Currently, eight drugs are effective for the treatment of acute leukemia of childhood. With the exception of BCNU each drug alone has produced a significant percentage of complete remissions (temporary disappearance of all signs and symptoms of disease). Some drugs are called inducers, as they bring about remission rapidly but fail in maintaining remission. Others are of great value in maintaining remission and are called maintainers.
Thirty-two of the 35 patients (91 percent) achieved a complete remission within a period averaging 22 days. The median duration of this remission was 13 1/2 months, almost twice as long as was achieved in Institute studies in which drug combinations were given in smaller doses for shorter periods. Of 24 patients who relapsed, 20 were brought into a second remission by further therapy with the same four drugs.
Sixteen children are surviving for periods up to 3 years and 2 months following the start of therapy. Life-table analysis of all 35 patients in this continuing study shows a median survival time of about 3 years for the group, a year longer than was achieved in two previous Institute studies. It is 12 times the life expectancy of children with acute leukemia 20 years ago.
P. George and his coworkers of the St. Jude Children's Research Hospital, Memphis, reported results of a study designed to test another hypothesis for producing prolonged complete remission in children with untreated acute lymphocytic leukemia. Following induction of remission and an intensive short-term, high-dosage phase of treatment, continuous maintenance chemotherapy was given with a combination of four antileukemic agents concurrently in conjunction with cobalt-60 radiation therapy to the central nervous system.
Vincristine and prednisone were given to induce complete remission; then a 7-day course of short-term, high-dosage treatment with methotrexate, mercaptopurine, and cyclophosphamide, while prednisone was discontinued gradually over a 14-day period; and finally the phase of maintenance therapy consisting of mercaptopurine, vincristine, methotrexate, and cyclophosphamide. The radiation therapy was given early in the maintenance phase. Maintenance chemotherapy was continued until the disease reappeared in the bone marrow.
Of 31 children treated according to this procedure, 27 (87 percent) achieved complete remission in a median time of 28 days. The median duration of complete remission was 18 months, and the median survival was more than 31 months. Six patients, off therapy for 6 months or longer, have survived in continuous complete remission for an average of 3 years.
Radiation therapy by the method and dosage used appeared to have no influence on the subsequent development of leukemia in the central nervous system (meningeal leukemia). Also, systemic relapse of leukemia appeared unrelated to the occurrence of central nervous system leukemia and apparently did not result from re-entry into the systemic circulation of leukemic cells persisting in the central nervous system during complete remission.
Extended survival of children with acute lymphocytic leukemia is being observed by I. Djerassi and his colleagues, Children's Hospital of Philadelphia. Several of the children were already resistant to methotrexate at the time they entered the study. A series of 15 patients were maintained in remission by infusions of large amounts of methotrexate at intervals of 3 to 4 weeks, supplemented as needed by other drugs, such as cyclophosphamide, prednisone, mercaptopurine, and vincristine, as well as by intensive auxiliary care. Drug doses were based on biochemical models of the mechanism of action and resistance to methotrexate, and the large doses were given with safety. The median survival at the time of reporting was more than 30 months, and 12 patients (80 percent) were alive at this time.
Supportive Therapy. Transfusions of biood platelets are effective in preventing or stopping hemorrhage in patients with acute leukemia. Platelets are obtained by plasmapheresis, a process in which platelets and plasma are removed from whole blood by centrifugation, while the donor's red blood cells are promptly returned to him. Thus, he may be able to give platelet donations as frequently as twice a week without ill effects.
This type of platelet therapy has been made available in more than 30 leukemia centers throughout the country. To facilitate this effort, the Acute Leukemia Task Force under the leadership of the National Cancer Institute supports studies of methods of freezing and storing platelets, and is also organizing courses to train medical personnel in the techniques of platelet preparation and administration.
Control of many infections is possible with transfusions of granulocytes, but the problems of harvesting adequate amounts of these white blood cells from normal donors have not been completely solved. A continuous flow blood-cell separator is being developed under the sponsorship of the National Cancer Institute for this purpose. Other engineering developments are in progress to protect patients from the infectious agents of room air. These include isolators that enclose a bed in a protective plastic bubble, and laminar-flow rooms in which a patient is safeguarded from infection by a circulating flow of virtually germfree air.
Control of kidney damage in acute leukemia patients has been made possible through use of a drug, allopurinol. Kidney damage is one of the side effects of administration of antileu-kemia drugs; in the course of their destructive action on leukemic cells, these drugs release uric acid into the bloodstream. In large amounts, uric acid crystallizes and forms kidney stones. Allopurinol blocks the formation of uric acid and therefore reduces the risk of kidney stone production.
Long-term Survivors. A registry established by the Acute Leukemia Task Force lists patients surviving 5 years or more after diagnosis of their disease. The latest report shows 157 such patients, on whom information was collected by questionnaire from hematologists (specialists in diseases of the blood) all over the world. Of the 127 children in the registry, 87 were reported alive and well, and without evidence of disease.
Questions arise as to whether patients with acute leukemia who have survived longer than 5 years need continued therapy. Examination of the histories of the patients in the survivor registry has suggested that, in those who have lived 7 years from the time of diagnosis of the disease and have had no evidence of leukemia for 4 years, it is reasonable to assume that all leukemic cells have been eradicated. Discontinuing therapy at such time would appear justifiable and perhaps even advisable.
More than 157 patients with acute leukemia, most of them children, have survived 5 years or longer after diagnosis of their disease, according to records of the Acute Leukemia Long-Term Survival Registry, a worldwide survey of the Acute Leukemia Task Force of the National Cancer Institute.