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Favorable Outcome for Adolescents With Acute Lymphoblastic Leukemia Treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols

Elly Barry, Daniel J. DeAngelo, Donna Neuberg, Kristen Stevenson, Mignon L. Loh, Barbara L. Asselin, Ronald D. Barr, Luis A. Clavell, Craig A. Hurwitz, Albert Moghrabi, Yvan Samson, Marshall Schorin, Harvey J. Cohen, Stephen E. Sallan, Lewis B. Silverman

From Departments of Pediatric Oncology, Medical Oncology, and Biostatistical Science, Dana-Farber Cancer Institute; Department of Pediatrics, Children's Hospital; Harvard Medical School, Boston, MA; Department of Pediatric Hematology-Oncology, University of California, San Francisco; Department of Pediatrics, Lucile Packard Children’s Hospital, Palo Alto, CA; Department of Pediatric Hematology-Oncology, Hospital Sainte Justine, Montréal; Department of Pediatrics, Centre Hospitalier Universitaire de Québec, Québec; Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; Department of Pediatric Hematology-Oncology, University of Rochester Medical Center, Rochester, NY; Department of Pediatric Oncology, San Jorge Children's Hospital, San Juan, Puerto Rico; Department of Pediatric Oncology, Maine Children's Cancer Program at Maine Medial Center, Portland, ME; and Department of Pediatrics, Tulane Hospital for Children, New Orleans, LA

Address reprint requests to Elly Barry, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: elly_barry{at}dfci.harvard.edu

	ABSTRACT

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Purpose Historically, adolescents with acute lymphoblastic leukemia (ALL) have had inferior outcomes when compared with younger children. We report the outcome of adolescents treated on Dana-Farber Cancer Institute (DFCI; Boston, MA) ALL Consortium Protocols conducted between 1991 and 2000.

Patients and Methods A total of 844 patients aged 1 to 18 years, with newly diagnosed ALL were enrolled onto two consecutive DFCI-ALL Consortium Protocols. We compared outcomes in three age groups: children aged 1 to 10 years (n = 685), young adolescents aged 10 to 15 years (n = 108), and older adolescents aged 15 to 18 years (n = 51).

Results With a median follow-up of 6.5 years, the 5-year event-free survival (EFS) for those aged 1 to 10 years was 85% (SE, 1%), compared with 77% (SE, 4%) for those aged 10 to 15 years, and 78% (SE, 6%) for those aged 15 to 18 years (P = .09). Adolescents were more likely to present with T-cell phenotype (P < .001) and less likely to have the TEL-AML1 fusion (P = .05). The incidence of pancreatitis and thromboembolic complications, but not asparaginase allergy, was higher in patients 10 years of age compared with those younger than 10 years. However, there was no difference in the rate of treatment-related complications between the 10- to 15-year and 15- to 18-year age groups.

Conclusion Adolescents were more likely to present at diagnosis with biologically higher risk disease (T-cell phenotype and absence of the TEL-AML1 fusion) and more likely to experience treatment-related complications than younger children. However, the 5-year EFS for older adolescents was 78% ± 6%, which is superior to published outcomes for similarly aged patients treated with other pediatric and adult ALL regimens. Based on this experience, we currently are piloting our regimen in patients aged 18 to 50 years.

	INTRODUCTION

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Historically, children with newly diagnosed acute lymphoblastic leukemia (ALL) who are 10 years of age at diagnosis have had worse outcomes than younger patients.^1-3 With current treatment regimens, patients aged 1 to 9 years achieve 5-year event-free survival (EFS) in excess of 80%.^4-8 However, older pediatric patients consistently have had poorer outcomes, with reported EFS rates ranging from 46% to 68%.^2,8-12 To improve outcomes, contemporary childhood ALL protocols stratify older patients into high-risk groups and treat them with more intensive chemotherapy.¹

Biologically, adolescents with ALL differ from younger patients by presenting more frequently with adverse prognostic features, such as high WBC count, T-cell immunophenotype, a higher frequency of the BCR-ABL translocation, and a lower frequency of favorable cytogenetic features such as hyperdiploidy and the TEL-AML1 fusion gene.^2,10,11

Emerging evidence suggests that adolescents and young adults treated with adult ALL protocols have poorer outcomes than similarly aged patients treated with pediatric protocols.^13-16 It is not clear if these outcome differences are due to variations in treatment regimens alone or differences in patient or leukemia cell biology. We examined presenting features and treatment outcomes in the oldest patient population (adolescents aged 15 to 18 years) enrolled onto two consecutive Dana-Farber Cancer Institute (DFCI) -ALL Consortium Protocols conducted between 1991 and 2000, and compared them with younger patients who were similarly treated.

	PATIENTS AND METHODS

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Patients
Between 1991 and 2000, newly diagnosed children with ALL aged 0 to 18 years were enrolled onto two consecutive DFCI ALL Consortium Protocols, 91-01 (December 1991 to December 1995) and 95-01 (January 1996 to September 2000). Institutional review board approval was obtained at all participating institutions and informed consent was obtained for each patient before initiation of therapy.

A total of 386 children were enrolled onto Protocol 91-01, 377 of whom were eligible for evaluation. Nine patients were ineligible because of incorrect diagnosis (n = 6), pretreatment with other antileukemia therapy (n = 2), and absence of signed parental consent before therapy (n = 1). A total of 498 children were enrolled onto Protocol 95-01, of whom 491 were eligible for evaluation. Seven patients were ineligible because of incorrect diagnosis (n = 4), pretreatment with corticosteroid (n = 1), infection with HIV (n = 1), and incorrect consent (n = 1). All infants aged 1 to 12 months were excluded from this analysis (n = 21), as were three patients for whom follow-up information was not available. Therefore, a total of 844 patients aged 1 to 18 years were included in this analysis. The definition of age groups at diagnosis was as follows: 1 to 10 years included all patients who were at least 12 months but younger than 10 years old, 10 to 15 years included those were at least 10 years but younger than 15 years old, and 15 to 18 years included those who were at least 15 years but younger than 18 years old.

Treatment
Details of the treatment regimens have been published previously^4,17 and are summarized in Table 1. Patients were stratified into two groups, standard risk (SR) and high risk, based on characteristics at the time of diagnosis. On Protocol 91-01, SR was defined as age between 2 and 9 years, WBC count less than 20,000/µL, B-cell progenitor phenotype, and absence of all the following: the Philadelphia chromosome, a mediastinal mass, and CNS leukemia at diagnosis (defined as CNS-2 or CNS-3⁷). On Protocol 95-01, risk criteria were identical except age and leukocyte count criteria were modified to be in accordance with guidelines recommended by the National Cancer Institute.¹ SR was defined as age between 1 and 10 years and presenting WBC count less than 50,000/µL.

Statistical Analysis
The Wilcoxon rank sum test was used to test for a difference in continuous variables between two groups, and the Kruskal-Wallis test was used to test differences in continuous variables among more than two groups. The method of Kaplan and Meier was used to estimate the survival curves, and the log-rank test was used to compare the curves.^18,19 Outcome events included induction failure, death during induction, death during remission, and relapse. EFS was defined as the time from complete remission to the first outcome event. Induction failure and induction deaths were considered events at time zero. Overall survival (OS) was defined as the time from start of treatment to time of death as a result of any cause. Remission duration was defined as the time from complete remission to time of relapse. No statistical adjustment was made for performing multiple tests; all P values were two sided and results were considered significant if P < .05.

	RESULTS

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Baseline Patient Characteristics
Of the 844 patients, 685 were aged 1 to 10 years (median age, 3.9 years), 108 were 10 to 15 years (median age, 12.6 years), and 51 were 15 to 18 years (median age, 16.2 years). As of March 2006, the median follow-up was 6.5 years (8.9 years for patients enrolled onto Protocol 91-01 and 5.3 years for patients enrolled onto Protocol 95-01).

Baseline patient characteristics were similar between the two studies. Overall, the median age of patients at the time of diagnosis was 4.6 years (4.5 years for patients enrolled onto Protocol 91-01 [range, 1 to 17.9 years], and 4.8 years for patients enrolled onto Protocol 95-01 [range, 1.2 to 18.0 years]). The median presenting WBC count was 9,600/µL (range, 700 to > 1,000,000/µL). Ten percent of patients presented with T-cell ALL.

Patient Characteristics by Age Group
Patient characteristics of the three age groups are listed in Table 2. There was a marginal difference in WBC counts at presentation among the three age groups, with older patients presenting with lower WBC. There was a statistically significant difference in the percentage of patients with T-cell phenotype, with a greater proportion of patients presenting with T-cell phenotype with increasing age (P < .0001). The proportion of patients with T-cell phenotype was highest in the 15- to 18-year age group. Accordingly, the proportion of patients presenting with a mediastinal mass increased with patient age (P = .02). The proportion of patients presenting with CNS disease (CNS-2 or CNS-3) did not differ among the three age groups (range, 8% to 12%; P = .78).

Response to Therapy and Survival
EFS at 5 years was not statistically different among the three age groups, although there was a trend toward superior outcome in the youngest age group. As shown in Figure 1A, 5-year EFS was 85% (SE, 1%) for patients aged 1 to 10 years, 77% (SE, 4%) for those 10 to 15 years, and 78% (SE, 6%) for those 15 to 18 years (P = .09). Although we detected a significant difference in EFS when comparing patients aged younger than 10 years with those aged 10 years (85% [SE, 1%] and 77% [SE, 3%], respectively; P = .04), a subgroup analysis, comparing only the age groups 10 to 15 years versus 15 to 18 years, demonstrated similar EFS (P = .87). OS at 5 years differed significantly among the three age groups. As shown in Figure 1B, 5-year OS was 92% for those aged 1 to 10 years, 78% for those aged 10 to 15 years, and 81% for patients aged 15 to 18 years (P < .0001).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Event-free survival by age group; (B) overall survival by age group.

Toxicity
Table 4 summarizes adverse treatment-related toxicities. There were no differences in the incidence of asparaginase-related allergy, either localized or systemic, among the three age groups (P = .38). However, there were significant differences in the incidences of pancreatitis (grades 1 to 4; P = .02) and thromboembolic complications (P < .001), with more events in the older age groups. The highest rates of both pancreatitis and thromboembolic complications were observed in patients aged 10 to 15 years at diagnosis, with lower rates observed in the age group 15 to 18 years, although this difference was not significant (P = .2).

	DISCUSSION

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We demonstrated that adolescents, aged 15 to 18 years, treated for newly diagnosed ALL on two consecutive DFCI-ALL Consortium Protocols, had a favorable 5-year EFS of 78% (SE, 6%). The favorable EFS in these patients is superior to published outcomes for similarly aged patients treated on other pediatric and adult ALL regimens (EFS rates ranging from 46% to 68%).^8,10-16 We focused our analysis on the 15- to 18-year-old age group to compare our results with the published literature. However, we did evaluate alternative age cutoffs and found similar results.

The presenting features of our 15- to 18-year-old age group, including the presenting median WBC count and frequency of T-cell phenotype, BCR-ABL rearrangements, and TEL-AML1 fusion, were similar to those reported in other series of similarly aged patients.^13,16 This suggests that the relatively favorable outcome of this age group on our protocols, when compared with other studies, was not due to differences in underlying biology of our adolescent population, but due to differences in treatment.

Recent studies have suggested that older adolescents and young adults with ALL have superior outcomes when treated on pediatric rather than adult cooperative group clinical trials.^13-16,20 It has been suggested that the superior outcome of older adolescents treated with pediatric rather than adult regimens may be due, in part, to the intensity of drug doses delivered. Pediatric regimens generally include more doses of corticosteroids, asparaginase, and vincristine.²¹ Our regimen, which includes frequent (every 3 weeks) vincristine and corticosteroid pulses during postremission therapy, as well as treatment with high-dose asparaginase for 20 to 30 weeks, may be beneficial to this older group of patients. Another distinctive feature of the DFCI-ALL Consortium high-risk regimen is the use of doxorubicin every 3 weeks (up to a cumulative dose of 300 to 360 mg/m²), which also may have contributed to the relatively favorable outcome of older adolescent patients.

Adolescent patients more frequently present with adverse features at diagnosis, including higher presenting WBC counts, a higher frequency of the T-cell phenotype, and a lower frequency of high hyperdiploidy.^2,10,11 Despite these variations in presenting features, the difference in EFS among age groups was not large and did not achieve statistical significance (P = .09), although younger patients seemed to have a slightly better prognosis. This lack of significant difference may be due, in part, to the relatively small number of adolescents in this series, but also seems to reflect the relatively favorable EFS for patients in the older age groups, especially those with T-cell phenotype. We previously have reported that children with T-cell ALL have a favorable outcome when treated on the DFCI-ALL Consortium regimen.²² In this study, we did not find any significant difference in outcome based on age for patients with T-cell ALL; older T-cell patients did as well as younger patients. Conversely, we observed that adolescents with B-lineage ALL had significantly lower EFS than younger patients, likely reflecting that different biologically distinctive subtypes vary in frequency by age. For instance, the TEL-AML1 fusion, associated with a favorable prognosis, is much less common in older adolescents than in younger patients.

Although we observed only a small number of adolescents with the Philadelphia chromosome, recent publications have shown similar low rates of this translocation in this patient group.^13,16 Therefore, the low rate of Philadelphia chromosome positivity we observed does not entirely explain the improved outcomes for adolescents treated with our protocols. However, it is possible that we may have underestimated the frequency of Philadelphia chromosome positivity because during the time that these protocols were open, patients were screened only by karyotype analysis. Since 2000, we have screened all patients for the BCR-ABL fusion by either fluorescent in situ hybridization or PCR analysis.

Although EFS was similar among age groups, OS rates differed significantly, with lower OS rates observed in adolescent patients. This suggests that younger patients who experienced a relapse had a higher likelihood of responding to salvage therapy than older patients. Many previous studies have shown that outcome postrelapse is related to the time (patients with early relapses have poorer outcomes than those with later relapses) and site of relapse (patients with isolated extramedullary relapses have better outcomes than those involving the marrow, and patients with combined marrow/extramedullary relapses may have better outcomes than isolated bone marrow relapses^23,24). Among patients in our series who experienced relapse, isolated CNS and combined CNS/bone marrow relapses were more common in younger patients, whereas isolated marrow relapses were more common in adolescents. This may reflect the fact that in the past, all older patients received cranial radiation routinely on our protocols, whereas younger patients did all not receive radiation. Currently, we administer cranial radiation only to patients with very high presenting leukocyte counts, CNS positivity (CNS-3) at diagnosis, or T-cell phenotype, so the majority of adolescent patients are being treated without radiation.

Furthermore, adolescents tended to experience relapse earlier than younger patients. Timing of relapse, in part, may be due to differences in leukemia biology among the age groups; patients with T-cell ALL (more common in adolescents) tend to experience relapse early, whereas those with TEL-AML1 rearranged and hyperdiploid B-lineage ALL (more common in younger patients) tend to experience relapse late. The lower likelihood of salvage postrelapse in older patients may also be due to more intensive initial therapy (all adolescents were treated as high-risk patients) or higher toxicity rates with salvage treatments. For example, transplantation-related mortality increases with increasing age.^25,26 However, not all studies show a relationship between the intensity of initial therapy and poor response to salvage therapy in older patients.²³

Our intensive regimen was generally well tolerated by older patients, although we observed an increased risk of treatment-related toxicity in the older patients. We have reported previously that patients who were unable to tolerate nearly all of the consolidation doses of asparaginase were at higher risk of subsequent relapse, and that older patients (10 to 18 years) were more likely to experience a dose-limiting asparaginase toxicity than younger children.⁴ Here, we report that the incidence of local and systemic allergic reactions (the most common asparaginase-related toxicity) was similar in all age groups, but the incidences of pancreatitis and deep venous thrombosis were higher in older patients. Interestingly, the highest rate of treatment-related toxicity occurred in patients aged 10 to 15 years, rather than in our oldest patients, suggesting that the incidence of toxicity was not simply related to patient age. The reasons that younger teenagers are more likely to experience treatment-related toxicities than older adolescents are not clear, but this pattern suggests that it may be feasible to test the tolerability of high-dose asparaginase in even older patients, such as young adults with ALL.

Our observations emphasize the importance of continued collaboration between pediatric and adult cooperative oncology groups. Given the overall poor outcomes for adult patients with ALL, as a result of the successful treatment of older adolescents with newly diagnosed ALL on DFCI-ALL Consortium protocols, we are now investigating our regimen in adult patients with ALL aged 18 to 50 years. Our goal is to develop a uniform, age-unrestricted, biologically based treatment regimen that will improve outcome for all patients with ALL.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Stephen E. Sallan, Enzon Inc Stock: N/A Honoraria: Stephen E. Sallan, Enzon Inc Research Funds: Stephen E. Sallan, Enzon Inc Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Donna Neuberg, Stephen E. Sallan, Lewis B. Silverman

Provision of study materials or patients: Mignon L. Loh, Barbara L. Asselin, Ronald D. Barr, Luis A. Clavell, Craig A. Hurwitz, Albert Moghrabi, Yvan Samson, Marshall Schorin, Stephen E. Sallan

Collection and assembly of data: Donna Neuberg, Kristen Stevenson, Stephen E. Sallan, Lewis B. Silverman

Data analysis and interpretation: Elly Barry, Donna Neuberg, Kristen Stevenson, Harvey J. Cohen, Stephen E. Sallan, Lewis B. Silverman

Manuscript writing: Elly Barry, Daniel J. DeAngelo, Donna Neuberg, Mignon L. Loh, Barbara L. Asselin, Ronald D. Barr, Craig A. Hurwitz, Albert Moghrabi, Marshall Schorin, Stephen E. Sallan, Lewis B. Silverman

Final approval of manuscript: Elly Barry, Daniel J. DeAngelo, Donna Neuberg, Mignon L. Loh, Ronald D. Barr, Luis A. Clavell, Craig A. Hurwitz, Albert Moghrabi, Yvan Samson, Marshall Schorin, Harvey J. Cohen, Stephen E. Sallan, Lewis B. Silverman

	NOTES

 
Supported by Grant No. CA 68484 from the National Institutes of Health.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted August 14, 2006; accepted December 5, 2006.

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