Below is the text of Donald Pinkel’s second speech upon accepting the 1986 Kettering Prize. His award acceptance remarks from June 1, 1986 are posted here. The following speech was accompanied by slides and presented on June 6, 1986.
In 1947, Sidney Farber and his associates discovered that antifolate drugs produced temporary remissions in some children with acute lymphocytic leukemia.
By 1962, several drugs with antileukemic properties were available to prolong survival of these children in comfort. However, the disease remained almost always fatal. My colleagues at St. Jude Children’s Research Hospital and I recognized 4 major obstacles to the cure of acute lymphocytic leukemia:
- Drug resistance, initial or acquired, resulting in failure to enter remission or relapse soon after remission
- Central nervous system relapse due to poor diffusion of antileukemia drugs into cerebrospinal fluid
- Drug side effects, which inhibited dosage and combination of drugs
- Pessimism, the conviction that leukemia that incurable with available knowledge and agents.
We adopted the following premises:
- Combination chemotherapy can have additive antileukemia effects and overcome drug resistance
- Different drugs are optimal for inducing remission and for long term continuation treatment
- Specific central nervous system therapy is needed to prevent central nervous system relapse
- Cure is the goal of treatment, not palliation
- If treatment is curative 2 to 3 years should be adequate. Longer therapy might only add side effects without benefit
- Quality of survival and capacity for growth and development–physical, mental, emotional and social–are important.
Based on these premises we developed a total therapy plan aimed at cure of acute lymphocytic leukemia in children. It consisted of 4 phases:
- Remission induction to restore hematopoiesis and health, utilizing drugs that act rapidly, are not hematosuppressive, do not act on DNA synthesis and are not so useful for long term treatment.
- Consolidation chemotherapy to reduce the pool of potentially resistant leukemia cells, using antimetabolites and an alkylating agent
- Central nervous system therapy early during remission to eradicate leukemia cells in the arachnoid meninges and thus prevent central nervous system relapse. We used cranial irradiation plus intrathecal methotrexate or craniospinal irradiation.
- Continuation chemotherapy for 2 to 3 years to eliminate residual systemic leukemia, using drugs that act on DNA synthesis, are hematosuppressive and are tolerable over long periods of time.
The early studies from 1962 to 1967 demonstrated that total therapy was tolerable and resulted in superior remission and survival experience. However, central nervous system relapse remained a major problem and only 15% of children were surviving off treatment. In 1967, in study V, we increased the intensity of systemic and central nervous therapy with the result that approximately 1/2 of the children attained permanent remissions. They survive free of leukemia today, 18 years since diagnosis and 16 ears since stopping all treatment. None have relapsed in the past 14 years.
These results have been confirmed throughout the United States and throughout the world. Thousands of children treated by the total therapy plan or its variations are being cured of leukemia. Acute lymphocytic leukemia is now generally accepted to be 50% curable.
The quality of survival is generally good. This one-year old with ALL is now a healthy young man. This adolescent boy with massive spleen and liver and a WBC over 200,000 is a healthy adult.
The challenges today are threefold: to cure all children with leukemia, to reduce the risks and side effects of treatment, and to make curative treatment available and accessible to all children who need it.
This afternoon I will share with you some concepts of acute leukemia therapy in 1986.
1. Acute leukemias are genetic disorders of hematopoietic cells
This concept is based on the following information:
- The risk of leukemia is increased in certain genetic diseases, such as Down’s syndrome, and after exposure to mutagens such as ionizing radiation.
- Leukemia cell phenotypes are disorderly and asynchronous, indicating disordered genetic control.
- Chromosome morphology is disturbed in most acute leukemias.
- Nonrandom chromosome abnormalities are often associated with distinct species of acute leukemia, such as the 15;17 translocation in acute promyelocytic leukemia
- Finally, increased oncogene activity has been noted in many acute leukemias.
2. Drug therapy produces remissions by cytotoxicity but cures by overcoming the genetic disorder. This premise is speculative but has some basis. Drugs that do not act on DNA synthesis, such as prednisone and vincristine, are not curative. On the other hand, the curative drugs tend to alter DNA structure as well as inhibit DNA synthesis. For example, methotrexate produces chromosomal breaks and sister chromatid exchange. Cytosine arabinoside causes double replication of DNA segments. More important, children with ALL cured by chemotherapy retain the capacity for proliferation of lymphoblasts that often have the phenotypic characteristics of the leukemia lymphoblasts but not their malignant properties. This observation suggests that “total cell kill” is not responsible for cure but that alteration of leukemia cell genetics may be the key.
3. Drug selection and combination depends on the genetic features of the leukemia cells. For many years we have used morphology to guide drug selection, choosing different agents for acute lymphocytic vs. acute myelocytic leukemia. More recently we have learned to use immunophenotype as well, selecting different drugs and combinations for T cell ALL than for early pre–B ALL. There is now evidence that chromosomal rearrangements should also be considered in drug selection. For example, CALLA negative early pre-B ALL often has alterations of chromosome 11 similar to those seen in acute monocytic leukemia. There is increasing data to suggest that this type of ALL has a more favorable course when treated with drugs used for acute monocytic leukemia in addition to those used for early pre-B ALL. Since morphology and immunophenotype are reflections of leukemia cell genetics, also, it seems fair to say that genetic features of leukemia cells are the real determinants for drug selection and combination.
4. The frequency of drug administration and the duration of drug therapy depends on the rate of proliferation of leukemia cells. More rapidly proliferating leukemia is better controlled by more intensive drug treatment for a shorter time while slowly proliferating leukemia can be successfully treated by more intermittent therapy for a longer time. For example, B-cell ALL, with its rapid proliferation rate, is either cured or not within 6 months while slowly proliferating CALLA early pre-B ALL is at risk of relapse for 4 to 5 years.
5. Drug combinations need to be selected, dosed and scheduled for additive or synergistic effects. For example, weekly methotrexate and daily mercaptopurine appear to be synergistic. On the other hand, methotrexate effects are blocked by prior asparaginase.
6. Maximum dosage of few but more effective drugs is superior to lower dosage of many but less effective drugs. Many antileukemia drugs have overlapping side effects so that dosage must be lowered if there are combined. The administration of relatively ineffective drugs can inhibit the administration of more effective agents, resulting in less overall therapeutic efficacy. The use of rotating combinations can compromise therapeutic efficacy, also, if one or more of the combinations consists of agents that are relatively ineffective for the particular leukemia.
7. “Prognostic factors” in acute leukemia are artifacts of data analysis and treatment. For example patients with high white blood cell counts tend to relapse earlier while those with low white cell counts tend to relapse later. If complete remission duration instead of cute rate is used to assess prognostic factors the white blood cell count has false prognostic power. More important, selection of the incorrect drugs for a particular subtype of ALL will result in features of that subtype becoming labeled “poor prognostic factors.” For instance, when T cell ALL is treated like early pro-B ALL its typical features such as older age, male sex, high white blood cell count and mediastinal mass are associated with poor prognosis. When T cell ALL is treated with more appropriate drugs these features lose their prognostic significance.
8. As cure rates improve quality of survival acquires added significance. As more children with leukemia survive to become adults it becomes more critical to assure that they retain their full capacity for normal growth and development–physical, mental, emotional and social–and for normal health
9. The value of treatment depends on its accessibility as well as its efficacy. Curative treatment of leukemia needs to be simplified and provided to all children who need it, regardless of their socio-economic, ethnic or geographic status.
In summary, modern therapy can cure approximately 1/2 of children with ALL. The challenge is to achieve and provide curative treatment for all children with all types of leukemia. Evolving concepts of leukemia biology and therapy hold this potential.
In conclusion, I wish to express my deep gratitude to the General Motors Research Foundation and its committees for bringing me here, the American Lebanese Syrian Associated Charities and the National Cancer Institute for supporting my work, the staff and employees of St. Jude Children’s Research Hospital who did the work; and most o all the children with leukemia and their families who have participated in our studies.