The number and quality of first brief, temporary remissions produced in 1947 in acute lymphocytic (or lymphoblastic) leukemia, which is the form that occurs most frequently in children, have been greatly improved. Modern therapy can induce complete remissions in almost all patients with this disease and the median survival, or the time of survival of half the patients, in some specialized centers is at least 2 1/2 years. With today's therapy, some investigators estimate that many patients will survive longer than 5 years. This progress has resulted from intensive research on effective utilization of drugs and of auxiliary care to overcome problems resulting from the leukemic process or drug side effects.
Without treatment, death usually occurs within weeks or a couple of months after onset of symptoms related to replacement of the bone marrow by leukemic cells and a resultant decrease within the circulating blood of the elements produced in the marrow. Lack of these elements, including the red blood cells, granulocytes (white blood cells), and platelets, is responsible for the anemia, infection, and bleeding, respectively, of leukemia patients. The most important causes of death are infection, massive hemorrhage, and the effects of widespread infiltration of organs and tissues of the body by leukemic cells. Acute leukemia kills more than 2,100 children a year in the United States and is the cause of nearly half of the deaths due to cancer among children between the ages of 3 and 15.
Modern Concepts. Modern therapy is based on concepts derived from studies of leukemic cells in animals. From these studies investigators have reasoned that a single leukemic cell may double and redouble and finally produce fatal disease. It follows, then, that 100 percent kill of leukemic cells would be necessary to achieve cure.
The lethal number of leukemic cells in the body of a patient has been estimated at approximately one trillion (101J). A patient apparently can be in "complete remission," that is, blood and bone marrow considered normal and all signs and symptoms of disease absent, and still have a leukemic cell population of one billion (10»). It has been estimated that the best therapies to date, incorporating intensive courses of drug combinations and optimal supportive care, can reduce the leukemic cell population in patients with acute lymphocytic leukemia to approximately one million (10^6). The patient at this time has no sign of his disease.
Thus, there is a critical need for a precise method of measuring the number of leukemic cells remaining during drug-induced complete remission, as a guide to the intensity and duration of treatment required for complete destruction of leukemic cells. In the absence of such a method, duration of remission without drug maintenance is a measure of the number of leukemic cel s persisting in a patient at the end of treatment.
Calculations have suggested that one human leukemic cell, doubling every four days, would require about 160 to 170 days to develop to the lethal number of one trillion. Thus, if treatment reduced the number of leukemic cells to very few persisting ones, recurrence of disease after 170 days might be attributed to re-induction of the malignant process, reinfection by cells that had persisted in anatomically inaccessible pockets, or to a drug-induced lag in the doubling time of the residual population of leukemic cells. However, the duration of unmaintained remissions following intensive chemotherapy is often longer than that which may be predicted by the estimated doubling time of leukemic cells. The reasons for this are unknown.
Reduction in leukemic cells from one trillion (10^12 to zero is the goal of therapy. Best results to date have been achieved with intensive courses of drug combinations and with optimal supportive care, including transfusions of platelets and antibiotic therapy.
Studies of leukemic cells in animals have demonstrated a direct relationship between dosage level and the percent, or fraction, of a given leukemic cell population killed by a single dose of an active drug. The results also indicated that given dosages of certain drugs kill approximately the same percentage of leukemic cell populations regardless of their size. These studies indicated the importance of the size of the leukemic cell population as well as the level of the drug and the schedule of its administration in any attempt to kill all leukemic cells.
Pertinent laboratory studies by other investigators demonstrated that combined chemotherapy and irradiation of the central nervous system produced a highly significant prolongation of survival of mice compared with that in mice treated with either drugs or irradiation alone. These findings indicated that the potential for cure of leukemia is related to the distribution as well as to the number of leukemic cells present at the beginning of therapy.
Active Drugs. Clinical trials of the past several years have utilized combinations of drugs to produce increased therapeutic efficacy over their activity when used singly, and to take advantage of their qualitatively different, and therefore not additive, toxicities. Dosage schedules have shifted away from daily administration and toward short, intensive courses to provide selective toxicity and opportunity for recovery of the bone marrow and gastrointestinal tract.
Methotrexate, 6-mercaptopurine, prednisone, and vincristine are the most frequently used drugs. Cyclophosphamide and three more recently discovered drugs, cytosine arabinoside, daunomycin, and BCNU [l,3-bis(2-chloroethyl)-l-nitrosourea], make up the group of eight currently effective drugs for the treatment of acute lymphocytic leukemia. A drug apparently identical with the antibiotic, daunomycin, is called rubidomycin.
With the exception of BCNU, each drug used alone has produced a significant percentage of complete remissions. BCNU is active only in prolonging maintenance of remission. Some, such as prednisone, vincristine, cytosine arabinoside, and daunomycin, are called inducers, as they bring about remission rapidly, but fail in maintaining remission. Cyclophosphamide is another but slower inducer. Methotrexate and 6-mercaptopurine induce remission slowly when given singly, but are of great value in maintaining remission and are referred to as maintainers. However, as dosage schedules are improved in accordance with new information from laboratory and clinical studies, the difference between induction and maintenance becomes blurred.
Methotrexate injected into the spinal fluid is temporarily effective against meningeal acute lymphocytic leukemia. This condition has been found on autopsy in a majority of children with acute leukemia and occurs as a result of the penetration of leukemic cells through the blood-brain barrier of the central nervous system. The blood-brain barrier excludes certain foreign substances from the brain, the meninges (sheathing membranes) of the brain and spinal cord, and the spinal fluid. Proliferation of leukemic cells in the central nervous system causes obstruction to spinal fluid flow and increased intracranial pressure, with accompanying symptoms such as headache and nausea. Most antileukemic drugs given systemically do not penetrate the blood-brain barrier, but BCNU has this property. Preliminary results of clinical studies in which BCNU is included in the combination of drugs suggest that it is an advantageous adjunct in reducing central nervous system leukemia and maintaining remissions of patients with acute lymphocytic leukemia.
Clinical Results. Brief summaries of a few clinical studies will illustrate the types currently in progress and the results being obtained.
In 1964 a study of intensive, intermittent combination chemotherapy was undertaken by E. S. Henderson and his colleagues of the National Cancer Institute with 35 previously untreated children suffering from acute lymphocytic leukemia. They were treated with massive doses of 4 drugs, vincristine, prednisolone (related to prednisone), mercaptopurine, and methotrexate, given intravenously on an intermittent schedule for up to 14 months. At the start of therapy, the regimen consisted of 5-day courses of drug infusion, separated by drug-free intervals of 5 to 10 days depending upon toxicity encountered. After a complete remission was induced, 4 additional courses were given during a median period of 66 days, the so-called "consolidation" period. Following this, 12 additional "maintenance" courses were given at monthly intervals. Supportive therapy with platelet transfusions and antibiotics was given throughout the course of treatment as needed.