Childhood Leukemia As a Model for Cancer Research: the Richard and Hinda Rosenthal Foundation Award Lecture1

[CANCER RESEARCH 39, 4301 -4307. November 1979| 0008-54 72 / 797 0039-OOOOS02.00 Childhood Leukemia as a Model for Cancer Research: The Richard and Hinda Rosenthal Foundation Award Lecture1

Joseph V. Simone

SÃJude Children s Research Hospital. Memphis, Tennessee 38(01

therapy during remission, phase-specific therapy, and the in terrelationships of phases of therapy were developed first in ALL. Since leukemia cell features, such as T-cell characteris tics, correlate with responsiveness to therapy, powerful new tools may be developed to improve the biological specificity of therapy. In addition to the gratifying results of therapy over the past two decades, childhood ALL continually offers opportun ities for biological research as well as improved therapy for ALL and other forms of disseminated cancer.

Dr. Zubrod, Mr. and Mrs. Rosenthal, members and guests, I am deeply honored to receive this award, and I accept it as a representative of all the staff, past and present, of St. Jude Children's Research Hospital whose work over the past 17 years is responsible. I am indeed privileged to be a member of the St. Jude family. For those of you who have never been engaged in clinical research, and particularly therapeutic re search, it is difficult to convey how many dedicated people are involved in a successful venture. I shall attempt to impress on you with the next few illustrations some of the components that have contributed to our effort in a major way. Fig. 1a shows a chromosome to remind us of our debt to our scientific fore bears. In the chemotherapy of leukemia, the early work of Drs. Sidney Farber, David Karnofsky, Joseph Burchenal, Emil Frei, III, and their colleagues is particularly relevant. Fig. 1Ã¶sym bolizes our debt to the leukemia studies in animals, particularly in the laboratories of Drs. Howard Skipper and Frank Schabel, which have continually provided us with challenging concepts to help us develop more rational therapy for our patients. Their work continues to stretch our horizons. There are several important components that have made the leukemia studies productive at St. Jude Cnildren's Research Abstract Hospital. Fig. 1c serves to remind us that no endeavor can proceed without a constant source of energy. This represents Childhood acute lymphocytic leukemia (ALL) is a model for the enormous, growing support of our fund-raising organization the study of disseminated cancer. It is always disseminated put together many years ago by Danny Thomas. It also repre and relatively uniform, it is accessible to repetitive tissue sam sents our debt to all of you who, as taxpayers, support the pling, and we have highly effective chemotherapy for it. The National Cancer Institute, which in turn, has been a generous first systematic, controlled trials of cancer therapy were de supporter of our work. A successful endeavor usually has in its signed for patients with ALL by physicians with the courage and audacity to aim for cure of a "hopeless" disease. The early years at least one person with penetrating, unwavering, and far-reaching vision (Fig. 1d). Our visionary was Dr. Donald concept of leukemia cell subpopulations in each patient re Pinkel, without whom our leukemia studies would not exist. ceived major clinical support from ALL. The pharmacological The life blood of the clinical research endeavor is our patients sanctuary, typified by the meninges, was first discovered and and their parents (Fig. 1e). Without their faith and confidence specifically attacked in ALL. Combination therapy, aggressive in us, our studies would not be possible. Fig. 1f symbolizes the power provided by a wide variety of individuals essential to move our work. Staff members, fellows, nursing, medical rec ' Presented at the 1979 Meeting of the American Association for Cancer ords, pharmacy, and believe it or not, a helpful, cooperative Research in New Orleans. Louisiana. Supported by Grants CA20180. CA08480. CA21765. and CA23099 from the National Cancer Institute and ALSAC. administration make the operation go. Leukemia studies at St. Received August 9, 1979. accepted August 10, 1979 Jude have one person at the heart who is the central force (Fig.

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1g). Dr. John Aur has made the studies move with his persist including responsiveness to specific therapeutic agents. This ence, dedication, and a legendary first-hand knowledge of is manifest in the clinical observation that selective therapeutic each and every patient. Finally, you might ask what my role pressures can lead to the emergence of resistant populations has been in these leukemia studies. If John Aur is the heart of of cells. It was natural to apply the principle of combination our group, then my role, shown in Fig. 1h, has been to provide therapy in an attempt to prevent therapeutic failure. This ap pedestrian support and locomotion. proach was already demonstrably effective in the antibiotic The thesis of my address is that studies of childhood ALL? chemotherapy of tuberculosis. A key concept developed in have been and will continue to be major sources of our under childhood leukemia with little preclinical direction is that of the standing of cancer in humans. This shall be a personal view, pharmacological sanctuary. By this is meant a specific anatom with admitted bias, and with pride in all of my colleagues world ical site which systemic circulating chemotherapy does not wide who have taken advantage of the opportunity to learn penetrate as well as other tissues. The classic example is the from this tragic disease. ALL is a model disease for the study development of CNS leukemia in the face of remission of the of disseminated cancer. This is so despite the fact that of all disease elsewhere in the body. Lastly, childhood leukemia is the cases of cancer estimated to occur in the United States the best example of a human disseminated cancer curable with annually, childhood ALL accounts for only 0.3% of the total chemotherapy. Whether this is accomplished by specific erad and only 10% of all leukemias (21). Why has such a relatively ication of every last leukemia cell is not known. infrequent disease had such profound impact on our thinking Impact on Therapeutic Strategy. Studies of childhood leu about cancer? kemia have had a major impact on our therapeutic strategy in Childhood Leukemia Model-Features. Childhood leukemia cancer. Systematic combination therapy for cancer begun in has proved to be a useful model because of several important this disease has been refined considerably over the years. The features. The disease, by definition, is always disseminated at concept of aggressive therapy during clinical remission, that diagnosis. Therefore, it has always demanded the use of sys is, maintaining pharmacological pressure to prevent regener temic rather than local therapy. Experience with systemic ther ation of tumor cells, was proposed, fostered, and proven early apy is 32 years old in childhood leukemia. Its clinical presen in the therapeutic history of this disease. Studies of childhood tation is relatively uniform, which has permitted standardization leukemia have played a major role in demonstrating the inter of specific and supportive therapy. Also, the diagnosis is not relationships of therapy. In a complete therapeutic regimen, it difficult to make in most instances. A key feature of this clinical is almost impossible to make a major change in one facet without influencing another. Lastly, in the late 1960's, it was research model is the ease of sampling of the tumor from marrow or blood which has permitted a wide variety of sequen recognized in some centers that much of the treatment for tial studies over the years. The foregoing features would be childhood leukemia could be given on an outpatient basis with less important if it were not for the availability of effective less interruption of the normal activities of a child. It is possible therapy since the introduction of aminopterin by Dr. Sidney to give aggressive, potentially curative chemotherapy in this Farber and his colleagues. A range of therapeutic responsive manner. In our own institution, we currently follow 550 patients ness has been essential for elaboration of its biological behav with leukemia and receive over 100 new patients a year. Yet ior. our average inpatient census is 7 leukemia patients. General Impact. Since the 1940's, studies in childhood Subpopulations of Cells-Combination Chemotherapy. I leukemia have had an enormous general impact on our under shall use examples drawn from our studies to illustrate some of standing of cancer therapy. The first systematically controlled the points I have made regarding the impact of this disease on therapeutic cancer trials were carried out in childhood leukemia our understanding of cancer. Table 1 provides clinical evidence in the now classic studies by Dr. Emil Frei, III, and the Acute of the existence of subpopulations of leukemic cells and the Leukemia Group B during the 1950's (8, 9). That group also effectiveness of combination therapy. Remission was induced had to develop criteria for responses and for toxicity of the in about 40 to 50% of patients who were given either predni- various treatment regimens so that studies in different institu sone or vincristine alone. When these 2 agents were combined, tions could be validly compared. Supportive therapy received the remission rate was increased to 90%, an almost perfect tremendous impetus in those leukemia studies, particularly at additive effect. This suggested either that there were 2 com the NIH under the direction of Dr. Emil J Freireich. In my view, pletely discreet populations of cells sensitive to only one of the however, the most important contribution made by the clinical agents or, more likely, subpopulations of cells with ranges of investigators working with this disease was their audacity in sensitivity to each of the agents and to the combination. In later the early 1960's to aim for cure of a uniformly fatal disease. It years, when daunorubicin or asparaginase was added to these is impossible to convey today just how much courage and 2 agents, the remission rate was improved little because there perseverance was required. The hoots of derision have hardly was little room for improvement. However, as I shall point out faded away even now. later, the intensity of this early treatment may have an influence

Biological Impact. Several important biological concepts Table 1 which were borrowed from bacterial systems and developed in Remission induction frequency ol childhood ALL with single agents and ar.l.nal models found their first clinical support in studies of combinations childhood leukemia. The concept is now well established that Remission frequency there are subpopulations of leukemia cells in each patient. Agents These subpopulations differ in a variety of characteristics, Prednisone or vincristine 40-50 Prednisone + vincristine 90 â€¢'Theabbreviations used are: ALL, acute lymphocytic leukemia; CNS, central Prednisone + vincristine + daunorubicin 94 Prednisone + vincristine + asparaginase 95 nervous system.

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1979 American Association for Cancer Research. Childhood Leukemia as a Cancer Research Model on the duration of remission, if not on the frequency of remis instance, therefore, not only was the 2-drug regimen at least sion induction. as effective, but it was clearly less toxic. Table 2 illustrates the salient results of a study done at St. Interrelationship of Phases of Therapy. Although one might Jude which asked the question: when giving combination ther arrive at the concept intuitively that treatment in one phase of apy during remission, must one give moderately toxic full doses therapy can influence the outcome in another phase, direct of all agents, or might one achieve as good a result with lesser evidence is difficult to obtain because of the remoteness of the doses because the combination of agents would have an measurement from the therapy. In groups of patients whose additive or synergistic effect? This study clearly showed that prognostic features and therapy during remission were approx the patients given maximum tolerated, full dosage had a better imately the same, we discovered retrospectively (23) that the response to the treatment (19). This principle has not been duration of remission in patients who received only prednisone refuted today, but we have learned that more is not necessarily and vincristine induction therapy was shorter than in patients better. Table 3 shows the results of a more recent study who had received 3 drugs for remission induction (Table 5). comparing the effectiveness of 2-, 3- or 4-drug therapy during One explanation for this observation is that although the 3-drug remission; in each case, the combination was given to maxi therapy did not significantly improve the remission induction mum tolerated dosage (4). Not all of these agents are equally rate, it may have reduced the tumor cell number by an addi effective, and the question was whether one could obtain an tional log or 2. Consequently, therapy given later during remis increasingly better effect with the addition of each agent. sion is required to control a much smaller tumor mass with a However, the proportion of patients in continuous complete greater likelihood of eradication. Another example of therapy remission for 30 months or more is not significantly different in in one phase affecting another aspect of the disease is shown the 3 groups. If anything, results are slightly better with the 2- in Table 6. You will recall that in our Study 4 (Table 2) patients drug regimen. Furthermore, as shown in Table 4, the frequency were randomized to receive full or one-half dosage chemo of complications due to immunosuppression differed by group. therapy during remission (19). In this study, no preventive CNS The frequency of Pneumocystis carinii pneumonia, varicella therapy of any kind was given. Nonetheless, patients who zoster infections, and death in continuous complete remission received only one-half dosage systemic chemotherapy had a was directly related to the number of agents given. In this significantly higher CNS relapse rate in a shorter period of time at risk than did the group receiving full-dosage systemic chem otherapy. Observations such as these demonstrate why the Table 2 Results of Total Therapy Study 4 comparing the proportion of patients attaining results of clinical studies are so easily misinterpreted. If we had 3 years ol continuous complete remission with either full- or half-dosage used 2 forms of preventive CNS therapy in this study, we might combination chemotherapy during remission have concluded that any difference in CNS relapse rate was 3-yr continuous complete Systemic chemotherapy3 due solely to the CNS therapy. Patients remission Preventing CNS Leukemia. It was in the late 1950 s that Dr. Full dosage 21 10 Donald Pinkel and others made the observation that CNS Half dosage 21 4 ' Chemotherapy consisted of daily mercaptopurine and weekly methotrexate, leukemia frequently occurred in patients despite the fact that cyclophosphamide, and vincristine (19) the disease was in remission elsewhere in the body. There are 2 common explanations for this observation. First, since un- Table 3 detectable leukemia is undoubtedly present in the bone marrow Results of Total Therapy Study 8 comparing the proportion of patients attaining despite clinical remission, CNS leukemia is the result of mÃ©tas 30 months of continuous complete remission with 2-. 3-. or 4-drug therapy during remission tases to the CNS from these clinically undetectable sources. Dr. Pinkel suggested an alternative explanation because there mos. continu ous complete re did not seem to be a direct relationship between the frequency No. of drugsDrugs"2 mission(%)665459 Table 5 mercaptopurine3Methotrexate and As immediately above + cyclo Relationship of initial chemotherapy and duration of continuous complete phosphamide4 remission in children with ALL As1-/ÃŒ-D-arabinofuranosylcytosinePatients68707030 immediately above + mos. continuous com therapy"PrednisoneRemission induction plete remission(%)386051 Each regimen was given in maximum tolerated dosage. Initial therapy and vincristinePrednisone+ prognostic features were the same for each group (4). dauno-rubicinPrednisone+ vincristine +

aspa-ragmasePatients945525530+ vincristine + Table 4 Results of Total Therapy Study 8 comparing the relative frequency of 2 tile- threatening infections and deaths during initial complete remission with 2-. 3~. Other therapy and prognostic features were similar in each group or 4-drug therapy during remission (4)

carinii Table 6 No of pneumo in re Results of Total Therapy Study 4 comparing the relationship of full- or half- drugs234DrugsMethotrexate nia1719Varicella-Zoster91620Diedmission045 dosage systemic chemotherapy with the frequency of CNS relapse No and mer preventive CNS therapy was given in this study captopurineAs Systemic chemotherapy" -t-cyclophosphamideAsimmediately above Patients Initial relapse in CNS Full dosage 21 9 +1immediately above Half dosage 21 15 -/<-D-arabinofurano-sylcytosinePatients687070P. 11Chemotherapy consisted of daily mercaptopurine and weekly methotrexate. cyclophosphamide. and vincristine (19)

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1979 American Association for Cancer Research. J. V. Simone of CMS leukemia and of bone marrow relapse. He postulated spinal cord or, even more rarely, of intrathecal chemotherapy. that at the time of diagnosis, leukemia cells already reside in A few years ago, computerized axial tomography brain scan the meninges and, even after clinical remission is achieved, changes were first observed in patients who had received cells remain in the meninges. He further postulated that a high irradiation and methotrexate, although there were no associ pharmacological threshold protected the meninges from cir ated clinical abnormalities (18). The intellectual function of culating chemotherapy. Thus, CNS relapse occurred because patients given CNS therapy appeared grossly normal in a insufficient concentrations of systemically administered drugs variety of studies (25, 26); however, in one of our own studies, reached these sites. He suggested that irradiation of the CNS the teachers response to a questionnaire showed that the early in remission could eradicate these residual cells and attention span in some patients was below average (26). Eiser prevent CNS relapse. This led to a series of studies which are and Landsdown reported that children who were over 5 years depicted in Table 7. The frequency of initial relapse in the CNS old when they received irradiation subsequently performed was 50 to 60% without preventive therapy. In 1962 to 1965, 2 normally in I.Q. tests, and those less than 5 years of age studies were performed with 500 or 1200 rads craniospinal performed somewhat below average (6). In another ongoing irradiation early in remission (13, 22). This radiation dosage study in our institution, patients performed normally in most had little impact on the frequency of CNS relapse. Drs. Pinkel tests, but short-term memory was below average in approxi and Omar Hustu at St. Jude did not abandon the concept, mately one-half of patients.3 A study reported yesterday from however. They attributed failure to insufficient dosage, and in Mayo Clinic shows a low frequency of decreased scores on 1967, they initiated trials in which the dosage was increased I.Q. tests with a variety of forms of CNS therapy (1 7). One to 2400 rads (3, 13). This was found to be effective in that pilot problem with all of our studies of this type is that there are no study and in a subsequent controlled study in which patients good controls for school performance and psychosocial ad were randomized to receive or not receive preventive cranio justment in patients with chronic illnesses receiving long-term spinal irradiation (1). Thus, Dr. Pinkel's hypothesis was sup therapy. This has made drawing causal relationships extremely ported by the results of these studies. It appeared that if one difficult. could eradicate residual leukemia cells in the meninges early Other Forms of CNS Therapy. Nonetheless, as with other in remission, one could prevent CNS relapse in most patients. facets of therapy, there are continual attempts to find treatment Coincident with the advent of successful preventive CNS ther regimens which are demonstrably as effective and less toxic. apy, an increasing proportion of patients with ALL experienced A variety of forms of alternative CNS therapy are under study. prolonged initial complete remission. The low frequency of The first, a regimen introduced at Memorial Hospital in New CNS relapse is even more impressive when one views the York with intrathecal methotrexate and aggressive systemic relapse rate as a function of the duration of time at risk for therapy, appears to control CNS leukemia as effectively as developing the complication shown in Table 7. regimens which use irradiation (11). Intrathecal methotrexate Undesirable Late Effects of Therapy. Because of long-term with conventional systemic therapy is currently under study by survival following combination therapy in childhood leukemia, several groups. The third regimen, introduced by Drs. Freeman, we have both the concern and opportunity to study late effects. Wang, and Sinks at Roswell Park Memorial Institute, has shown The majority of children who receive this therapy and survive early promise (7). It attempts to overcome the pharmacological appear to function normally. However, CNS disorders have threshold of the meninges with i.v. infusions of MTX. Versions been observed following a variety of conditions and have been of regimens with intrathecal methotrexate have failed in the under study for a number of years in our institution and else past (14, 16), but the modifications currently under study will where. Leukoencephalopathy was the most severe disorder. probably be shown effective for specific subpopulations of We observed this complication in 9 of 20 patients who received patients. CNS therapy with lower doses of irradiation is also brain irradiation with intrathecal methotrexate, followed by under study with early indications of success (12, 16). In the weekly i.v. methotrexate in doses of 50 to 80 mg/sq mm, a case of each of these regimens, however, it will be important dose 2 to 4 times that usually given (4). This complication has to have long-term follow-up studies of efficacy and potential also been observed in a proportion of patients who have toxicity so that the most effective and least toxic regimen may recurrent CNS leukemia (4), patients given intrathecal metho be used. The irony of the potential late effects of therapy, trexate or high doses of i.v. methotrexate without brain irradia however, is that they do not occur in patients who die of their tion (1 5). Paraplegia is a rare complication of radiation of the disease. The patients must be cured of their tumor first before any consequences of therapy can be of concern. Table 7 Prognosis and Leukemia Cell Biology. When therapy for Frequency of initial relapse in the CNS in children with ALL who received either childhood leukemia improved leading to long-term, leukemia- no preventive therapy or one of several regimens free survival, there emerged certain clinical features which re were associated with a poor prognosis (24). Some of these lapseinCNS atrisk"19 therapy500-1200Preventive CNS (%)406010467Time were an initial leukocyte count above 50,000, a thymic mass, craniospinalNone2400rads mos.19 or early CNS leukemia before preventive therapy could be mos.10yr8yr4 given. In the more recent past, studies of immunological fea rads cranial + intrathecal metho tures of the surface of the leukemia cells have demonstrated a trexate2400 radscraniospinalNonePatients3742314549Initial correlation between prognosis and the clinical and the cellular yr features (5, 20). The following work done by Drs. Sue Melvin a Since the efficacy of preventive therapy also depends on the time at risk for this complication, this is the median duration of initial hematological remission for each group. [This is an extension of data from Hustu et al. (13)]. 1 J. R. Goff, unpublished observations.

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1979 American Association for Cancer Research. Childhood Leukemia as a Cancer Research Model and Paul Bowman at St. Jude illustrates the point. As shown in Table 8, 13 of 17 patients with T-cell leukemia have elevated WBC, and one-half of them have a thymic mass. Patients with antigenic determinants for common ALL rarely had the clinical features associated with a poor prognosis. Patients with neither of these markers had an intermediate correlation. A preliminary evaluation of the outcome of treatment of patients in these various categories is shown in Table 9. Among patients with antigenically common ALL, the frequency of failure to attain remission or to relapse has been 9 of 55 patients. In patients IO 20 30 40 50 + with the T-antigen on the leukemic cells, 9 of 17 have already YEARS OF AGE Chart 1. Relative frequency of types of acute leukemia by age This schematic failed. And in those with neither marker, 6 of 12 have already diagram shows the greater proportion of the common, responsive type of ALL in failed therapy. These results are preliminary, but there is little children. Acute myelocytic leukemia and the more resistant types of ALL account for a greater proportion of acute leukemias in adults. chance that the general conclusions will be changed. This is one of the more exciting opportunities in cancer biology. Fur operational definition of cure of ALL in childhood (2). Although ther elaboration of these cellular features may elucidate the later relapse is always possible, in our studies, if a patient pathogenesis of human leukemia and provide biological op remains in complete remission during therapy for a minimum of portunities for developing specific therapeutic advantages. 2.5 years and if the patient remains in remission for an addi Adult ALL. In addition to the clinical and cellular features, tional 4 years after therapy has been stopped, it is likely that there is another prognostic feature of ALL that is most puzzling. the patient is cured. Chart 1 is a stylized version of the relative frequency of acute Conclusions of Studies and Opportunities for Advance leukemia by years of age, divided according to general cellular ment. Finally, I list below some conclusions derived from stud type and relative resistance or responsiveness to current ther ies of childhood leukemia from 1962 to 1979. These conclu apy. In the childhood age group, most of the acute leukemias are ALL, and most of the ALL'S are responsive to chemotherapy sions may seem self-evident today, but I assure you that they have not always been, (a) It is clear that combination therapy with a large proportion of patients attaining long remissions. With increasing age, however, the proportion of ALL'S declines is superior at every phase of therapy, although one may not add agents with a guarantee of increasing effectiveness or with and the proportion of the more resistant acute myelocytic leukemias increases. Furthermore, the proportion of ALL'S impunity from toxicity. (fa) It is also clear that CNS leukemia is preventable, and it is likely that a variety of therapeutic methods which are relatively responsive to therapy also declines sharply. is effective, (c) We and others have shown that, with careful Thus, a high proportion of all leukemias in the adult age group studies, therapy may be safely reduced to the essentials, thus are more resistant to therapy. The reason for this difference is lowering the risk of complications, (d) From our vantage point unknown, but we now have some tools with which to explore now, advances in our understanding of leukemia cell biology biological differences in the cells or host. and the clinical correlations will be the basis for the next Outcome of Therapy. Although studies of childhood leuke generation of therapy. Within reach are what I consider 2 mia have shown it to be a good teaching model, one might ask paramount advances. One of these is detection of small con what the bottom line is of all of these studies. Very simply, it is centrations of residual leukemia cells, say one in 106, so that that with currently available therapy, about 50% of all children we may follow the response to therapy during remission when with ALL will remain in initial complete remission for 3 years. cells are undetectable by current methods. This would be a Furthermore, if therapy is stopped at that point, the hazard of most powerful tool in assessing therapeutic specificity during relapse after cessation of therapy declines to virtually zero by remission now hidden. The other is making meaningful corre the fourth year (2). In fact, we have not yet had a relapse later lations between the cellular phenotype, such as presence of than 45 months after cessation of therapy. From these data, fetal thymus antigen, and the biochemical basis for relative my colleague, Dr. Stephen George, has developed with us an resistance to therapy, (e) And, finally, I mention once again because it is such a remarkable therapeutic advance in only Table 8 20 years, childhood leukemia has been changed from a uni Correlation of clinical features and leukemia cell surface markers in childhood versally fatal disease to one curable in nearly one-half of all ALL patients. I consider it a singular honor to have played a small featureTotalLeukemia cell antigenic role in that progress. patients Leukocyte count of >50.000/cu mm 5 13 2 Thymic mass 0 85Undifferentiated1201 References Early CNS leukemiaCommon55 0T-Cell17 1 Aur. R. J. A.. Simone, J. V.. Hustu. H. O.. and Verzosa, M. S. A comparative study ot central nervous system irradiation and intensive chemotherapy Table 9 early in remission of childhood acute lymphocytic leukemia. Cancer (Phila.) 29 381-391, 1972. Preliminary correlation of leukemia cell antigenic features and treatment 2. Aur, R. J. A.. Simone, J. V., Hustu. H O.. Verzosa, M. S . and Pinkel, D outcome (see Table 8) Cessation of therapy during complete remission of childhood acute lympho featureTotalLeukemia cell antigenic cytic leukemia N Engl. J. Med.. 291. 1230-1234, 1974. 3. Aur. R J A., Simone. J. V . Hustu, H. O . Walters. T . Borella. L.. Pratt. C . patients and Pinkel. D. Central nervous system therapy and combination chemother Remission induction failure 27T-Cell17 36Undifferentiated1233 apy of childhood lymphocytic leukemia. Blood, 37. 272-281, 1971. RelapseCommon55 4. Aur, R. J. A., Simone. J. V.. Verzosa. M S.. Hustu. H. O . Barker. L F..

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Pinkel. D. P.. Rivera. G.. Dahl. G V.. Wood, A.. Stagner. S., and Mason. C. J. Combination therapy in 130 patients with acute lymphoblastic leukemia. Childhood acute lymphocytic leukemia. Study VIII. Cancer (Phila.), 42: (Procotol 06 LA 66-Paris) Cancer Res.. 33 3278-3284, 1973. 2123-2134,1978 15 Meadows, A. T.. and Evans. A. E Effects of chemotherapy on the central 5. Dow, L W.. Borella. L.. Sen. L.. Aur, R. J. A., George, S. L., Mauer, A. M.. nervous system. A study of parenteral methotexate in long-term survivors of and Simone, J. V. Initial prognostic factors and lymphoblast-erythrocyte leukemia and lymphoma in childhood. Cancer (Phila.), 37. 1079-1085, rosette formation in 109 children with acute lymphocytic leukemia. Blood, 1976. 50: 671-682. 1977 16 Nesbit. M. E . Sather. H. N., Robison. L. L.. D Angio. G. J.. Liftman, P.. 6 Eiser. C., and Lansdown. R. Retrospective study of intellectual development Donaldson, M., and Hammond. G. D. Presymptomatic CMS treatment in in children treated for acute lymphoblastic leukemia. Arch. Dis. Child., 52. childhood acute lymphoblastic leukemia: comparison between 1800 and 525-529. 1977. 2400 rads. Proc. Am. Assoc. Cancer Res., 20. 343, 1979. 7. Freeman, A. I., Wang. J. J.. and Sinks. L F. High-dose methotrexate in 17 Obetz, S W . Smithson. W A.. Groover. R. V., Houser, O. W., Klass. D. W.. acute lymphocytic leukemia. Cancer Treat. Rep.. 61: 727-731, 1977. Ivnik, R. J.. Colligan. R C . Burgert. E. O., and Gilchrist. G. S. Neuropsy- 8. Frei. E.. III. Holland. J. F , Schneiderman. M. A., Pinkel. D.. Selkirk, G.. chological follow-up study of central nervous system function in children Freireich. E. J. Silver, R. T., Gold.. G. L., and Regelson. W. A comparative with acute lymphocytic leukemia. Proc. Am. Assoc. Cancer Res., 20 342, study of two regimens of combination chemotherapy in acute leukemia. 1979 Blood, 13 1126-1148, 1958 18 Peylan-Ramu. N.. Poplack, D G., Pizzo, P. A , AdÃ³rnalo. B. T., and DiChiro. 9. Frei, E , III. Karon. M.. Levin. R H., Freireich, E. J. Taylor. R. J.. Hananian. G. Abnormal CT scans of the brain in asymptomatic children with acute J.. Selawry, O.. Holland. J F , Hoogstraten, B.. Wolman, I. J.. Abir, E., lymphocytic leukemia after prophylactic treatment of the central nervous Sawitsky. A.. Lee. S.. Mills. S. D., Burgert. E. O.. Spurr, C. L.. Patterson, R. system with radiation and intrathecal chemotherapy. N. Engl. J. Med., 298. B.. Ebaugh, F. G.. James. G. W.. and Moon. J. H. The effectiveness of 535-540, 1978. combinations of antileukemic agents in inducing and maintaining remission 19 Pinkel. D , Hernandez, K.. Borella. L.. Holton. C.. Aur, R.. Samoy. G., and in children with acute leukemia Blood. 26 642-656. 1965 Pratt. C. Drug dosage and remission duration in childhood lymphocytic 10 George, S. L.. Aur. R J A , Mauer, A. M , and Simone. J. V. A reappraisal leukemia. Cancer (Phila.), 27. 247-256. 1971. of the results of stopping therapy in childhood leukemia. N. Engl. J. Med., 20. Sen, L., and Borella. L. Clinical importance of lymphoblasts with T markers 300 269-274, 1979 in childhood acute leukemia. N. Engl. J. Med., 292 828-832. 1975. 11 Haghbm. M.. Tan. C. T. C.. Clarkson, B. D.. Mike. V . Burchenal. J H , and 21. Silverberg, E. Cancer statistics. 1979. CA-Cancer J Clin.. 29. 6-21. 1979. Murphy. M. L. Treatment of acute lymphoblastic leukemia in children with 22. Simone, J. V. Acute lymphocytic leukemia m childhood- Semin. Hematol., 2. prophylactic intrathecal methotrexate and intensive systemic therapy. 25-39, 1974. Cancer Res.. 35 807-811, 1975. 23. Simone. J. V. Factors that influence haematological remission duration in 12 Henze. G., Langermann. H J. Lampert, F , Neidhart. M . and Riehm, H. Die acute lymphocytic leukaemia Br J Haematol.. 32 465-472. 1976 Studie zur Behandlung der akuten lymphoblastischen LeukÃ¤mie 1971-1974 24. Simone. J. V.. Verzosa, M. S.. and Rudy. J. A. Initial features and prognosis der Deutschen Arbeitsgemeinschaft fÃ¼rLeukamie-forschung und Behan in 363 children with acute lymphocytic leukemia. Cancer (Phila.), 36. 2099- dlung im Kindesalter e.V. Analyse der prognostischen Bedeutung von Ini 2108. 1975. tialbefunden und Therapievarianten. Klin. Padiat., 191. 114-126, 1979. 25 Soni. S. S.. Marten, G. W.. Pitner. S. E.. DueÃ±as.D A., and Powazek. M. 13. Hustu. H. O.. Aur, R. J. A.. Verzosa, M. S.. Simone, J V . and Pinkel. D. Effects of central nervous system irradiation on neuropsychologic function Prevention of central nervous system leukemia by irradiation. Cancer ing of children with acute lymphocytic leukemia N Engl J. Med.. 293. (Phila.), 32 585-597. 1973. 113-118. 1975. 14 Jacquillat. C.. Weil, M., Gemon, M-F.. Auclerc, G., Loisel, J-P., Delobel. J.. 26. Verzosa. M. S.. Aur. R J. A., Simone. J. V . Hustu. H O., and Pinkel. D. Flandrin. G.. Schaison. G.. Izreal, V., Bussel. A., Dresch, C.. Weisgerber. Five years after central nervous system irradiation of children with leukemia. C., Ram, D.. Tanzer. J.. Naiean, Y . Seilgmann. M , Boiron. M., and Bernard, Int. J RadiÃ¢t Oncol Biol. Phys . ; 209-215. 1976

Fig. 1. This figure symbolizes and represents key factors in the success of leukemia research at St. Jude Hospital. A. the chromosome recognizes our debt to our scientific forefathers who laid the groundwork with their early studies and enthusiasm, ÃŸ,the mouse represents our debt to studies of murine leukemia which have provided important concepts. C. no effort can succeed without a constant source of energy, in this case, from our fund-raising efforts and from the National Cancer Institute D. Dr. Donald Pinkel had the vision and determination to put and keep us on the right track. E, the lifeblood of our studies is our patients and their parents who have so much faith in us. F, many individuals at St. Jude in a wide variety of professions have provided the muscle to carry the enormous work load of these studies. G. the heart of the leukemia studies at St Jude is Or John Aur H. my role has been to provide pedestrian support and locomotion.

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1979 American Association for Cancer Research. Childhood Leukemia as a Model for Cancer Research: The Richard and Hinda Rosenthal Foundation Award Lecture

Joseph V. Simone

Cancer Res 1979;39:4301-4307.

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