BAYARD CLARKSON and (by invitation) JEFFREY GAYNOR, ..... In: Yarbro. J, Murphy S, eds. Seminars in Oncology. New York: Grune & Stratton, Inc.; 1984: In.
RECENT ADVANCES IN THE TREATMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS AND FUTURE PROSPECTS*, t, t BAYARD CLARKSON and (by invitation) JEFFREY GAYNOR, B. ROBERT FRANZA, JR.,** and MARK FURTH NEW YORK
Acute lymphoblastic leukemia (ALL) comprises approximately 20% of the acute leukemias occurring in patients above the age of 15, whereas it accounts for almost 90% of the acute leukemias in children. Without effective treatment, the disease is uniformly fatal with a median survival of only a few months. With modern combination chemotherapy programs, over 90% of children have complete remissions and it appears that about half of them are now being cured (1-3), but the results in adults using the same or similar treatment regimens have generally yielded a lower incidence of remission and a smaller proportion of long survivors (4-10). Recently, however, there have been several reports of improved results in adults with ALL treated with various intensive treatment protocols, which are more comparable to those in children (11-18). I will first summarize our own experience in treating adults with ALL during the last 15 years with 3 successive combination chemotherapy protocols, each calling for approximately 3 years of treatment, and then discuss the future prospects for successfully treating patients who are still at high risk of dying of their disease. The design of the first protocol, the L-2, was based on a combination of empirical, cytokinetic, pharmacologic and theoretical considerations (4, 19). Remission was induced with prednisone, vincristine (VCR), and daunorubicin; this was followed by 3 cycles of arabinosylcytosine (AraC) and 6-thioguanine (TG) and then by asparaginase, VCR and 1,3Bis(2-chloroethyl)-1-nitrosourea (BCNU). Making several assumptions, we estimated the average cell kill caused by each component of the protocol and the regrowth which occurred during the treatment free intervals (19); according to these estimates, very few leukemic cells should survive the first part of the protocol. However, since these estimates From the Laboratory of Hematopoietic Cell Kinetics, Biostatistics Laboratory and the Laboratory of Molecular Oncogenesis, Sloan-Kettering Institute for Cancer Research, New York, NY; and ** The Cold Spring Harbor Laboratory, Cold Spring Harbor, New York t Supported in part by grants awarded from The National Cancer Institute, CA-20194, CA-19117, CA-05826. t Reprint requests should be sent to: Bayard Clarkson, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021 *
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failed to consider important variables such as differences in drug sensitivity or cell growth rates among different leukemic populations, or the problem of long-term dormant leukemic cells which may survive the treatment and later resume dividing (19, 20), we assumed the extent of cell kill was over-estimated. Accordingly, after completing the first part of the protocol, patients were treated with a regimen designed for outpatient use for a total of 3 years. This maintenance regimen consisted of sequential cycles of four two-drug combinations (4), and its intent was to destroy any remaining leukemic cells including those in a resting state. Unlike the majority of treatment programs for children and adults with ALL in which both cranial irradiation and intrathecal chemotherapy were given prophylactically to prevent central nervous system (CNS) leukemia, our own protocols relied entirely on intrathecal or intraventricular methotrexate (MTX) for CNS prophylaxis (21) in order to avoid the late consequences of cranial irradiation (22). While the final answer is not yet in, our results (14-16, 21) and those of several other clinical trials (23, 24) suggest that chemoprophylaxis alone may be equally effective in preventing CNS leukemia. With the L-2 protocol, about half the children and one fourth of the adults have remained in continuous remission for over 10 years (1, 15), and most of these patients are presumably cured. The second protocol, the L-10, had a similar but more intensive induction schedule and a lengthened consolidation, alternating cycles of MTX with Ara-C and TG for a total of 6 cycles (14, 15). Patients then received a regimen, termed the eradication phase of treatment, whose objective was to kill all residual leukemic cells; this consisted of 2 alternating regimens containing VCR and prednisone, adriamycin, cyclophosphamide, BCNU, 6-mercaptopurine (6MP), MTX and actinomycin D. Treatment was continued for 3 years. With the L-10 and its modified form (L-1OM), the remission incidence was 85%, and about 40% of all patients entered, and nearly half of those who achieved remission survived over 5 years with no evidence of recurrent disease (15, 16). The third protocol, the L-17/L-17M, had the same induction and eradication sequences as the L-10/L-1OM; the main difference was a randomized comparison between the lengthy L-10 consolidation sequence and an abbreviated consolidation consisting of a single course of daunorubicin, Ara-C and thioguanine plus one cycle of Ara-C and MTX; the shorter consolidation seems at least equally effective and greatly reduces the time spent in the hospital and the number of septic episodes. So far there are no significant differences between the overall results of the L10 and L-17 protocols (15, 16). The proportion of long-term remissions was higher on the later protocols than on the L-2 (16), but the difference is not significant so the
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results of the three protocols were combined for analysis of prognostic factors. Overall, 83% of the total of 149 previously untreated patients entered on these 3 protocols had complete remissions (CR), and their median duration of remission was 44 months (16). Since the remission duration curve reaches a plateau at 45% with no relapses occurring after 51 months, it is reasonable to assume that most of the patients remaining in continuous remission longer than 5 years are cured. Most of the relapses first occurred in the bone marrow, but there were 9 central nervous system (CNS) relapses, 6 of which occurred concurrently or nearly so in the marrow. Of the 26 patients who failed to achieve CR, 16 died of sepsis or other complications during attempted induction and the other 10 were judged to be primary treatment failures as they had persistence of leukemic cells in the marrow at the end of induction. Whereas these results are better than previously reported in adults with ALL, over half of the patients died of their disease or of complications associated with the intensive treatment. Because an alternative form of treatment-bone marrow transplantation (BMT)-is now available, it is important to identify as accurately as possible patients who have a high probability of failing or ultimately relapsing from existing therapeutic regimens. The potential advantage of selecting patients with a poor prognosis for alternative therapy early in the course of the disease before a high degree of drug resistance has developed has now been confirmed, because the results of BMT are significantly better when performed in first remission than after patients have had extensive prior treatment and the procedure is carried out during relapse or in second or subsequent remissions (25-31). Over 50 factors of possible prognostic significance were examined to see if it would be possible to predict prognosis with reasonable probability. Age was an important variable; the median age was 25 in this series and younger patients did significantly better (15, 16). Only 58% of patients over 60 years of age had complete remissions, compared to 77% of the patients between 25 and 60, and 92% of those less than 25 years old. The median survival for patients over 60 was only 5 months, patients aged 25 to 60 had an intermediate prognosis with 31% alive and well over 5 years, and 51% of patients younger than 25 are living longer than 5 years with no evidence of disease (p < 0.001). Males had a lower remission incidence (78%) than females (89%), and only 31% of males survived >5 years compared to 46% of females (p = 0.057) (16). As in many other series, a high initial WBC was associated with a worse prognosis (16). Both the remission incidence and remission duration were worse for patients with pretreatment WBC of 30,000/mm3 or higher compared to those with WBC 14) had significantly shorter survival (p = 0.023) and remission durations (p = 0.005) than the majority with lower values (16). Phenotype was another important prognostic variable. The remission incidences for the T, null and B cell groups were respectively 85%, 84%, and 25%, and their remission durations (p = 0.048) and survival (p = 0.001) differed significantly, with the T phenotype being most favorable and B the worst (16). We had insufficient data on expression of c-ALLA, the common ALL antigen, but based on the findings in other series (17), if it had been possible to subdivide the null group into c-ALLA negative and positive, presumably the latter's remission duration would be similar to the T cell group while that of the c-ALLA negative patients would be worse. Patients presenting with large extramedullary masses or lymph nodes diagnosed histologically as lymphoblastic lymphoma (LBL) and whose tumor cells had the same phenotypes by marker analysis as ALL cells, but who had less than 50% blasts in the marrow at diagnosis, were not included in this series (16). However, they were treated with the same protocols and their response and survival were the same as the ALL patients. Another important prognostic factor for remission duration was the length of time required to achieve remission after the start of treatment (16); patients who had rapid clearing of leukemic cells from the marrow (20,000/mm3 or % circulating blasts >80% or both. 2. Either age >60 years or RNA index >14. 3. WBC 80%, and phenotype non-T or undetermined; 2) WBC 60 years or RNA index >14, days to 28 days, and phenotype non-T or undetermined.
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Similar risk factors have been reported in a recent multicenter trial conducted in Germany in which over 350 patients have been entered since 1978 (17, 18). Favorable factors were: age
