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Original Article

Acute Myeloid Leukemia in Children Treated with Epipodophyllotoxins for Acute Lymphoblastic Leukemia

List of authors.
  • Ching-Hon Pui, M.D.,
  • Raul C. Ribeiro, M.D.,
  • Michael L. Hancock, M.S.,
  • Gaston K. Rivera, M.D.,
  • William E. Evans, Pharm.D.,
  • Susana C. Raimondi, Ph.D.,
  • David R. Head, M.D.,
  • Frederick G. Behm, M.D.,
  • M. Hazem Mahmoud, M.D.,
  • John T. Sandlund, M.D.,
  • and William M. Crist, M.D.

Abstract

Background and Methods.

Treatment of cancer with the epipodophyllotoxins (etoposide and teniposide) has been linked to the development of acute myeloid leukemia (AML) in children and adults, but the factors that might influence the risk of this complication of therapy are poorly defined. We therefore assessed the importance of potential risk factors for secondary AML in 734 consecutive children with acute lymphoblastic leukemia who attained complete remission and received continuation (maintenance) treatment according to different schedules of epipodophyllotoxin administration.

Results.

Secondary AML was diagnosed in 21 of the 734 patients, in 17 of whom this complication was the initial adverse event. Prolonged administration of epipodophyllotoxin (teniposide with or without etoposide) twice weekly or weekly was independently associated with the development of secondary AML (P<0.01 by Cox regression analysis). The overall cumulative risk of AML at six years was 3.8 percent (95 percent confidence interval, 2.3 percent to 6.1 percent); but within the subgroups treated twice weekly or weekly, the risks were 12.3 percent (95 percent confidence interval, 5.7 percent to 25.4 percent) and 12.4 percent (95 percent confidence interval, 6.1 percent to 24.4 percent), respectively. In the subgroups not treated with epipodophyllotoxins or treated with them only during remission induction or every two weeks during continuation treatment, the highest cumulative risk was 1.6 percent (95 percent confidence interval, 0.4 percent to 6.1 percent). After adjustment for treatment frequency, there was no apparent relation between the total dose of epipodophyllotoxins and the development of secondary AML. The relative hazard of etoposide as compared with teniposide could not be determined.

Conclusions.

The risk of epipodophyllotoxin-related AML depends largely on the schedule of drug administration. Other factors, including the cumulative dose of epipodophyllotoxin, radiotherapy, and the initial biologic features of the leukemic blast cells, do not appear to have critical roles. (N Engl J Med 1991;325: 1682–7.)

Introduction

ETOPOSIDE and teniposide, two semisynthetic derivatives of podophyllotoxin, have a broad range of antineoplastic activity and have been used widely in the treatment of children and adults with malignant diseases.1 , 2 Reports appearing over the past four years have implicated these agents in the development of acute myeloid leukemia (AML) in patients treated for solid tumors or acute leukemia of lymphoid origin (ALL).3 4 5 6 7 8 9 10 In contrast to the myeloid leukemias induced by alkylating agents,11 cases of leukemia linked to epipodophyllotoxin therapy tend to appear early after diagnosis of the primary tumor (i.e., within six years), to lack a myelodysplastic phase, and to involve monoblasts or myelomonoblasts and abnormalities of the long arm of chromosome 11 (11q23 region).4 , 5 , 9 , 10

In 1989, we reported a relatively high cumulative risk of secondary AML in patients who had received intensive combination chemotherapy and cranial irradiation for ALL.4 At that time, we were unable to show an independent association between this complication and any specific component (or components) of therapy, including the epipodophyllotoxins. A T-cell immunophenotype was the only clinical or biologic feature significantly associated with the development of secondary AML after adjustment for competing covariates. With longer follow-up and the accrual of additional cases of secondary AML, risk-factor analysis has indicated that prolonged exposure to etoposide or teniposide given weekly or twice weekly exerts the greatest influence on leukemogenesis.

Methods

Patients

From May 1979 to September 1988, 792 consecutive patients less than 19 years old were registered in successive therapeutic studies of newly diagnosed ALL at St. Jude Children's Research Hospital. Of the 785 patients who could be evaluated, 734 entered complete remission and were randomly assigned to receive continuation (maintenance) treatment; this group was the focus of our analysis. All treatment protocols were approved by the institutional review board and the National Cancer Institute; signed informed consent was obtained from the patients or their parents.

Cytochemical Studies

Bone marrow cells, obtained at both diagnosis and relapse, were stained according to standard techniques, including the use of Wright—Giemsa, periodic acidSchiff, myeloperoxidase, Sudan black B, naphthol AS-D chloroacetate esterase, and α-naphthyl butyrate esterase. The diagnosis of ALL or AML was based on morphologic and cytochemical criteria of the French—American—British (FAB) Working Group,12 , 13 as modified in a recent workshop.14 Thus, by definition, all patients with ALL had less than 3 percent blast cells positive for myeloperoxidase and Sudan black B (myeloid pattern) staining or less than 20 percent positive for butyrate esterase (myeloid pattern) staining; none of the cells contained Auer rods.

Immunologic Cell Typing

Bone marrow cells were separated on a Ficoll–Hypaque gradient. Cell-surface antigens were detected by a standard indirect immunofluorescence assay with monoclonal antibodies to lymphoid-associated antigens. Cells were analyzed for fluorescent activity by fluorescence microscopy or flow cytometry (Coulter EPICS C). Blast cells were also tested for surface immunoglobulin, cytoplasmic immunoglobulin, and in earlier cases, rosette formation with sheep erythrocytes. Depending on the pattern of reactivity, cells were classified as T cells (i.e., positive for at least two of the three antigens CD7, CD5, and CD2, regardless of E-rosette formation), B cells (positive for surface immunoglobulin), preB cells (positive for cytoplasmic immunoglobulin), or early preB cells (positive for CD19; negative for CD7, CD5, CD2, cytoplasmic immunoglobulin, and surface immunoglobulin; and positive or negative for CD22, CD24, and CD10).15

Cytogenetic Studies

Bone marrow samples were prepared according to the method of Williams et al.,16 and metaphases were G-banded by treatment with trypsin and staining with Wright's stain. Chromosomal abnormalities were classified according to the International System for Human Cytogenetic Nomenclature.17

Treatment

Table 1. Table 1. Risk of Secondary AML According to Regimen.

As summarized in Table 1, patients were enrolled in either Total Therapy Study X or Total Therapy Study XI.18 , 19 In Study X, they were treated according to a protocol for lower-risk ALL (X-LR) if they had an initial leukocyte count below 100×109 per liter and had no mediastinal mass, no blast cells in the cerebrospinal fluid, and no sheep-erythrocyte receptors on leukemic blast cells. All patients treated with regimen X-LR received remission-induction therapy consisting of prednisone, vincristine, and asparaginase for four weeks; those who entered complete remission were then randomly assigned to receive either of two continuation treatments. One regimen (X-LR1) consisted of weekly intrathecal and intravenous administration of a high dose of methotrexate (1 g per square meter of body-surface area) for 3 weeks, followed by continuation therapy for 120 weeks with oral mercaptopurine daily (50 mg per square meter) and oral methotrexate weekly (25 mg per square meter), interrupted every 6 weeks (to week 72 only) for pulse administration of a high dose of methotrexate. The other regimen (X-LR2) comprised cranial irradiation (1800 cGy) and intrathecal methotrexate followed by oral mercaptopurine daily (50 mg per square meter) and oral methotrexate weekly (25 mg per square meter) for the first 35 weeks, six courses of cyclophosphamide (100 mg per square meter per day orally on days 1 to 7) and doxorubicin (30 mg per square meter intravenously on day 8) during weeks 36 to 53, nine courses of teniposide (150 mg per square meter intravenously) plus cytarabine (300 mg per square meter intravenously) every 2 weeks during weeks 54 to 71, and mercaptopurine plus methotrexate (as described above) during weeks 72 to 120.

The 85 patients judged to be at higher risk for relapse in Study X were treated with regimen X-HR, consisting of intensive chemotherapy with teniposide (165 mg per square meter intravenously) plus cytarabine (300 mg per square meter intravenously) twice weekly in four doses immediately before and after a conventional four-week induction course of prednisone, vincristine, and asparaginase. Continuation therapy consisted of oral mercaptopurine daily (50 mg per square meter) and oral methotrexate weekly (40 mg per square meter) for 2.5 years, with five pulse doses of teniposide and cytarabine (as described above) given over a 2-week period every 10 weeks during the first year. Periodic intrathecal methotrexate and delayed cranial irradiation (2400 cGy at one year) were administered as therapy for subclinical central nervous system leukemia.

In Study XI,19 patients were classified as being at higher risk of relapse if they had an initial leukocyte count of ≥100×109 per liter or two or more unfavorable prognostic features (leukemic-cell DNA index <1.16, black race, chromosomal translocation in leukemic cells, leukocyte count >25×109 per liter, and age <2 years or ≥10 years). All other patients were considered to be at lower risk. Both risk groups received remission-induction therapy consisting of prednisone, vincristine, asparaginase, and teniposide (200 mg per square meter intravenously), plus cytarabine (300 mg per square meter intravenously) on days 22, 25, and 29 and a high dose of methotrexate (2 mg per square meter intravenously) on day 43. On attaining complete remission, patients in both risk groups were stratified according to leukocyte count, age, and sex and randomly assigned to one of three continuation-treatment groups.

A third of the lower-risk group (39 patients) received standard 120-week continuation therapy (regimen XI-LR1) with oral mercaptopurine daily (75 mg per square meter) plus parenteral methotrexate weekly (40 mg per square meter) for 3 weeks, alternating with treatment with prednisone daily (40 mg per square meter) and vincristine weekly (1.5 mg per square meter) during the fourth week. Two thirds of the lower-risk group (69 patients) were randomly assigned to a treatment regimen (XI-LR2) in which four pairs of drugs were given in rotation weekly over a 120-week period: etoposide (300 mg per square meter intravenously) plus cyclophosphamide (300 mg per square meter intravenously) once a week; mercaptopurine plus methotrexate (as in regimen XI-LR1); teniposide (150 mg per square meter intravenously) and cytarabine (300 mg per square meter intravenously) once a week; and prednisone and vincristine (as in regimen XI-LR1).

Two thirds of the higher-risk group (148 patients) were randomly assigned to the same treatment given the patients assigned to regimen XI-LR2, with additional cranial irradiation (1800 cGy) after one year of complete remission (regimen XI-HR2). Finally, a third of the higher-risk group (84 patients) were assigned to regimen XI-HR3, in which the same pairs of drugs were given in rotation every six weeks; irradiation of the central nervous system (1800 cGy) for subclinical leukemia was also given at one year. Patients who had central nervous system leukemia at diagnosis received cranial irradiation (2400 cGy) after they had been in remission for one year. Thus, with the exception of the frequency of epipodophyllotoxin treatment (every other week vs. every week), the planned cumulative doses of epipodophyllotoxins, as well as those of other agents and radiation, were equivalent in regimens XI-HR2 and XI-HR3.

Statistical Analysis

The cumulative risk of secondary AML during initial complete remission was estimated with the Kaplan–Meier method.20 Ninety-five percent confidence intervals for each estimate were calculated with the use of a logarithmic transformation.21 Data on patients who died or had any type of relapse were censored as of the time of death or relapse; patients in whom relapse occurred and AML subsequently developed were studied only for their demographic features and chromosomal abnormalities, to avoid confounding the statistical analyses with the complex regimens used to reinduce remission.

The following clinical and biologic features were analyzed for their relation to the development of AML: age (1 to 9 years vs. <1 year and ≥10 years), race (white vs. nonwhite), sex, leukocyte count (<25×109 vs. ≥25×109 per liter), serum lactate dehydrogenase level (<400 vs. ≤400 U per liter); the presence or absence of central nervous system leukemia, a mediastinal mass, hepatomegaly, and splenomegaly; cellular DNA content (DNA index <1.16 vs. ≥1.16); leukemic-cell ploidy (hyperdiploidy vs. other types); chromosomal translocation; FAB subtype (L1 vs. L2); immunophenotype; and components of treatment (teniposide, etoposide, cyclophosphamide, radiotherapy, and epipodophyllotoxin treatment schedule and dosage). The dosages of teniposide and etoposide were weighted equally, since the potency of teniposide in vitro22 — 10 times that of etoposide — is offset in vivo by extensive protein binding, resulting in 10 times less unbound (active) drug.23 , 24 The contributions of all covariates (features at presentation and treatment components) to the development of AML were estimated with the Cox proportional-hazards model.25 Relative risks were calculated with the coefficient and standard error from the Cox analyses, and P values with the likelihood-ratio test.

Results

Table 2. Table 2. Clinical Characteristics of the 21 Patients with Secondary AML.

Secondary AML developed in 21 patients — as a first adverse event in 17 — accounting for 10.4 percent of all hematologic relapses during continuous complete remission (Table 2). These 21 patients consisted of 13 boys and 8 girls whose ages ranged from 2 to 17 years at the time of diagnosis of ALL (median, 6). Their median leukocyte count was 8.4×109 per liter (range, 1.6 to 246). Central nervous system leukemia was present in five (Patients 3, 5, 6, 8, and 12), and a mediastinal mass in five (Patients 3, 4, 6, 7, and 8). The median time from the diagnosis of ALL to the development of AML was 40 months (range, 15 to 100). None of the 17 patients in whom secondary AML was the first adverse event had this complication more than six years after the diagnosis of ALL.

Figure 1. Figure 1. Cumulative Risk of Secondary AML during Initial Complete Remission of ALL in Patients Given Epipodophyllotoxins either Weekly or Every Other Week (Biweekly).

P = 0.01 by the log-rank test for the difference between groups. Values in parentheses are 95 percent confidence intervals.

Figure 2. Figure 2. Schedules of Epipodophyllotoxin Treatment Associated with an Increased Risk of Secondary AML.

Regimen XI-HR2 is included to illustrate a treatment schedule (involving administration of epipodophyllotoxin every other week) that was associated with a lower risk. Drug dosages are given in the Methods section.

The probability that AML would develop within six years in any patient in continuous complete remission was 3.8 percent (95 percent confidence interval, 2.3 percent to 6.1 percent; number at risk at six years, 243). Higher risks were apparent in the subgroups treated with the X-HR and XI-HR3 regimens — 12.3 percent (95 percent confidence interval, 5.7 percent to 25.4 percent) and 12.4 percent (95 percent confidence interval, 6.1 percent to 24.4 percent), respectively (Table 1). The risk in patients treated with the XI-HR3 regimen contrasted sharply with the low cumulative risk of secondary AML (1.6 percent; 95 percent confidence interval, 0.4 percent to 6.1 percent) in patients treated with the XI-HR2 regimen (Fig. 1). These subgroups (XI-HR2 and XI-HR3) had comparable risk factors and received identical forms of radiotherapy and chemotherapy, but their schedules of chemotherapy were different (Fig. 2). The cumulative risks of the development of AML were low or negligible in groups not given epipodophyllotoxins or given them with a frequency other than weekly or twice weekly (Table 1).

Table 3. Table 3. Relation of Presenting Characteristics and Lymphoblast Biologic Features to the Development of Secondary AML in Patients in First Complete Remission.

Factors that were significantly related to the development of secondary AML according to the univariate Cox analysis are shown in Table 3. Half the factors were characteristic of higher-risk ALL (T-cell immunophenotype, mediastinal mass, and initial central nervous system leukemia), and the other half were related to treatment (prolonged treatment with weekly or twice-weekly doses of an epipodophyllotoxin, higher cumulative dose of epipodophyllotoxin, teniposide therapy, and radiotherapy). The relative risk of secondary AML was highest among patients who received prolonged epipodophyllotoxin therapy in weekly or twice-weekly doses (12.1; 95 percent confidence interval, 3.9 to 37.1). None of the three biologic factors, or the treatment-related factors (teniposide therapy, radiotherapy, and the cumulative dose of epipodophyllotoxin), remained significantly related to secondary AML after adjustment for the frequency of epipodophyllotoxin treatment. The frequency of treatment remained significant (relative risk, 6.7; 95 percent confidence interval, 1.5 to 30.9; P<0.01) after adjustment for all competing covariates.

Table 4. Table 4. Leukemic-Cell FAB Phenotype and Karyotype at Diagnosis of Secondary AML.*

According to standard FAB criteria, eight cases of secondary AML were characterized as M5, six as M4, three as M2, and one each as M1 or M7; the remaining two cases were of the M0 FAB subtype (Table 4). Only four cases of AML were preceded by a preleukemic phase (Patients 3, 6, 8, and 19). Chromosomal abnormalities were present in all but 1 of the 21 cases at the time of diagnosis of AML. Translocations, observed in 18 cases, were the most prominent finding. The chromosomal regions most commonly involved in structural abnormalities included 11q23 (16 cases), 9p21—p22 (8 cases), 21q22 (3 cases), 19p13 (2 cases), 16p13 (2 cases), and 18q23 (2 cases). Previously recognized nonrandom chromosomal abnormalities included t(9;11)(p21—p22;q23) in seven cases, t(11;19)(q23;p13) in two, and t(11;16)(q23;p13) in one. Sequential cytogenetic studies revealed that the original karyotype was replaced by a completely different leukemic stem line at the time of diagnosis of AML in 16 of the 18 cases. The original karyotypes in these 18 cases were typical of the findings in childhood ALL in general (data not shown).

Thirteen patients entered remission after receiving reinduction therapy for AML; one (Patient 13) is still receiving reinduction therapy at this writing. Only two patients have remained in remission (to date, for 18 and 32 months): Patient 6, who underwent autologous bone marrow transplantation, and Patient 11, who received intensive chemotherapy for 9 months. The remaining 11 patients relapsed 2 to 51 months after the diagnosis of AML (median, 9).

Discussion

The results of this study establish a relation between the schedule of epipodophyllotoxin therapy and the development of secondary AML. Patients who received these agents in weekly or twice-weekly doses for prolonged periods had a risk of secondary AML approximately 12 times that of patients treated according to other schedules. The effect of the timing of epipodophyllotoxin treatment was most apparent in Total Therapy Study XI, which compared slow and rapid rotation of drug combinations in higher-risk patients stratified according to age, sex, and leukocyte count.19 The patients in the XI-HR3 subgroup, who received epipodophyllotoxins weekly, had a clearly increased risk of AML as compared with the patients in the XI-HR2 subgroup, who received the agents every other week. This schedule-dependent effect is supported by the very low risk of AML associated with the X-LR2 regimen (teniposide every other week), as compared with the high risk associated with the X-HR regimen (teniposide twice weekly). The limited use of the epipodophyllotoxins in the high-risk schedules for remission-induction—consolidation therapy did not increase the risk of secondary AML.

These observations suggest that weekly or twice-weekly administration of teniposide or etoposide for prolonged periods leads to transforming mutations in normal myeloid progenitor cells. Epipodophyllotoxin-induced cytotoxicity is mediated largely by the enzyme topoisomerase II, which regulates the superhelical configuration of cellular DNA.26 27 28 29 30 31 By stabilizing a complex between DNA and topoisomerase II and inhibiting its repair, etoposide and teniposide induce single- and double-strand breaks in DNA which have been related to the agents' cytotoxic effects.27 The epipodophyllotoxins are also potent clastogenic agents, causing high frequencies of sister chromatid exchange and chromosomal aberrations in vitro.32 33 34 Interruption of normal genetic sequences and the illegitimate recombination of chromosomal fragments could be expected to lead to transforming mutations in some hematopoietic progenitors. In this regard, the long arm of chromosome 11 is one of the most frequently deleted or rearranged chromosomal regions in cells exposed to epipodophyllotoxins,33 a finding that may explain the preferential involvement of the 11q23 region in our patients. Less intensive use of these agents (e.g., administration every two weeks) may allow sufficient time for damage to DNA to be repaired, so that relatively high cumulative doses can be given without appreciably increasing the risk of AML.

Interaction with other antileukemic agents could greatly worsen the DNA damage mediated by the epipodophyllotoxins. In both of our treatment subgroups with an increased cumulative risk of AML, two antimetabolites — methotrexate and mercaptopurine —were given immediately before teniposide, a sequence that has been shown to reduce purine nucleotide pools and increase epipodophyllotoxin-induced DNA damage in vitro.35 , 36 Combination therapy with other agents that interact with DNA, such as cisplatin,37 might also be expected to increase the risk of transforming mutations. Indeed, Ratain et al.3 reported four cases of secondary AML among 24 patients with small-cell carcinoma of the lung who received cisplatin and etoposide intravenously (weekly for 12 weeks and then biweekly) and then survived for more than 1 year after therapy began.

We could not determine reliably whether the cumulative dose of epipodophyllotoxins plays a major part in the development of AML. That is, the distribution of patients according to the dosages of teniposide and etoposide was not adequate to permit clear delineation of a dose–response effect. Even though, in our cohort, the cumulative dose was significant in univariate analysis, it did not remain significant after adjustment for the treatment schedule. It should be stressed that patients treated with regimens XI-LR2 and XI-HR2 were at much lower risk for AML than were those treated with regimen XI-HR3, even though all three subgroups were scheduled to receive the same cumulative dose of epipodophyllotoxin. In fact, patients treated with regimen XI-HR3 actually received a lower cumulative dose: only 60 percent of this subgroup received 90 percent or more of the planned treatment, as compared with 84 percent of the other two subgroups.19 Moreover, the risk of AML was high among patients treated with the X-HR regimen, which specified twice-weekly administration of epipodophyllotoxin up to a relatively low cumulative dose (4620 mg per square meter).

Although teniposide4 5 6 , 8 and etoposide3 , 5 , 7 , 10 have each been associated with the development of AML, their relative carcinogenic effects are uncertain. We were unable to resolve this issue in our analysis because all patients treated with an epipodophyllotoxin received teniposide and none received etoposide alone. Moreover, the treatment schedules and cumulative doses of teniposide of the patients who received both agents differed from those of the patients who received teniposide by itself. The commercial availability of etoposide and its wide use in the treatment of cancers of adults contrast with the experimental status of teniposide and its currently limited applications. Thus, further studies are needed to establish the relative leukemogenic potential of these agents.

In our earlier study,4 the risk of secondary AML was greatly increased in patients with T-cell ALL, suggesting that epipodophyllotoxins had a carcinogenic effect related to the patient's immunophenotype. With longer follow-up and the accrual of additional cases, this relation has disappeared. Indeed, the biologic characteristics of the blast cells were not independently associated with the development of AML, a finding consistent with induction of a new neoplasm rather than a switch in lineage within the original clone.

Increasing concern about the carcinogenic effect of the epipodophyllotoxins has raised questions about the future of these agents in cancer chemotherapy. The results of this study suggest that the risk of secondary AML may become acceptable if treatment schedules leave adequate time between doses of epipodophyllotoxin. Administration every other week, associated with an acceptable risk of AML, did not compromise outcome in patients with either lower- or higher-risk ALL. The estimated four-year event-free survival (±SE) in the subgroup given teniposide or etoposide every other week was 76±4 percent, a result comparable to the best outcomes in other contemporary trials.19 Our study illustrates well the costs of intensifying therapy for childhood ALL; the challenge now is to minimize the mutagenic effects of the epipodophyllotoxins without losing their full therapeutic benefits and to identify patients at increased risk for AML.

Funding and Disclosures

Supported by grants (CA-20180 and CA-21765) from the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC).

We are indebted to John Gilbert for editorial review, to Mary Rafferty for data management, and to Peggy Vandiveer for assistance in the preparation of the manuscript.

Author Affiliations

From the Departments of Hematoiogy-Oncology (C.-H.P., R.C.R., G.K.R., M.H.M., J.T.S., W.M.C.), Pathology and Laboratory Medicine (C.-H.P., S.C.R., D.R.H., F.G.B.), and Biostatistics and Information Systems (M.L.H.) and the Pharmaceutial Division (W.E.E.), St. Jude Children's Research Hospital, and the Department of Pediatrics and Pathology, University of Tennessee, Memphis, College of Medicine, all in Memphis. Address reprint requests to Dr. Pui at St. Jude Children's Research Hospital, 332 N. Lauderdale, P.O. Box 318, Memphis, TN 38101.

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Citing Articles (535)

    Figures/Media

    1. Table 1. Risk of Secondary AML According to Regimen.
      Table 1. Risk of Secondary AML According to Regimen.
    2. Table 2. Clinical Characteristics of the 21 Patients with Secondary AML.
      Table 2. Clinical Characteristics of the 21 Patients with Secondary AML.
    3. Figure 1. Cumulative Risk of Secondary AML during Initial Complete Remission of ALL in Patients Given Epipodophyllotoxins either Weekly or Every Other Week (Biweekly).
      Figure 1. Cumulative Risk of Secondary AML during Initial Complete Remission of ALL in Patients Given Epipodophyllotoxins either Weekly or Every Other Week (Biweekly).

      P = 0.01 by the log-rank test for the difference between groups. Values in parentheses are 95 percent confidence intervals.

    4. Figure 2. Schedules of Epipodophyllotoxin Treatment Associated with an Increased Risk of Secondary AML.
      Figure 2. Schedules of Epipodophyllotoxin Treatment Associated with an Increased Risk of Secondary AML.

      Regimen XI-HR2 is included to illustrate a treatment schedule (involving administration of epipodophyllotoxin every other week) that was associated with a lower risk. Drug dosages are given in the Methods section.

    5. Table 3. Relation of Presenting Characteristics and Lymphoblast Biologic Features to the Development of Secondary AML in Patients in First Complete Remission.
      Table 3. Relation of Presenting Characteristics and Lymphoblast Biologic Features to the Development of Secondary AML in Patients in First Complete Remission.
    6. Table 4. Leukemic-Cell FAB Phenotype and Karyotype at Diagnosis of Secondary AML.*
      Table 4. Leukemic-Cell FAB Phenotype and Karyotype at Diagnosis of Secondary AML.*

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