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Sex Differences in Prognosis for Children With Acute Lymphoblastic Leukemia

From the Departments of Hematology-Oncology, Biostatistics and Epidemiology, Pharmaceutical Sciences, and Pathology and Laboratory Medicine, St. Jude Children's Research Hospital, and University of Tennessee, College of Medicine and Pharmacy, Memphis, TN.

Address reprint requests to Ching-Hon Pui, MD, Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Whether recent improvements in the treatment of childhood acute lymphoblastic leukemia (ALL) have nullified the adverse prognosis associated with male sex remains unclear. Therefore, we analyzed the survival experience and presenting clinical and laboratory features of boys and girls with newly diagnosed ALL who were treated at our institution over the past three decades.

PATIENTS AND METHODS: One thousand one hundred fifty-one boys and 904 girls were treated in 13 consecutive Total Therapy studies between 1962 and 1994. An overview analysis was used to investigate the impact of sex on overall and event-free survival, both for the entire cohort and for subgroups defined by treatment era and blast-cell immunophenotype. Stratified analyses were performed to adjust for treatment protocol and known risk factors, and in the modern treatment era, for protocol, immunophenotype, and the DNA content of leukemic cells (ie, DNA index). The pharmacokinetics of methotrexate, teniposide, and cytarabine, as well as the thiopurine methyltransferase activity of erythrocytes, were compared between boys and girls treated on a single protocol.

RESULTS: Compared with girls, boys were more likely to have T-cell ALL (20.9% v 10.7%, P < .001) and seemed less likely to have a favorable DNA index (17.8% v 25.1%, P = .072). There were no other statistically significant differences between the two sexes with respect to presenting features, including leukemic-cell genetic abnormalities, nor were there significant sex differences in the pharmacokinetics of methotrexate, teniposide, or cytarabine or in erythrocyte thiopurine methyltransferase activity. Girls clearly fared better than boys (P < .001) on protocols used during the early era of treatment (10-year event-free survival ± 1 SE, 43.1% ± 2.1% v 31.5% ± 1.7%). Although prognosis improved for both sexes in the modern era, the difference in outcome between girls and boys persisted (P = .025) (10-year event-free survival, 73.4% ± 3.7% v 63.5% ± 4.0%). However, stratification of modern-era patients by protocol, immunophenotype, and DNA index mitigated statistical evidence of a sex difference in overall survival (P = .263) and event-free survival (P = .124).

CONCLUSION: Although boys and girls alike have benefited from improvements in ALL therapy, these gains have not completely eliminated the sex difference in prognosis that has persisted since the early 1960s. The apparent difference in outcome is partially explained by differences between boys and girls in the distributions of ALL immunophenotype and DNA index.

	INTRODUCTION

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SEX HAS LONG been recognized as a significant prognostic factor in childhood acute lymphoblastic leukemia (ALL).¹ In all but two clinical trials,^2,3 boys have fared worse than girls given equivalent therapy.^1,4-18 Despite the consistency of this finding, sex differences have attracted only scant attention from leukemia therapists. In fact, in a recent workshop sponsored by the U.S. National Cancer Institute, sex was not considered sufficiently important to be included in the risk evaluation of newly diagnosed patients.¹⁹ With recent improvements in ALL therapy, and the loss of predictive strength of many conventional risk factors,²⁰ we sought to determine whether sex has retained its prognostic significance and, if so, whether other clinical or biologic features were contributing to this effect.

	PATIENTS AND METHODS

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From 1962 through 1994, 2,055 consecutive patients younger than 18 years of age with newly diagnosed ALL were enrolled onto 13 treatment protocols at St. Jude Children's Research Hospital. The diagnosis was based on morphologic evaluation of Wright-Giemsa–stained smears of bone marrow aspirates and negative staining for myeloperoxidase (< 3% positive blasts). Since 1968, an institutional review board has approved each protocol, with signed informed consent obtained from parents or guardians.

Complete immunophenotyping, cytogenetic analysis, and flow cytometric determination of blast-cell DNA content have been part of the routine evaluation of patients since 1979. Molecular genetic studies of MLL rearrangement and ETV6-CBFA2(TEL-AML1) fusion were performed on fresh or frozen samples of patients treated after 1988.

Treatment
Details of the St. Jude Total Therapy program have been given in earlier publications.^21-25 In brief, studies I through IV (1962 to 1966) were characterized by efforts to prolong the duration of hematologic remission by use of combination chemotherapy.²¹ Studies V through IX (1967 to 1979) featured CNS-directed therapy with 2,400 cGy of cranial irradiation and intrathecal chemotherapy.²¹ Study X (1979 to 1983) introduced limited intensification of treatment with high-dose methotrexate as well as a teniposide-cytarabine combination.²² Study XI (1984 to 1988) was marked by the early intensification of systemic chemotherapy and alternating use of non–cross-resistant pairs of drugs during the postremission period.²³ Study XII (1988 to 1991) tested the concept of individualized dosing of chemotherapy to prevent low or excessive systemic exposure to antileukemic drugs.²⁴ Study XIIIA (1991 to 1994) investigated up-front methotrexate therapy, early intensification of intrathecal chemotherapy, and reinduction treatment.²⁵ The modern (studies XI to XIIIA) and early (studies I to X) treatment eras were distinguished by the introduction of intensive, multidrug induction regimens in 1984 (study XI). A variety of remission retrieval therapies, including hematopoietic stem-cell rescue in the modern era, were used for patients who relapsed or failed to achieve remission on a Total Therapy protocol.

Pharmacologic Analysis
The clearance of methotrexate, teniposide, and cytarabine was assessed in all 182 patients who achieved a complete remission in study XII,²⁴ and the thiopurine methyltransferase activity of erythrocytes was measured²⁶ in 109 of the 182 patients during continuation treatment (at least 90 days from the last RBC transfusion).

Statistical Analysis
Fisher's exact test and the Cochran-Mantel-Haenszel test²⁷ for general association were used to identify known adverse risk features that differed in distribution between subsets of boys and girls. The stratified Cochran-Mantel-Haenszel test was used to determine whether the risk features found to be associated with sex remained significant after controlling for the confounding factor (ie, immunophenotype).

Survival was assessed from the date the patient entered the study to the date of the last follow-up examination or death. Event-free survival was measured from the date of study entry to the first failure of any kind (relapse, second malignancy, or death) or to the date of the last follow-up examination. Patients who did not achieve a complete remission by day 43 of induction therapy were assigned an event-free survival time of zero. Distributions of overall and event-free survival were estimated by the methods of Kaplan and Meier, with SEs calculated as suggested by Peto et al.²⁸ All estimates of outcome are reported plus or minus (±) 1 SE. Distributions of overall survival for boys and girls were compared with the Mantel-Haenszel statistic.²⁹ Stratified comparisons were performed to adjust for treatment protocol as well as other risk features known over time. An overview analysis with stratification to control for potential differences in the distribution of risk features between boys and girls was conducted to avoid overinterpretation of P values arising from numerous subgroup comparisons.³⁰ Odds ratios and corresponding 95% confidence intervals (CIs) were calculated using the same stratification scheme to emphasize the differences (or lack thereof) in overall survival between boys and girls. Estimates of the cumulative incidence of isolated CNS relapse, isolated testicular relapse, and induction failures plus leukemic relapse were calculated by the methods of Kalbfleisch and Prentice.³¹

The median duration of follow-up was 13.7 years (range, 3.1 to 34.1 years). Ninety-nine percent of surviving patients were contacted within 2 years of the first analysis date.

Clearances of teniposide, cytarabine, and methotrexate during the first course of treatment were compared between boys and girls using the t statistic from a multiple linear regression model, which controlled for age at diagnosis and treatment arm. The Wilcoxon rank-sum test was used to compare the distributions of thiopurine methyltransferase activity between boys and girls. Bonferroni's correction was applied to the four comparisons of pharmacologic data; thus, each was considered significant at a type I error rate of 0.05/4 = 0.0125. All P values are two-sided, and all statistical analyses were conducted using SAS release 6.12 (SAS Inc, Cary, NC).

	RESULTS

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Of the 2,055 patients enrolled onto Total Therapy studies since 1962, 1,151 (56%) were boys. Compared with girls, boys were more likely to have unfavorable presenting features, including a T-cell immunophenotype, high leukocyte count, and age 10 years or older, and less likely to have a favorable DNA index (ratio of the DNA content in leukemic G₀/G₁ cells v that in normal diploid G₀/G₁ cells) (Table 1). There were no sex differences in the frequency of CNS leukemia at diagnosis (presence of at least five leukocytes per microliter of CSF with leukemic blast cells in cytocentrifuged preparations or the presence of cranial nerve palsy), MLL gene rearrangement, or the Philadelphia chromosome in leukemic lymphoblasts. After stratifying for T-cell immunophenotype, there were no significant sex differences in any of the clinical or biologic features examined, with the exception of DNA index. Boys were more likely to have a poor early response to remission induction therapy than girls (Table 1).

Patterns of Treatment Failure
The patterns of treatment failure varied according to the Total Therapy study (Table 2). With the introduction of CNS-directed therapy in study V and its routine use since study VII, the rate of meningeal relapse in both boys and girls decreased from over 33% in study VI to 5% to 14% in studies VII through XII, whereas the hematologic relapse rate remained high (over 50% in studies VI to IX). With limited intensification of systemic chemotherapy in study X, treatment failures due to refractory or relapsed leukemia decreased to less than 50% in both sexes. This improvement continued in study XI, when early intensification of systemic chemotherapy was made available to all patients. The frequency of testicular relapse, once as high as 9%, has declined to less than 1% with better control of systemic leukemia (since study XI). The overall control of leukemic relapse improved still further with early intensification of intrathecal therapy in study XIIIA, in which the rate of isolated CNS relapse was reduced to 2% in boys and 0% in girls.

Comparison of Treatment Outcome
An overview analysis of event-free survival disclosed a significantly inferior result for boys (P < .001). This sex difference was seen in both the early (P < .001) and modern (P = .025) treatment eras (10-year estimates, 31.5% ± 1.7% v 43.1% ± 2.1% and 63.5% ± 4.0% v 73.4% ± 3.7%, respectively; Fig 1). The risk of failure for boys relative to that of girls was 1.33 (95% CI, 1.15 to 1.53) in the early treatment era and 1.41 (95% CI, 1.04 to 1.89) in the modern era.

View larger version (13K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimates of event-free survival for boys versus girls according to treatment era. Numbers on the curves represent patients at risk of failure at specific time points. Event-free survival was worse for boys in the early era (P < .001) and in the modern era (P = .025); however, the ability to adjust for immunophenotype and DNA index lessened the impact of sex in the modern treatment era (P = .124).

Because T-cell ALL, which is generally associated with a poorer prognosis compared with that of B-cell–precursor ALL,³² and a less favorable DNA index were more common among boys than girls (P < .001 and P = .072, respectively), we also analyzed the sex difference in the modern era by stratifying for protocol, immunophenotype, and DNA index. Controlling for such risk features lessened the significance of the impact of sex on event-free survival in the modern era (P = .124). Distributions of event-free survival by immunophenotype for modern era patients are shown in Fig 2. In a stratified analysis, boys with B-cell–precursor ALL had poorer event-free survival than did girls with the same blast-cell immunophenotype (P = .065) (10-year estimates, 67.5% ± 4.4% for boys v 76.0% ± 3.9% for girls). However, among a very favorable subgroup of B-cell–precursor ALL (DNA index, 1.16 to 1.6; age, 1 to 10 years; and leukocyte count, 50 x 10⁹/L), sex had no impact on treatment outcome (P = .57). Event-free survival did not differ between boys and girls with T-cell ALL (P = .71) (10-year estimates, 54.0% ± 9.2% for boys [n = 79] v 50.7% ± 11.3% for girls [n = 37]). Similar analyses could not be performed for patients treated in the early era, as immunophenotypes were not available for most of these cases.

View larger version (17K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimates of event-free survival in the modern treatment era for boys versus girls according to blast-cell immunophenotype. Numbers on the curves represent the number of patients at risk of failure at specific time points. Event-free survival was significantly worse for boys than girls with B-cell–precursor ALL (P = .065), but not among those with T-cell ALL (P = .71).

Another useful gauge of prognosis in ALL is the proportion of patients who become long-term survivors, including those treated with retrieval therapy. Stratified analysis of the overall survival experience revealed a significantly worse treatment outcome for boys (P = .005). In the early treatment era, survival was worse among boys than girls (P = .019) (10-year survival estimates, 45.4% ± 1.8% v 54.1% ± 2.1%). In the modern era, survival seemed worse for boys (P = .121) (10-year estimates, 74.8% ± 3.6% v 81.8% ± 3.2%). The risk of death for boys relative to that of girls was 1.20 (95% CI, 1.03 to 1.41) in the early treatment era and 1.31 (95% CI, 0.93 to 1.84) in the modern era. Stratification of patients for protocol, immunophenotype, and DNA index decreased the impact of sex on overall survival in the modern era (P = .263).

Among patients with B-cell–precursor ALL treated in the modern era, boys tended to have a poorer survival than girls after stratification for protocol and DNA index (P = .108), with 10-year estimates of 78.6% ± 3.8% and 83.9% ± 3.3%, respectively. Sex did not have an impact on the survival experience of patients with T-cell ALL (P = .99).

Finally, we sought to determine whether certain antileukemic agents might have more favorable pharmacokinetics in girls and thus account for some of the sex differences in treatment response. Comparison of methotrexate, teniposide, and cytarabine clearance and erythrocyte thiopurine methyltransferase activity between boys and girls enrolled onto study XII²⁴ failed to demonstrate a pharmacokinetic advantage for girls, at least with the agents and end points studied (Table 3).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Treatment outcome for children with ALL has improved remarkably since the instigation of CNS-directed therapy in the mid-1960s. Yet, as demonstrated here, a sex difference in prognosis still persists, but it may be explained in part by presenting risk features. This finding agrees with a recent Pediatric Oncology Group study of B-cell–precursor ALL,¹⁸ in which boys had a significantly lower 5-year event-free survival rate than did girls (66.8% ± 1.6% v 75.8% ± 1.6%, respectively). We find that boys continue to be at higher risk for hematologic, but not extramedullary, relapse compared with the probability of these events in girls. It is noteworthy that the CNS relapse hazard has virtually been eliminated for both sexes in our most recent clinical trial.²⁵ Likewise, Chessells et al¹⁷ reported no sex difference in the CNS relapse rate among 4,126 children treated in nine consecutive clinical trials. Although high in the early treatment era, the testicular relapse rate has become negligible in the modern era. In one randomized study, prophylactic testicular irradiation prevented overt testicular relapse but did not improve overall disease-free survival.³³ Consequently, this mode of therapy is no longer used in clinical trials.

The poorer prognosis of boys overall can be attributed in part to a higher incidence (2:1) of T-cell ALL, as well as a lower incidence of favorable DNA index. At our center, with the exception of the most recent clinical trial, the T-cell immunophenotype has consistently been associated with a poorer outcome than has B-cell–precursor ALL (Fig 2).³² In one study by others, boys with T-cell ALL fared worse than girls with the same immunophenotype; however, the outcome for boys in that study was especially poor (10-year event-free survival, 25.9% ± 11.1%).¹⁶ The more common finding, as in the present study, is a lack of sex difference in survival among children with T-cell ALL.³²

We suggest that most of the sex difference in outcome reflects the poorer prognosis of boys with B-cell–precursor disease (Fig 2), which is explained in part by a lower frequency of favorable DNA index in them. There were no differences between boys and girls in the frequency distributions of other genetic features with prognostic relevance (eg, MLL rearrangement or the Philadelphia chromosome).³⁴

Previous studies showed that girls generally do not tolerate mercaptopurine as well as boys do and experience more episodes of neutropenia (hence, more interruptions of chemotherapy),^35,36 suggesting a pharmacologic basis for the sex difference in treatment outcome. However, this prediction could not be substantiated in the present study or in others,^37-39 as boys and girls had similar levels of erythrocyte thiopurine methyltransferase activity—an enzyme that inactivates mercaptopurine. We also could not demonstrate sex differences in the pharmacokinetics of other commonly used antileukemic agents (eg, methotrexate, cytarabine, and teniposide). However, one study showed that boys accumulated more methotrexate polyglutamates (active metabolites of methotrexate) in erythrocytes than did girls when treated on the same protocol.⁴⁰

How could treatment outcome for boys be improved? Chessells et al³⁶ observed that myelosuppression in the context of conventional antimetabolite-based therapy was associated with a lower risk of relapse. Although Dibenedetto et al⁴¹ could not demonstrate an association between myelosuppression during continuation treatment and outcome, a high cumulative dose of mercaptopurine correlated with improved event-free survival. Thus, one might extend the continuation phase or intensify early treatment for boys with good tolerance of chemotherapy, especially those with high levels of minimal residual disease after remission induction.⁴² Advances in the treatment of T-cell ALL, apparent from the results of several recent clinical trials,^3,15,43 should further reduce the gap in survival between the two sexes. The development of specific therapy for boys with B-cell–precursor ALL will require greater knowledge of the biologic factors that underlie responses to otherwise effective treatment.

	ACKNOWLEDGMENTS

 
Supported by grant nos. P30 CA 21765, P01 CA 20180, R37 CA 36401, and R29 CA 51001 from the National Cancer Institute, by a Center of Excellence grant from the State of Tennessee, and by the American Lebanese Syrian Associated Charities

We thank Emily Melton, Lisa McNinch, Margaret Needham, Barbara Alexander, Ya Qin Chu, Natasha Lenchik, Eve Su, and May Chung for their technical assistance and John Gilbert for editorial review.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted September 1, 1998; accepted November 9, 1998.

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