytic leukemia.

The compound is ATRA (all trans retinoic acid), a form of vitamin A. It is currently classified by NCI as a Group C experimental drug, available to physicians only through the institute. Clinical studies in China, France, and most recently the United States have found that ATRA brings about complete remission, with few side effects, in about 80 percent of patients with acute promyelocytic leukemia.

In acute promyelocytic leukemia, immature white blood cells called promyelocytes do not mature normally. Instead, masses of abnormal, immature cells accumulate in the blood and bone marrow and produce chemicals damaging to surrounding tissues. Scientists think ATRA works by inducing these cells to grow normally again.

But for reasons scientists do not yet fully understand, ATRA eventually stops working. "It disappears after a patient has been on it for a while," said Cheson. "You can no longer detect it in the blood, even though the patient is still taking it. We're trying to figure out why that is and how it can be reversed."
New Drugs for Chronic Leukemia

Most of the recent advances in drug therapy for leukemia involve compounds effective against chronic leukemia, particularly chronic lymphocytic leukemia (CLL), the most common form of adult leukemia in the United States. It is a slowly progressing disease that usually affects people over 50.

Treatment for chronic leukemia is generally less aggressive than for acute leukemia and is often given on an outpatient basis. The current standard therapy for CLL is cyclophosphamide or chlorambucil (Leukeran), sometimes in combination with prednisone (Deltasone) or prednisolone (Hydeltra, Pediapred). While these drugs can relieve symptoms, many patients experience significant side effects and eventually stop responding.

Fludarabine (Fludara) was approved by FDA in April 1991 to treat patients who do not respond to other therapies for CLL. In NCI-sponsored clinical trials involving such patients, 32 to 48 percent responded to fludarabine and 13 percent achieved complete remission.

Researchers think fludarabine works by inhibiting reproduction of abnormal lymphocytes, a type of white blood cell. The drug belongs to a unique class of medications known as purine analogues. Purines are nitrogen-based molecules used as building blocks of DNA, the basic genetic material of living organisms.

Another type of chronic leukemia is chronic myelogenous leukemia (CML). Currently approved drugs for CML are busulfan (Myleran) and hydroxyurea (Hydrea).

In January 1992, FDA approved pentostatin (Nipent) for treating patients with a rare form of chronic leukemia called hairy cell leukemia who do not respond to alpha interferon, the standard therapy. In clinical trials, 70 percent of patients taking pentostatin achieved complete, long-term remission. The drug is a derivative of Streptomyces antibioticus, a fungus from which many antibiotics, including tetracycline, are derived.

An experimental drug, 2CDA, has also shown results against hairy cell leukemia, achieving long-term remissions in 80 to 85 percent of patients treated in clinical trials. This drug is currently available under FDA's Treatment IND regulations. (IND stands for investigational new drug.) Under these regulations, desperately ill patients who do not respond to conventional therapy can receive promising experimental drugs before completion of the review needed for full approval.

Last June, FDA's oncologic drug advisory committee recommended that FDA approve 2CDA for the treatment of hairy cell leukemia. At press time, the agency had not reached a decision on the drug's approval.

2CDA is an antimetabolite, one of a group of drugs that prevent cell growth by interfering with essential enzyme reactions. A major difference between 2CDA and pentostatin, said NCI's Cheson, is that a complete course of 2CDA can be given in one week, while treatment with pentostatin extends over a six-month period.

Fludara, Nipent and 2CDA, Cheson said, all have fewer side effects than other drugs currently in use. "There is surprisingly little nausea, vomiting, generally no hair loss, and they are very well tolerated. The biggest side effect is immunosuppression." Suppression of the immune system puts patients at risk for infections.

One curiosity of cancer treatment, observed both Henderson and Cheson, is why breakthroughs tend to occur more often in rarer forms of a disease. Leukemia is no exception: ATRA, Nipent and 2CDA all are targeted to rare forms of leukemia.

"The rare tumors tend to be the ones that respond," said Henderson. "It may be that they are even further differentiated from normal, with special characteristics that make them more susceptible to treatment if you push the right button."

Future progress will be made against all forms of leukemia, Cheson predicted, "when we become smarter than the leukemias.... We need to overcome the various cellular mechanisms of drug resistance." As scientists learn more about the molecular biology of leukemia, he said, they will be able to develop compounds that can halt or reverse cancerous changes at the cellular level.

"Biotechnology is the hope and promise of the future," said Henderson. "If we can identify specific genetic defects, we can then look for ways of correcting those defects. The product of those genes can be switched on or off, or drugs can be given to switch off a signal that shouldn't be given or provide one that's missing.

"It's the most optimistic time for that sort of approach that there's ever been," he said. "I have no real doubts that leukemia will be cured-but whether it will take a few years or a few decades is hard to say."

PHOTO: Otteau Christiansen, who defied his doctor's prediction and survived leukemia, gets ready to waterski near his Minnesota home.

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By Eleanor Hayfield

Eleanor Mayfield is a freelance writer in Silver Spring, Md.

BONE MARROW TRANSPLANTS CONTROVERSIAL

The role of bone marrow transplantation in leukemia therapy remains somewhat controversial. The technique involves first injecting a patient with near-lethal doses of chemotherapeutic drugs and then "rescuing" the patient from the drugs' toxic effects by injecting healthy bone marrow from a matched donor.

Transplantation used to be done almost automatically if a patient had a suitable donor, said Bruce Cheson, M.D., head of the medicine section of the National Cancer Institute's cancer therapy evaluation program.

"Then we realized we were curing people with chemotherapy alone, and some patients were dying from bone marrow transplantation who might have been cured by chemotherapy." Between 5 and 10 percent of patients die of complications of the transplantation procedure.

Other specialists are more positive about the role of bone marrow transplantation. "I've seen very few cures in acute leukemia with just chemotherapy-and we treat aggressively," said Peter Quesenberry, M.D., professor of hematology and oncology at the University of Virginia School of Medicine and a medical adviser to the Leukemia Society of America. "We've finally begun to see cures in our transplant program."

The approach likely to produce the highest percentage of cures is to treat patients with chemotherapy first and transplant those who relapse early, said Edward Henderson, M.D., of the oncology division at FDA's Center for Drug Evaluation and Research.

But transplantation is still considered too risky for patients over 50, and its use in younger patients is limited by a shortage of suitable donors. Traditionally, a tissue-matched sibling has been considered the ideal donor, although recent advances in tissue typing-and in drug treatment to suppress rejection of the transplanted marrow--have permitted transplants of marrow from unrelated donors.

The major complication of bone marrow transplantation is graft versus host disease (GVHD), in which the transplanted marrow cells attack the patient's own immune system. The development of the immunosuppressive drug cyclosporine (Sandimmune) has enabled doctors to control GVHD, said Henderson. But physicians have also learned that patients who suffer mild GVHD do better in the long run than patients who do not experience the complication, he said.

"It's been shown beyond a doubt that if there is no reactivity to the transplanted marrow, the patient is more likely to relapse. We know this because marrow from an identical twin is only about half as effective in long-term disease control than a graft from a non-identical sibling."

The reason is that the identical twin's marrow cells are too similar to the patient's, said Henderson. "It seems that a low level of immunoreactivity is necessary for the graft to mount a suppressive reaction against the leukemic cells surviving the intensive pre-transplantation therapy."

Bone marrow transplantation using marrow donated by another individual is known as allogeneic transplantation. Another approach, which is still considered experimental, is autologous transplantation, in which a portion of the patient's own bone marrow is removed, treated with drugs to purge it of leukemic cells, and given back to the patient.

In June 1991 FDA authorized the drug 4HC (Pergamid) to be used as a bone marrow purging agent under Treatment IND regulations. These regulations provide a way for drug developers to make investigational therapies for life-threatening illnesses available to patients before marketing under certain circumstances.

Pergamid may be used to treat patients with acute myelogenous leukemia who have achieved two or more remissions with conventional drug therapy. The drug-a form of the approved chemotherapeutic drug cyclophosphamide (Cytoxan, Neosar)-kills leukemic cells in the bone marrow without destroying the marrow's capacity to generate new blood cells after it is reinfused in the patient.

Clinical studies have shown that patients with acute myelogenous leukemia in a second or later remission who receive autologous bone marrow transplants that have been treated with Pergamid may have a better chance of sw-viva] than similar patients who receive standard chemotherapy alone.

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