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Should Adolescents With Acute Lymphoblastic Leukemia Be Treated as Old Children or Young Adults? Comparison of the French FRALLE-93 and LALA-94 Trials

From the Services d’Hématologie Pédiatrique et Adulte, Laboratoire Central d’Hématologie, Hôpital Saint-Louis; Service d’Onco-Hématologie, Hôpital Trousseau, Paris; Service d’Hématologie, Hôpital Edouard Herriot, Lyon; Unité d’Onco-Hématologie Pédiatrique, Hôpital des Enfants, Bordeaux; Laboratoire de Biochimie et de Biologie Moléculaire, Faculté de Médecine Nord, Marseille; Service d’Hématologie, Hôpital Lapeyronie, Montpellier; Service d’Hématologie, Hôpital Dupuytren, Limoges; Service d’Hématologie, Hôpital Purpan, Toulouse; Service d’Hématologie, Hôpital Morvan, Brest; Service d’Hématologie, Hôpital Haut-Levêque, Lyon; Service d’Hématologie, Hôpital Henri Mondor, Créteil; Hématologie Pédiatrique, Hôpital d’Enfants La Timone, Marseille, France.

Address reprint requests to André Baruchel, MD, Service d’Hématologie Pédiatrique, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France; email: andre.baruchel{at}sls.ap-hop-paris.fr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To compare pediatric and adult therapeutic practices in the treatment of acute lymphoblastic leukemia (ALL) in adolescents.

Patients and Methods: From June 1993 to September 1994, 77 and 100 adolescents (15 to 20 years of age) were enrolled in the pediatric FRALLE-93 and adult LALA-94 protocols, respectively. Among the different prognostic factors, we retrospectively analyzed the effect of the trial on achieving complete remission (CR) and event-free survival (EFS).

Results: Patients were younger in the FRALLE-93 than in the LALA-94 protocol (median age, 15.9 v 17.9 years, respectively), but other characteristics were similar, including median WBC count (18 x 10⁹ cells/L v 16 x 10⁹ cells/L), B/T-lineage (54 of 23 v 72 of 28 patients), CD10-negative ALL (13% v 15%), and poor-risk cytogenetics (t(9;22), t(4;11), or hypodiploidy less than 45 chromosomes: 6% v 5%). The CR rate depended on WBC count (P = .005) and trial (94% v 83% in FRALLE-93 and LALA-94, respectively; P = .04). Univariate analysis showed that unfavorable prognostic factors for EFS were as follows: the trial (estimated 5-year EFS, 67% v 41% for FRALLE-93 and LALA-94, respectively; P < .0001), an increasing WBC count (P < .0001), poor-risk cytogenetics (P = .005), and T-lineage (P = .01). The trial and WBC count remained significant parameters for EFS in multivariate analysis (P < .0001 and P = .0004). Lineage subgroup analysis showed an advantage for the FRALLE-93 trial for CR achievement (98% v 81%; P = .002) and EFS (P = .0002) in B-lineage ALL and for EFS (P = .05) in T-lineage ALL. Age was not a significant prognostic factor in this population of adolescents.

Conclusion: This study’s findings indicate that adolescents should be included in intensive pediatric protocols and that new trials should be designed, inspired by pediatric protocols, for the treatment of young adults with ALL.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PROGRESS IN the treatment of childhood acute lymphoblastic leukemia (ALL) over the last decades has dramatically improved the prognosis for these patients, but it has also increased the gap between results obtained in children and adults. Childhood trials recently reported complete remission (CR) rates of 95% to 99% and estimated 5-year event-free survival (EFS) rates reaching 80%.^1,2 Only 80% to 85% of patients with ALL treated in adult trials usually reach CR, and only 30% to 40% are still alive 5 years later.^3–5

As already reported, this difference in outcome is partially the result of the various characteristics of this disease in each subgroup. Adult ALL commonly displays higher WBC count, increased incidence of T-phenotype (20% to 25% in adult ALL v 15% in pediatric ALL)^6,7 and Philadelphia chromosome (20% to 25% v 3% to 5%), and decreased incidence of hyperdiploidy (5% v 25%), factors known to affect outcome.⁸ Several studies also reported differences in ALL cell sensitivity to corticosteroids and chemotherapy in vitro.^9,10 This greater frequency of high-risk subtypes of ALL in the adult population strongly interferes with any comparison of adult and pediatric therapeutic practices.

As in many other countries, French adolescents aged between 15 and 20 years of age are referred either to pediatric or to adult departments. We retrospectively compared the characteristics of adolescents with ALL treated in two contemporary French protocols: the pediatric FRALLE-93 and the adult LALA-94. In the pediatric FRALLE-93 trial, all adolescents were treated as high-risk patients, whereas the LALA-94 trial considered them a priori as standard-risk patients. We then compared the evolution of these similar populations to assess the effects of both treatment approaches on the outcomes of these patients.

	PATIENTS AND METHODS

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Patients
In France, adolescents with ALL (aged 15 to 20 years) are referred to pediatric departments and treated in pediatric trials when first diagnosed by pediatricians. They are referred to adult departments and usually treated in adult trials when first diagnosed by general practitioners or internists. In some cases, geographic circumstance may interfere, as pediatric or adult departments of hematology are not equally distributed.

From June 1993 to November 1999, 77 consecutive adolescents aged 15 years and less than 20 years with ALL were enrolled in the pediatric FRALLE-93 trial. In the same age range, 107 consecutive adolescents were enrolled in the adult LALA-94 trial from September 1994 to May 2000, but only 100 of them had a well-defined phenotype and complete follow-up data, allowing them to be eligible for this study. Patients with mature B-cell ALL were excluded from both trials. Informed consent was obtained from the guardians of all patients if they were aged less than 18 years or from patients themselves if they were aged 18 years or older. All patients were treated by pediatric or adult hematologists.

Therapy
In the FRALLE-93 trial, adolescents were treated in the high-risk arm of the protocol. After a four-drug induction (Tables 1, 2), patients in CR who presented unfavorable prognostic factors (Table 3)¹¹ were allografted if they had an HLA-identical sibling donor. Beginning in 1996, an amendment called for an intensified induction course for patients with T-ALL or those with slow response to prednisone or with Philadelphia chromosome-positive (Ph+) ALL (n = 35). Patients with slow response to prednisone (peripheral blast cell count > 1 x 10⁹/L on day 8 of induction therapy) or chemotherapy (marrow blasts > 25% on day 21), those who lacked an HLA-identical sibling donor or had t(4;11), t(9;22) chromosomal translocations, and those who lacked a marrow-unrelated donor underwent autologous hematopoietic stem-cell transplantation, followed by maintenance chemotherapy.¹² The majority of the patients were treated with chemotherapy alone, including CNS irradiation, and received a consolidation course, two delayed intensifications, and maintenance chemotherapy (Table 1).

Cytogenetics and Molecular Biology
Cytogenetic examination was performed on bone marrow and/or peripheral blood samples. A normal karyotype required a minimum of 20 normal metaphases. Hypodiploid and hyperdiploid karyotypes were defined as the presence of less than 45 and more than 50 chromosomes, respectively. The presence of t(4;11), t(9;22), or t(1;19) chromosomal translocations was assessed either by conventional cytogenetics or by reverse transcriptase polymerase chain reaction (RT-PCR).¹³ Because of its lower frequency in the adult population,¹⁴ the cryptic t(12;21) chromosomal translocation was only systematically detected in the FRALLE-93 trial by RT-PCR.¹⁵

Statistical Analysis
Cytogenetic features were classified as follows: 1) poor risk: t(4;11), t(9;22), or hypodiploidy (< 45 chromosomes); 2) standard risk: other abnormalities or normal karyotype; 3) unavailable. As a prognostic factor, cytogenetics was considered as a binomial variable: poor risk versus others. Outcome data were updated in May 2000 and August 2001 in the FRALLE-93 and LALA-94, respectively, to obtain comparable median follow-up (3.8 and 3.5 years for the FRALLE-93 and the LALA-94 trials, respectively). Response to initial therapy was evaluated in both protocols after the four-drug induction course. Overall survival was calculated from the diagnosis date until date of death, censoring patients alive at last follow-up date. Disease-free survival (DFS) was calculated as survival without relapse or death from the date of first CR, censoring patients alive in continuous complete remission at last follow-up date. Event-free survival (EFS) was calculated from diagnosis date to the failure of induction course, the date of relapse, or death, censoring patients alive in continuous complete remission at last follow-up date. Relapse-free survival (RFS) was calculated as survival without relapse from the date of first CR, censoring patients who died in continuous complete remission and patients still alive in continuous complete remission at last follow-up date. Patient characteristics and CR rate comparisons were performed using Fisher’s exact test for binary variables and the Mann-Whitney test for continuous variables. Kaplan-Meier curves were constructed for survival to compare both protocols.¹⁶ EFS, DFS, RFS, and survival comparisons were performed for prognostic subgroups using the log-rank test, after stratification on the protocol.¹⁷ For continuous variables (age and WBC count), univariate analysis was performed using a Cox regression. In multivariate analyses, outcome comparisons were adjusted with the Cox model and tested by the likelihood ratio test.¹⁸ A P value less than .05 was considered to indicate statistical significance. All calculations were performed using the StatView software, version 5.0 (SAS Institute Inc., Cary, NC).

	RESULTS

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Patient Characteristics
The characteristics of the 77 patients treated in the pediatric FRALLE-93 trial and of the 100 patients treated in the adult LALA-94 trial are summarized in Table 4. The sole significant difference between these two groups of patients was age (median age, 15.9 v 17.9 years in the FRALLE-93 and LALA-94 protocols, respectively). This difference in age was not correlated with difference in biometric characteristics, such as height, weight, and body surface area. These parameters were actually similar in both groups.

Differences in CR Rates
A higher percentage of patients achieved CR in the pediatric protocol than in the adult protocol (94% in FRALLE-93 v 83% in LALA-94; P = .04; Table 5). This difference was mainly observed among patients with BCP-ALL (98% in FRALLE-93 v 81% in LALA-94; P = .002). Patients with T-cell ALL had similar CR rates after induction (83% in FRALLE-93 v 89% in LALA-94; P = .7). Considering the whole population of 177 patients, the only other significant factor among age, WBC count, B- versus T-phenotype, and cytogenetics to achieve CR was WBC count (P = .005). Significantly higher WBC counts were observed in patients with BCP-ALL who failed to achieve CR (P = .008).

As indicated in Table 5 and in Fig 1, EFS was significantly shorter in patients treated in the adult LALA-94 trial (estimated 5-year EFS: 67% in FRALLE-93 v 41% in LALA-94; P < .0001). This difference was only partially explained by the higher rate of CR in the pediatric trial, as indicated by the significantly shorter DFS of patients treated in the adult trial (estimated 5-year DFS: 72% v 49%; P = .0004). Among the 72 patients of the FRALLE-93 who achieved CR, 11 patients relapsed and four patients died in first CR (allograft toxicity). Among the 83 patients of the LALA-94 who achieved CR, 38 patients relapsed and one patient died in first CR (treatment-related cancer). Relapse-free survival was significantly longer in the pediatric FRALLE-93 trial (estimated 5-year RFS: 77% v 49%; P < .0001).

View larger version (15K): [in this window] [in a new window]   Fig 1. Overall survival (A) and event-free survival (B) according to the protocol.

Prognostic Factors for Survival
Univariate analyses for parameters influencing EFS were performed for the 177 patients (Table 6). WBC count (as continuous variable), cytogenetics, T- versus B-phenotype, and the trial itself (in the favor of FRALLE protocol) significantly affected EFS in this population. In the entire population or in each trial population, age never appeared as a significant prognostic parameter, whatever the variable observed: overall survival, DFS, RFS, or EFS (data not shown). Among covariates tested in a multivariate model (WBC count, cytogenetics, phenotype, trial, age, and sex), the only prognostic factors identified for EFS were the WBC count (P < .0001) and the trial (P = .0004).

Comparison of Dose Intensity Between Protocols
To explain the differences in outcome observed between the two groups of adolescents, we calculated the cumulated doses of major drugs theoretically administered to patients treated by chemotherapy alone (Table 7). During the whole treatment period, about five times more prednisone was to be administered in the FRALLE-93 protocol. This difference was not counterbalanced by the use of enhanced doses of other steroids, particularly dexamethasone (Table 7). Fifty percent more prednisone was to be administered during the induction course. In the adult protocol, the use of vinca-alkaloids was restricted to the induction course and two consolidation courses (Adriamycin, vincristin, and Dexamethasone [VAD] courses). Three times more equivalent infusions were to be administered in the pediatric protocol. For L-asparaginase, 20 times more doses were used in the FRALLE-93 trial. Moreover, this drug was not included in the LALA-94 induction course. Duration of treatment was 4 months shorter in the pediatric FRALLE-93 protocol (26 months in FRALLE-93 v 30 months in LALA-94).

To evaluate whether differing therapeutic practices between pediatric and adult teams might interfere with dose intensity, we observed the interval between the CR date time and the first day of the first postremission course (consolidation or first block in the FRALLE-93, early intensification in the LALA-94). The observed median intervals were 2 days and 7 days, respectively (P = .0002). This interval was more than 7 days for only 15% of patients included in the FRALLE-93 protocol.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study compared the characteristics and outcome of 100 adolescents treated in the French adult LALA-94 trial and 77 adolescents treated during the same period in the pediatric FRALLE-93 trial. We observed similar clinical features in both subgroups and noticed a low frequency of poor prognosis cytogenetic features in this age range. The disease outcome comparison indicates that adolescents treated in the pediatric protocol had significantly better results for remission achievement and EFS. Our observation corroborates both the previous comparison of the FRALLE-83 and LALA-85 trials and the recent study performed by the Cancer and Leukemia Group B (CALGB) and the Children’s Cancer Group (CCG).^19,20

Clinical characteristics of adolescents with ALL displayed intermediate features between child and adult populations. The frequency of ALL with T-cell phenotype (29%; 95% confidence interval, 22% to 36%) was similar to the 25% observed in adults, about two times higher than in younger children (1 to 14 years). Few recurrent cytogenetical events were observed in this population. The frequency of hyperdiploidy of more than 50 chromosomes was 16%, an intermediate value between the 25% observed in children and the 5% displayed by adults.⁸ The frequencies of t(9;22), t(4;11), and t(1;19) chromosomal translocations were also relatively low. We observed four cases (2.5%) of Philadelphia chromosome or bcr-abl fusion, which corresponds to a child’s profile (3% to 5%). The incidence of Ph+ ALL is known to markedly increase in patients 20 to 39 years of age.^21,22 The cryptic t(12;21) rearrangement, observed in about 20% of childhood but in less than 3% in adult ALL, was present in 7% of adolescents in the FRALLE-93 trial.^14,23 This lack of cytogenetical events, at the frontier between adult and childhood populations, indicates the existence of unknown factors that would explain the worse prognosis of adolescents among children.

Among the clinical characteristics of both subgroups, the only significant difference was the median age of patients. This expected difference of age, resulting from the fact that older adolescents are more frequently referred to adult departments, was not correlated with a disparity in biometric features, which could have partially explained differences in outcome. Even if age is known to be a major prognostic factor in children with ALL, it never appeared in our study as a significant prognostic factor according to the global population or to each trial population. In a previous study of 143 adolescents between 16 and 21 years of age from the CCG, EFS for patients 16 to 17, 18 to 19, and 20 years of age did not differ significantly.²⁴ However, we have performed a matched-pair analysis, leading to the comparison of 44 pairs of patients matched for age, introducing a selection bias through the loss of about 50% of the initial population (data not shown). This analysis nevertheless confirmed the difference in EFS according to the protocol (P = .007), even after adjusting for such prognostic covariates as WBC count, cytogenetics, T/B phenotype, and sex (P = .002).

As illustrated by the Kaplan-Meier curves, we observed a better outcome for adolescents treated in the pediatric FRALLE-93 trial. This difference was partially the result of a better CR rate but also because of a lower relapse rate in the pediatric subgroup. The 5-year estimated relapse risk was indeed more than two-fold higher in the adult protocol. This disparity was particularly observed in patients with BCP-ALL, but was also present in patients with T-cell ALL. The low number of patients with T-ALL (n = 51) partially explained this variation. Differences in induction courses, which could explain this gain in CR rate, are essentially both the continuous administration of higher doses of prednisone and the use of L-asparaginase in the FRALLE-93 protocol. Little pharmacological data are available to further explain this difference of remission rates. However, the tid administration schedule of steroids was demonstrated early on to be superior to more spaced administration in children ALL.²⁵ Moreover, a recent study at the Dana-Farber Cancer Institute demonstrated an improved response to increased steroid exposure in patients aged 1 to 18 years.²⁶

Higher doses of ALL major drugs were used in the pediatric protocol within a shorter period of time (26 months v 30 months). Moreover, the intensive part of this protocol (before maintenance) was performed in only 10 months. In the recent study by the Dana-Farber Consortium, children aged 9 to 18 years may have benefited from higher doses of L-asparaginase despite an increased related toxicity.² In patients with T-ALL, repeated doses of L-asparaginase during early treatment significantly improved outcome in a randomized study of the Pediatric Oncology Group.²⁷ Moreover, the pediatric delayed intensifications contributed to improve outcome. The benefit of this strategy, initially proposed by the Berlin-Frankfurt-Munster study group,²⁸ has been demonstrated by the CCG study in children older than 10 years of age.²⁹ The increased benefit of an augmented therapy including a double-delayed intensification in slow early responders has also been shown.³⁰

Finally, to further investigate how therapeutic attitudes could interfere with the concept of dose intensity, we observed variations of intervals between CR date and day 1 of the first postremission course. A significantly longer recovery interval was allowed for patients treated in the adult LALA-94 protocol, indicated that dose intensity could also be modulated by the inclination of adult center physicians to give patients time "to get their breath back."

In this study, French adolescents with ALL had a better outcome when considered and treated as high-risk patients in a pediatric protocol. This more favorable outcome was not explained by significant differences in patient characteristics and was already apparent after the induction course. This indicates a major role for the drug selection and the dose intensity. Disparities in treatment practices between pediatric and adult departments of hematology may further contribute to this difference. These results indicate that adolescents should be treated in pediatric protocols and that new trials inspired by pediatric protocols should be designed for treating young adults.

	ACKNOWLEDGMENTS

 
We thank Professor Sylvic Chevret for her expert statistical aid and Professor Gérard Schaison for his continuous involvement in adolescent leukemia.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted February 11, 2002; accepted November 15, 2002.

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