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© 1999 American Society for Clinical Oncology Secondary Leukemia or Myelodysplastic Syndrome After Treatment With EpipodophyllotoxinsFrom the National Cancer Institute, Bethesda, and The EMMES Corporation, Potomac, MD; Intergroup Rhabdomyosarcoma Study Committee; Eastern Cooperative Oncology Group; Children's Cancer Study Group; and Pediatric Oncology Group. Address reprint requests to Dr. Malcolm Smith, Room 741, EPN, Cancer Therapy Evaluation Program, NCI, Bethesda, MD 20892; email smithm{at}ctep.nci.nih.gov
PURPOSE: The incidence of secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and risk are not well characterized. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodophyllotoxin treatment.
METHODS: Twelve NCI-supported cooperative group clinical trials were identified that use epipodophyllotoxins at low (< 1.5 g/m2 etoposide), moderate (1.5 to 2.99 g/m2 etoposide), or higher ( RESULTS: The calculated cumulative 6-year risks for development of secondary leukemia for the low, moderate, and higher cumulative dose groups were 3.3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively. CONCLUSION: Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols.
SINCE PUBLICATION IN THE 1980s of reports of acute myeloid leukemia (AML) after treatment with epipodophyllotoxins, compelling evidence has emerged for a unique clinical syndrome of secondary AML following therapy with topoisomerase II inhibitors (eg, etoposide, teniposide, and doxorubicin).1,2 In contrast to treatment-related myelodysplasia or secondary leukemia after alkylator therapy, cases following epipodophyllotoxin treatment generally occur with a relatively short latency period, are often associated with translocations involving the MLL gene at chromosome band 11q23, and are most commonly M4 or M5 FAB subtypes.
Important questions relating to secondary leukemia after epipodophyllotoxin treatment remain unanswered. Of primary clinical interest is the quantitative risk of developing secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and schedule and the risk of subsequent secondary leukemia. Rather high estimates of cumulative risk for leukemia (5% to > 10%) have been reported for children with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma treated with epipodophyllotoxins.3-8 These high estimates may not reflect the true rate for patients with solid tumors who receive epipodophyllotoxins, because the solid tumor treatment regimens that use epipodophyllotoxins generally differ from those used to treat ALL (both in schedule of administration and in epipodophyllotoxin cumulative dose). The estimate of risk for patients with germ cell tumors receiving etoposide (daily times five schedule and cumulative dose Because of the important role of epipodophyllotoxins in the treatment of a variety of adult and pediatric tumors,13-15 the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) developed a monitoring plan in 1991 to obtain reliable estimates as expeditiously as possible of the risk of secondary leukemia after epipodophyllotoxin treatment. A description of the CTEP monitoring plan and the first analysis of submitted data were previously published.16 This report describes results of the second analysis and includes results from the low, moderate, and higher epipodophyllotoxin cumulative dose groups.16
Twelve NCI-supported cooperative group clinical trials (11 for patients with solid tumors and one for patients with ALL) were identified (Table 1) that prescribed the use of an epipodophyllotoxin at low (< 1.5 g/m2 etoposide), moderate (1.5 to 3.9 g/m2 etoposide), or higher (  4.0 g/m2 etoposide) cumulative doses (using a 1:2 conversion for teniposide dose to etoposide dose for trials using teniposide). Because of amendments to these protocols subsequent to development of the monitoring plan, the boundary between the moderate and higher cumulative dose group was changed from 4.0 to 3.0 g/m2. These 12 trials were selected from a pool of approximately 100 clinical trials sponsored by CTEP/NCI that used either etoposide or teniposide; selection of the 12 trials was based on their relatively large accrual and their treatment of patient populations with significant numbers of survivors at 2 to 3 years after treatment. Selection was made without knowledge of the number of secondary leukemias that had occurred to date on the trials. The three different cumulative doses of epipodophyllotoxins were selected based on the current usage of etoposide in adult and pediatric oncology. A group of protocols (typified by germ cell tumor studies) prescribed use of etoposide for four to six courses (0.5 g/m2 per course), yielding a cumulative dose of 2.0 to 3.0 g/m2. Studies with cumulative doses within this range constituted the moderate dose group. Another group of studies prescribed significantly higher cumulative doses (eg, Ewing's sarcoma studies), and these are classified as higher cumulative dose studies. A third group prescribed lower cumulative doses than those commonly used for germ cell tumors, and these studies make up the lower cumulative dose group.
The plan was activated in November 1991 with the request for a retrospective reporting of all cases of AML following therapy for patients on these 12 protocols. Subsequent cases of secondary AML were to be reported prospectively to CTEP as adverse drug reactions via the mechanisms prescribed in each of the protocols. Beginning in 1995, all cases of secondary AML occurring on NCI-sponsored clinical trials were to be reported using a special NCI Secondary AML Case Report form. The cases from the monitoring plan represent a subset of the total cases of secondary leukemia reported. For this monitoring report, pathology reports confirming the secondary leukemia diagnosis were obtained for all cases, and cytogenetic reports were obtained when cytogenetics testing was performed. The completeness of ascertaining cases of secondary leukemia on the monitored protocols was verified by comparing the listing of cases reported to the NCI to those cases known to the collaborating cooperative groups through their reporting mechanisms. Institutional cytogenetics laboratory reports as well as previous publications of patient karyotypes were centrally reviewed by a single cytogeneticist. Additional information was obtained from investigators or institutional laboratory directors as needed. Cytogenetic interpretations were not changed; however, karyotypes were rewritten according to the International System for Human Cytogenetic Nomenclature (1995)17 when indicated.
The statistical methodology for the monitoring plan calls for a separate analysis of the rate of secondary leukemia within each of the three epipodophyllotoxin cumulative dose groups, with the initial analysis for a group occurring when four instances of secondary leukemia (including myelodysplastic syndrome [MDS]) have been observed among patients in that group. For each analysis, total patient follow-up is calculated for all protocols within the cumulative dose group (excluding the first 36 weeks of follow-up, since the incidence of leukemia development during this period is extremely low), and the 4-year and 6-year cumulative incidence rates are estimated, along with their respective upper 95% confidence bounds. Within each cumulative dose group, a second analysis is conducted when eight cases of secondary leukemia have been reported. A final analysis is conducted when most patients within a group have been followed for at least 2 years, in order to protect against the downward adjustment in the estimate of the rate of secondary leukemia caused by the number of patients with only limited follow-up (and limited opportunity to develop secondary leukemia) in the earlier analyses. Within each stratum, the estimates of the 4-year and 6-year cumulative incidence rates of secondary leukemia are calculated by assuming that the number of (secondary AML) events follows a Poisson distribution with uniform rate over total risk time (excluding the initial 36 weeks for each patient). The annualized event rate is estimated by the number of observed events divided by total years at risk (k/T). This annualized rate is also an exponential hazard rate (l) and can be extrapolated to the 4-year or 6-year cumulative risk by means of the formula for exponential survival probability, 1 - exp(-
For each stratum, the 95% upper confidence bound (U(k)) on the expected number of events observed over the total risk time is a function strictly of the observed number of events (k), and it is read from a table of upper bound for a Poisson variable.18 This bound translates to a 95% upper bound on the cumulative risk of 1 - exp( Parametric and nonparametric methods were used to test for the homogeneity of secondary leukemia risk across the cumulative dose strata. The parametric test of homogeneity of rates assumed exponential hazard rates and was performed using SAS software (SAS Inc, Cary, NC). The nonparametric log-rank test of the equality of the distributions of time to secondary AML for the low cumulative dose group versus the moderate and higher cumulative dose groups was performed using a Monte Carlo estimate of the P value performed by STATXACT, with 1,000,000 replications, and adjusting for the multiple comparison (the test was performed in this fashion because STATXACT will not compare more than two distributions with the log-rank test).
Table 2 lists the number of cases and patient-years of follow-up for each of the clinical trials included in the monitoring plan. Table 3 provides the estimates of secondary leukemia risk for each of the monitoring plan strata.
For the low cumulative dose group, the second analysis of the CTEP monitoring plan was triggered by the occurrence of eight cases of secondary leukemia in this category. A brief description of the eight patients is given in Table 4. The calculated cumulative 6-year risk for development of secondary leukemia was 3.3%, with a 95% upper confidence bound of 5.9% (Table 3). This estimate of risk was similar to the 3.2% estimate obtained for the first monitoring of the low cumulative dose group.16 Case 87981, which was included in the first monitoring because of unexplained low blood counts and the transient finding of monosomy 7 in a small percentage of analyzed cells, was not included in the second monitoring listing of cases because subsequent follow-up documented normal hematopoietic function. Thus, the initial finding apparently represented a clinically insignificant cytogenetic observation. Two patients in the low cumulative dose group (patient nos. 12 and 53) received additional therapy before leukemia developed. For patient no. 12, this additional therapy included etoposide, whereas for patient no. 53, the subsequent therapy included additional alkylating agents. For both patients, leukemia developed within 4 years of diagnosis, consistent with a contribution of the initial monitoring plan therapy to their leukemogenic event(s).
The first analysis of the CTEP monitoring plan for the moderate cumulative dose group was triggered by the occurrence of four cases of secondary leukemia in this category. A brief description of these patients is given in Table 5. The calculated cumulative 6-year risk for development of secondary leukemia was 0.7%, with a 95% upper confidence bound of 1.6% (Table 3). One patient in this group exhibited secondary AML prior to 36 weeks from treatment initiation. This case had characteristics of epipodophyllotoxin-associated secondary leukemia, and there was no evidence that this case represented evolution of the primary germ cell tumor. For these reasons, the case was included in our analysis, although we retained the policy of not including a patient's initial 36 weeks on trial as part of the period of risk that counts toward patient-years of follow-up, as there is a very low risk of secondary AML during this initial period. In terms of estimating the overall cumulative risk of secondary AML, this approach is conservative and may lead to a slight overestimate of the cumulative risk. There were two additional cases (patient nos. 17 and 126) reported from moderate cumulative dose protocols that were not included as monitoring plan cases because the leukemias clearly represented evolution of the primary germ cell tumors (see bottom of Table 5), a phenomenon extensively documented in previous reports.19-22
The first analysis of the CTEP monitoring plan for the higher cumulative dose group was triggered by the occurrence of five cases of secondary leukemia in this category. A brief description of these patients is given in Table 6. The calculated cumulative 6-year risk for development of secondary leukemia was 2.2%, with a 95% upper confidence bound of 4.6% (Table 3).
We performed both parametric and nonparametric tests of the homogeneity of secondary leukemia risk across the strata. The parametric test of homogeneity of rates yielded a P value of .012. The nonparametric log-rank test of the equality of the distributions of time to secondary AML for the low cumulative dose group versus the moderate and higher cumulative dose groups combined yielded a two-sided P value of .011. Thus, contrary to expectations, the risk of secondary leukemia seemed greater among patients treated on the monitoring plan protocols that prescribed lower cumulative dosages of epipodophyllotoxins than on the group of protocols that prescribed higher dosages of these agents. G-banded bone marrow chromosome analysis was performed at first diagnosis of myelodysplasia or acute leukemia in 16 monitoring plan patients. Results of five of these analyses (patient nos. 11, 12, 13, 126, and 127) have been previously published.22-24 Clonal cytogenetic abnormalities were found in 14 cases. Two of the patients with abnormal karyotypes (patient nos. 17 and 126) were those with leukemic transformation of their mediastinal germ cell tumors; thus, the incidence of clonal abnormalities among patients with treatment-associated myelodysplasia or acute leukemia was 86% in this series. One of the two patients with normal bone marrow karyotypes (patient no. 13) was studied at diagnosis of MDS, before transformation to AML; therefore, it is possible an abnormal clone evolved subsequently. Of note is the fact that three of these patients with treatment-associated myelodysplasia or leukemia had underlying constitutional chromosome abnormalities (patient nos. 9 and 118, Klinefelter's syndrome) or a genetic syndrome (patient no. 127, Beckwith-Wiedemann syndrome). One of the patients with secondary leukemia (patient no. 180) had T-cell ALL, with the characteristic 14q11.2 breakpoint in his bone marrow karyotype. The remaining patients were classified morphologically and/or immunophenotypically as having myelodysplasia or AML. All of their abnormal karyotypes were consistent with these diagnoses. However, only three patients had rearrangements generally associated with epipodophyllotoxin exposure: patient nos. 71 and 127 with rearrangement of band 11q231,2 and patient no. 9 with a 15;17 translocation.25,26
The primary objective of the epipodophyllotoxin monitoring plan was to establish whether the risk of secondary leukemia associated with regimens that used epipodophyllotoxins was prohibitively high. The data from the monitoring plan described in this article suggest that for cumulative etoposide doses of 5.0 g/m2 or less (given primarily on a daily times five schedule), the risk of secondary leukemia is not inordinately increased above that contributed by the other agents used in the regimens. These results confirm previous reports that the leukemogenicity of etoposide is low when it is used in regimens commonly used for the treatment of germ cell tumors.9-12 Specifically, the estimate of risk for the moderate cumulative dose group (0.7% at 6 years) is virtually identical to the 0.6% estimate of risk for more than 1,800 patients with a median follow-up of approximately 5 years who received etoposide at a dose of less than 2.0 g/m2.10 Thus, these data support the relative safety of using the epipodophyllotoxins in a manner similar to that of the monitoring plan regimens. The monitoring plan data provide no support for a clinically meaningful dose-response effect for the leukemogenic activity of the epipodophyllotoxins within the cumulative dose range encompassed by the monitoring plan and with the schedules for epipodophyllotoxin administration used in the monitoring plan studies. These data suggest that, within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, dactinomycin, and other agents, factors other than epipodophyllotoxin cumulative dose are of primary importance in determining the risk of secondary leukemia. This finding is important because previous reports demonstrated that higher cumulative alkylator doses are associated with an increased risk of secondary leukemia,27-36 and a critical goal of the monitoring plan was to determine whether a clinically relevant dose-response relationship existed for the epipodophyllotoxins within the cumulative dose range currently in clinical use. Although the monitoring plan data do not indicate an additional risk of secondary leukemia when epipodophyllotoxins are used to a cumulative dose of less than 5.0 g/m2 on daily times 2- to 5-day schedules of administration (within the context of regimens that use standard doses of alkylating agents and other DNA-damaging agents), data from lymphoid leukemia and lymphoma studies do indicate significant risk of secondary leukemia for regimens that include epipodophyllotoxins. Regimens without epipodophyllotoxins report cumulative risks of less than 1.0%,37 whereas regimens that use epipodophyllotoxins report risks in excess of 5%.3-8,38 Several factors may explain the difference between the findings reported here and those from leukemia studies that used epipodophyllotoxins. First, the leukemia studies generally used higher cumulative epipodophyllotoxin doses, in some cases as high as 9.2 to 19.0 g/m2 etoposide (assuming a 1:2 conversion for teniposide and etoposide doses).4 The schedule of administration also differed between the leukemia studies and those studies included in the monitoring plan. The epipodophyllotoxins are cell cycle–specific agents, and large differences in antitumor effect have been noted for different schedules (eg, daily times five administration of etoposide is much more active than 24-hour infusion of the same total dose).39 Thus, schedule may play an important role in determining leukemia risk. In vitro data support increased leukemia risk for intermittent exposure schedules modeled after those used in leukemia regimens,40,41 and clinical results also suggest increased leukemogenicity for intermittent administration schedules.4,38 The etoposide administration schedule associated with the highest cumulative incidence of secondary leukemia is weekly or twice-weekly administration, a schedule not commonly used in current treatment regimens. Almost all of the protocols included in the monitoring plan prescribed using the epipodophyllotoxin on a daily times three or daily time five schedule. The estimated 3.3% 6-year cumulative rate of secondary leukemia development for the low cumulative dose group (virtually identical to that reported after the first monitoring event) is similar to rates reported for other patient populations receiving alkylator-based therapy.28,29,31,42-46 The Intergroup Rhabdomyosarcoma Study III (IRS-III) patients included in the monitoring plan received a relatively high cumulative dose of cyclophosphamide. An increased risk of leukemia after treatment with cyclophosphamide has been reported,28,31,36,47,48 although cyclophosphamide seems to be less leukemogenic than some other alkylating agents and its leukemogenicity seems to be dependent on cumulative dose.28,35,36,49 Several recent reports have shown that the risk of secondary AML or MDS among patients with early breast cancer who receive standard-dose cyclophosphamide-containing adjuvant chemotherapy is not much higher than in the general population.36,50-52 For example, Valagussa et al50 observed a cumulative risk of 0.23% with cyclophosphamide, methotrexate, fluorouracil–based therapy, Tallman et al51 observed a cumulative risk at 6 years after cyclophosphamide, methotrexate, fluorouracil–based therapy of approximately 0.1%, and Curtis et al36 observed a barely detectable increase in leukemia risk for women treated for breast cancer who received total cyclophosphamide doses of less than 10 g. However, Curtis et al reported that when the cyclophosphamide cumulative dose was more than 20 g, the risk of secondary leukemia was 5.7 times that for women not treated with alkylating agents.36 Another recent report described a 10-year estimated leukemia risk of 2.0% for patients receiving both cyclophosphamide (to a dose of > 6 g/m2) and doxorubicin.53 Among a group of children with rhabdomyosarcoma treated at a single institution, three cases of secondary AML were observed among 68 treated patients (4.4%) who received more than 16.8 g/m2 cyclophosphamide, whereas no cases of secondary leukemia were observed among 62 children receiving lower cumulative doses of cyclophosphamide.54 Thus, available data indicate that cyclophosphamide has relatively low leukemogenic potential but that this potential may be enhanced by higher cumulative dosages and by combination with agents, such as doxorubicin, that inhibit topoisomerase II. For comparison with these previously published data, the IRS-III regimens of the lower cumulative dose group and all of the regimens of the high cumulative dose group prescribed cumulative cyclophosphamide doses of 25 to 35 g/m2 (or equivalent doses of ifosfamide). Recent reports highlight the concern of enhanced leukemogenic potential for regimens that use alkylating agents at very high doses in combination with agents that inhibit topoisomerase II. Miser et al55 reported five cases of secondary leukemia among 60 patients receiving very intensive therapy with high-dose ifosfamide and cyclophosphamide given with etoposide and doxorubicin. Similar high rates of secondary leukemia were observed at Memorial Sloan-Kettering Cancer Center, using alkylator-intensive regimens for neuroblastoma and Ewing's sarcoma.56 Thus, at least some of the very dose-intensive regimens that have been tested in children with tumors associated with very poor prognosis seem to have an unacceptably high risk of secondary leukemia, and the further escalation of doses will be limited by this unacceptable risk. Although abnormalities at chromosome band 11q23 (the locus for the MLL gene) and the M4 or M5 FAB subtype are considered typical for secondary leukemias after epipodophyllotoxin therapy,1 these were found in only a minority of cases reported from patients entered onto protocols of the monitoring plan. There are several possible explanations for this paucity of cases with abnormalities at chromosome band 11q23. Epipodophyllotoxins may increase the risks of leukemias with other cytogenetic abnormalities besides rearrangements of the MLL gene. Alternatively, the leukemias with cytogenetic abnormalities not involving chromosome band 11q23 may have been caused by the other chemotherapy agents given in the monitoring plan protocol regimens and may not be related to treatment with epipodophyllotoxins. Three of the patients who developed leukemia on monitoring plan protocols had hereditary conditions related to cancer susceptibility: patient no. 127 from the higher cumulative dose stratum had Beckwith-Wiedemann syndrome, and patient nos. 9 and 118 from the moderate dose plan had Klinefelter's syndrome. These patients highlight the importance of identifying host characteristics associated with inherent susceptibility for developing leukemia after chemotherapy treatment.57,58 In conclusion, data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols. Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia.
Supported by the Department of Health and Human Services, U.S. Public Health Service grant nos. CA-24507, CA-30138, CA-30969, CA-29139, and CA-13539 (J.R.A. and R.H.); grant no. CA-23318 (P.J.C.); grant no. CA-13539 (A.K., M.K., and J.M.); and grant nos. CA-30969 and CA-29139 (V.J.L. and J.S.). The authors gratefully acknowledge the clinical investigators and cytogeneticists of the institutions of the Children's Cancer Group, the Pediatric Oncology Group, and the Eastern Cooperative Oncology Group who contributed to this effort by their prompt and complete reporting of the cases of secondary leukemia described in this article.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2.0 g/m2) in combination with cisplatin and bleomycin is approximately 0.6%.
t), where t is the time at risk (4 years or 6 years, minus the initial 36 weeks). These estimates are the cumulative risk for surviving patients, because patients are censored at death for nonleukemia causes. The statistical methodology assumes a constant hazard rate for secondary leukemia across the entire at-risk period. 
