Choosing AML Consolidation Therapy After Remission

NEW YORK—Acute myelogenous leukemia (AML) is an aggressive disease. But improved diagnosis with cytogenetic examinations and other special studies have made it possible to select the most effective induction therapy, Frederick R. Appelbaum, MD, told patients at a teleconference sponsored by Cancer Care Inc. and the Leukemia Society of America.

Today, with good supportive care, complete remission can be achieved in most cases, he said. But consolidation therapy is needed after that first remission. Without it, most patients relapse.

“Probably the hardest decision once a patient has achieved complete remission is choosing the subsequent therapy,” said Dr. Appelbaum, director of the Clinical Research Center, Fred Hutchinson Cancer Research Center, and professor and head of the Division of Medical Oncology, University of Washington School of Medicine. He pointed out that cytogenetic risk group, age, and general health often dictate the choice.

The first and standard option for the majority of patients following complete remission is three or four subsequent cycles of intensive chemotherapy similar to the kind used for initial induction—an anthracycline and cytarabine (ara-C).

The M3 subtype of AML, acute promyelocytic leukemia (APL), Dr. Appelbaum said, is uniquely sensitive to the oral drug, all-trans-retinoic acid (ATRA). Combined with chemotherapy, ATRA dramatically increases the cure rate of APL. Randomized trials show that ATRA is useful both during initial induction and as a maintenance therapy.

Following up first remission with an allogeneic bone marrow transplant is an option open to AML patients with an HLA-matched sibling. In the absence of a matched donor, or if the patient is over 55, autologous transplantation is an option, using bone marrow harvested while the patient is in remission.

“Both kinds of transplantation have a far greater likelihood of producing a cure in patients who have failed first-line therapy than does further chemotherapy,” Dr. Appelbaum said, “but the odds of cure for patients who have failed first-line therapy are not as good as when they started initial therapy.”

‘More Risky, Most Beneficial’

Allogeneic transplants, Dr. Appelbaum said, “are more risky but are also the most beneficial. In Seattle, we recommend allogeneic transplant for patients who are less than age 55 because, in our experience, it is the form of therapy that gives patients the very best chance for long-term survival and ultimate cure.”

For older patients or those who don’t have a matched sibling, the alternative is an autologous transplantation. “The outcomes with autologous transplants during first remission are not as good as with allogeneic transplants, but they are better than with conventional chemotherapy and are better tolerated by older patients,” Dr. Appelbaum said. Autologous transplants are often done in patients up to age 65, but most transplant centers will not use either type of transplantation in patients over age 65, he added.

“In the majority of cases, the quality of life following transplantation is similar to what people enjoyed before they were ill,” Dr. Appelbaum said. But there are exceptions. Graft-versus-host disease can significantly diminish quality of life for months or even years, and if patients are planning to have children, there is a high risk of sterility.

In contrast, the drugs used to treat leukemia in the nontransplant setting do not, in general, cause permanent sterility in men, particularly younger men, or increase the risk of fetal malformation of their children. But they can induce premature menopause in women in their late 30s or early 40s.

When to Transplant

If allogeneic transplantation is chosen, the next decision is when to have it. “If the disease is in first remission, then it is preferable to be transplanted fairly soon. There is a realistic chance that, of course, the patient could relapse in 3 or 6 months if they choose to wait.”

The problem with waiting to see if the chemotherapy worked and only undergoing transplantation if there is a relapse, Dr. Appelbaum warned, is that transplantation is not as effective once patients have relapsed. But people have their reasons for waiting, he acknowledged.

“I understand that once in a while there may be important events coming up, a wedding or graduation, for example, and the patient may say—I want to wait 6 weeks before I get my transplant,” Dr. Appelbaum said. “But in general, if a patient is going to be transplanted while in first remission, we would recommend that they be transplanted within 2 months of achieving first remission to get the very best results.”

Clinical Trials

Dr. Appelbaum urged all AML patients to consider enrolling in clinical trials, especially the elderly for whom conventional therapies have been less successful.

Among the new approaches being studied in the treatment of AML, he said, are the use of targeted chemotherapy that acts only on leukemic cells and immunologic approaches, including vaccines and donor lymphocytes.

The Southwest Oncology Group recently completed a study of a compound that prevents the development of drug resistance by stopping proteins on the surface of some leukemic cells from pumping out chemotherapeutic agents directed at those cells.

In a later interview with ONI, Dr. Appelbaum explained that the agent STI 571, which, in early trials, has shown activity in chronic myelogenous leukemia (CML) [see ONI January 2000, page 1], is not likely to have activity in AML.

“STI 571 is a specific inhibitor of the tyrosine kinase associated with the abl gene, the gene that is turned on by the chromosomal translocation seen in chronic myelogenous leukemia,” Dr. Appelbaum said. “That abl gene is not activated in the vast majority of AML cases. Thus, while STI 571 may prove to be of great use in the treatment of CML, there is no reason to think that it has or could have any activity in AML.”