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Prognostic Factors for Leukemic Induction Failure in Children With Acute Lymphoblastic Leukemia and Outcome After Salvage Therapy: The FRALLE 93 Study

Caroline Oudot, Marie-Françoise Auclerc, Vincent Levy, Raphaël Porcher, Christophe Piguet, Yves Perel, Virginie Gandemer, Marianne Debre, Christiane Vermylen, Brigitte Pautard, Claire Berger, Claudine Schmitt, Thierry Leblanc, Jean-Michel Cayuela, Gérard Socie, Gérard Michel, Guy Leverger, André Baruchel

From the Service d’Hématologie et Oncologie Pédiatrique, Hôpital Mère-Enfant, Limoges; Service de Pédiatrie à Orientation Hématologique; Centre d’Investigations Cliniques; L’Institut National de la Santé et de la Recherche Médicale U717; Département de Biostatistique et Informatique Médicales; Laboratoire d’Hématologie Moléculaire, Service de Greffe de Moelle; Hôpital St Louis, Assistance Publique–Hôpitaux de Paris (AP-HP); Service d’Hématologie Pédiatrique, Hôpital Necker Enfants Malades, AP-HP; Service d’Onco-Hématologie Pédiatrique, Hôpital Trousseau, AP-HP, Paris; Service d’Onco-Hématologie Pédiatrique, Hôpital Pellegrin, Bordeaux; Service d’Onco-Hématologie Pédiatrique, Hôpital Sud, Rennes; Service d’Onco-Hématologie Pédiatrique, Hôpital Nord, Amiens; Institut de Cancérologie de la Loire, Saint-Priest en Jarez; Service d’Hématologie Pédiatrique, Hôpital des Enfants, Vandoeuvre les Nancy; Service d’Hématologie Pédiatrique, Hôpital La Timone, Marseille, France; and Service d’Onco-Hématologie Pédiatrique, Hôpital St Luc, Bruxelles, Belgique

Corresponding author: André Baruchel, MD, Service de Pédiatrie à Orientation Hématologique, Hôpital Saint-Louis, Assistance Publique–Hôpitaux de Paris and Université Denis Diderot Paris 7, 1 avenue Claude Vellefaux, 75010 Paris, France; e-mail: andre.baruchel{at}sls.aphp.fr

	ABSTRACT

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Purpose To identify prognostic factors and to evaluate the outcome of children with acute lymphoblastic leukemia (ALL) failure after induction therapy.

Patients and Methods Between June 1993 and December 1999, 1,395 leukemic children were included in the French Acute Lymphoblastic Leukemia 93 study.

Results Fifty-three patients (3.8%) had a leukemic induction failure (LIF) after three- or four-drug induction therapy. In univariate analysis, high WBC count (P = .001), mediastinal mass (P = .017), T-cell phenotype (T-ALL; P = .001), t(9;22) translocation (P = .001), and a slow early response (at day 8 and/or on day 21, P = .001) were predictive of LIF. The following three prognostic groups for LIF were identified by multivariate analysis: a low-risk group with B-cell progenitor (BCP) ALL without t(9;22) (odds ratio [OR] = 1), an intermediate-risk group with T-ALL and a mediastinal mass (OR = 7.4, P < .0001), and a high-risk group with BCP-ALL and t(9;22) or T-ALL without a mediastinal mass (OR = 28.4, P < .0001). Complete remission (CR) was subsequently obtained in 43 patients (81%). The 5-year overall survival (OS) rate of the 53 patients was 30% ± 6%. The 5-year OS rate among allogeneic graft recipients, autologous graft recipients, and after chemotherapy were 30.4% ± 9.6% (50% ± 26% after genoidentical transplantation), 50% ± 17.7%, and 41.7% ± 14.2%, respectively (P = .18). Fourteen patients (26%) were still in first CR after a median of 83 months (range, 53 to 117 months).

Conclusion Three risk categories for LIF in children with ALL were identified. Approximately one third of patients with LIF can be successfully treated with salvage therapy overall. Subsequent CR after LIF is mandatory for cure.

	INTRODUCTION

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In the last 30 years, the cure rate in childhood acute lymphoblastic leukemia (ALL) has increased to 80%.¹ Remission induction therapy generally consists of a combination of three or four drugs (vincristine, prednisone, and L-asparaginase, with or without an anthracycline), based on the risk classification at diagnosis. This multiagent therapy achieves complete remission (CR) in the vast majority (> 95%) of children with ALL.^2-6 Failure to enter CR after induction therapy portends an extremely poor outcome, and children with leukemic induction failure (LIF) have a high rate of relapse and a low survival rate.^7-10 However, few studies have specifically looked for prognostic factors of LIF.^9,11-17

The aim of this study was to identify prognostic factors for LIF and to evaluate the outcome of children with LIF identified within a large, multicenter, prospective trial, the French Acute Lymphoblastic Leukemia Pediatric group (FRALLE) 93 protocol.

	PATIENTS AND METHODS

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Patients
Between June 1993 and December 1999, 1,395 children aged less than 20 years with previously untreated ALL were enrolled onto the FRALLE 93 trial in 18 French pediatric centers and one Belgian pediatric center.

Diagnosis of Leukemia
ALL was diagnosed when 25% lymphoblasts or more were present in the bone marrow aspirate based on standard morphologic criteria. Immunophenotyping and cytogenetic studies were performed with standard methods. Molecular equivalents of the four major B-cell progenitor (BCP) ALL translocations (TEL-AML1, BCR-ABL, E2A-PBX1, and MLL-AF4) were systematically assessed after 1994. Mediastinal mass at diagnosis was diagnosed on chest x-ray. ALL patients with L3 morphology and/or mature B-cell phenotype were excluded.

Risk Groups
FRALLE 93 considered three risk groups defined at diagnosis (low-risk group A, intermediate-risk group B, and high-risk group C) based on the following features: age (< 1 year, 1 to 9 years, or 10 years), extramedullary disease (CNS disease and mediastinal mass), WBC more than 100,000/µL, T-immunophenotype ALL (T-ALL), and karyotype. The A, B, and C groups represented 13%, 48%, and 39% of patients, respectively. A prednisone-poor response (PPR) on day 8 and/or a slow early response (SER) with M2 or M3 bone marrow on day 21 were then used for secondary stratification (ie, assignment of type of consolidation and intensification treatment to be performed after induction).

Treatment
The FRALLE 93 trial is an intensive multiagent treatment consisting of a corticosteroid prephase, followed by induction, consolidation, and one or two delayed intensifications. This protocol was approved by the local human investigations committee, and an informed consent was obtained from each patient or the parents. The induction schedule is listed in Table 1.

Statistical Analysis
Patient follow-up was considered from time of evaluation of response to induction therapy, and patients who died during induction were excluded from analysis. Event-free survival was calculated from the beginning of follow-up to last follow-up or the first event (death of any cause, relapse, or failure of rescue therapy for LIF patients). Note that, for patients in CR, this end point corresponds to usual disease-free survival. The overall survival (OS) rate was based solely on deaths from all causes. In both analyses, the observation time was censored at the last follow-up date if no events occurred. Follow-up was updated to June 2005. The Kaplan-Meier method was used to estimate survival rates, and comparisons were based on the two-sided log-rank test.¹⁸ Associations between individual variables and remission were assessed with the Wilcoxon rank sum test for quantitative variables and with the ² test or Fisher's exact test when these were more appropriate for polytomous variables.

Multiple logistic regression was used to identify independent predictors of CR. Only a priori variables were used for multiple analysis (ie, characteristics existing before initiation of treatment). A subsequent analysis using day 8 prednisone sensitivity, a well-known prognostic factor in ALL, was added. All variables achieving statistical significance (P < .20) in univariate analysis were entered in the multiple regression model. A backwards variable selection procedure based on a cutoff value of P = .10 was used to identify the set of independent predictors of LIF. Interactions between age and other variables were also sought in the model. The validity of the logistic regression models was checked by using the Hosmer and Lemeshow¹⁹ lack-of-fit tests. The internal validation of the model selection procedure was based on the nonparametric bootstrap method.²⁰ This computer-based method creates numerically generated random samples with characteristics similar to those of the original sample. The procedure was based on random generation of 500 samples from the original data, respecting the balance between patients with and without LIF. The variable selection procedure was applied to these samples, and the results were evaluated as proportions of selection of each variable, proportion of selection of the same set of variables as in the original sample, and, in this latter case, as mean values of the estimated parameters compared with originally estimated ones. All analyses were performed with the SAS version 8.2 (SAS Institute, Cary, NC) and S-Plus 2000 (MathSoft Inc, Seattle, WA) software packages. All tests were two sided, with a significance cutoff of P = .05.

	RESULTS

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Nine children died early during induction therapy, with a median of 10 days after diagnosis (range, 2 to 51 days), before the response to therapy could be assessed. As mentioned earlier, these patients were excluded from this analysis, which thus included the 1,386 children who were evaluated at the end of remission induction chemotherapy.

Characteristics of the LIF Patients
Fifty patients had more than 5% of blasts in the bone marrow aspiration at days 35 to 42 after induction therapy, and three patients had an early disease relapse less than 4 weeks after entering CR. Thus, 53 patients (3.8%) were considered in LIF. The median age for these patients was 9.8 years (range, 0.3 to 17.6 years) compared with 5 years at the diagnosis (range, 0.1 to 19.7 years) for children who reached a CR. The median WBC count at diagnosis was 46/µL (range, 1.9 to 699/µL). Table 2 compares the clinical and biologic features of the 53 patients with LIF and the 1,333 patients who entered CR after induction therapy.

The following three risk groups for LIF were identified by multivariate analysis (Table 3): the low-risk group of patients had BCP-ALL with no Philadelphia chromosome (Ph1; n = 1,080; LIF rate, 1%); the intermediate-risk group had T-ALL and mediastinal involvement (n = 124; LIF rate, 9%); and the high-risk group had BCP-ALL and Ph1 or T-ALL without mediastinal involvement (n = 92; LIF rate, 27%). Prednisone sensitivity at day 8 was also significantly associated with LIF when adjusting on preceding variables (n = 142; LIF rate, 18%; adjusted odds ratio = 4.7; 95% CI, 2.3 to 9.8; P < .001, compared with the low-risk group).

Outcome
The 5-year OS rate is 30% (standard deviation [SD] = 6%) among the 53 patients with LIF compared with 85% (SD = 2%) among the 1,333 patients who entered CR after induction therapy (P < .001; Fig 1). The 5-year event-free survival rate is 29% (SD = 6%) among the 53 patients with LIF compared with 75% (SD = 2%) among the 1,333 patients who entered CR after induction therapy (P < .001). Among the 43 patients who finally entered CR, 18 experienced relapse after a median of 12 months (range, 1 to 66 months); 17 of these patients died, and one achieved a second CR (Table 5). Only two relapses occurred after 36 months (at 63 and 66 months), both in patients treated with chemotherapy alone. Eleven children died of toxicity (nine after BMT). Overall, 14 children remain in first CR, with a median follow-up time of 83 months (range, 53 to 117 months), and one child is in continuous second CR (CR2) at 20 months. The 5-year OS rate is 37.2% (SD = 7.4%) when CR is obtained after salvage therapy and 0% when CR is not obtained (P < .0001).

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival (OS) of the children with acute lymphoblastic leukemia treated in the FRALLE 93 trial. OS is compared in children in complete remission (CR; n = 1,333) and children with leukemic induction failure (LIF; n = 53) after induction therapy.

	DISCUSSION

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Our induction failure rate of 3.8% is within the range of the one observed in previous studies published during the last 20 years, which showed a failure rate of 0.25% to 10%.^6,8,9,21-35 This variability may be explained by differences in the study populations, the type of treatment administered, and the definitions used for LIF. LIF is often defined as M2 or M3 bone marrow (> 5% blasts) after 5 weeks of remission induction therapy on day 26, 28, 31, or 40.^{23,25,29,34-37} Chessells et al³⁸ defined LIF as M3 bone marrow (> 25% blasts) on day 28 after 1 month of therapy, and Reiter et al⁸ defined LIF as more than 10% blasts after 4 to 6 weeks of induction therapy. Others define LIF as failure to achieve CR after two courses of induction therapy.^5,8,24,39-41 We also considered early relapses (within 4 weeks after CR) as LIF in our study.

Our univariate analysis has indicated some predictive risk factors for LIF, including hyperleukocytosis more than 100,000/µL, mediastinal mass, T-cell immunophenotype, t(9;22) translocation or Ph1, PPR on day 8, and SER on day 21. Other studies have reported, using univariate analysis, similar risk factors.^{9,11-15,42,43}

In this study, Ph1 was present in 10 (20%) of 53 children with LIF, whereas it is usually present in only 2% to 3% of children with ALL. Ph1 has been linked to a high rate of LIF.^44-46 Ph1-positive ALL may need a more intensive induction therapy. It is of note that, after a FRALLE 93 protocol amendment intensifying induction therapy in June 1996, four (19%) of 21 children with Ph1 had LIF compared with six (32%) of 19 children with Ph1 before the amendment. An alternative strategy used in many Ph1-positive ALL adult protocols is to combine imatinib mesylate with induction chemotherapy, leading to unprecedented CR rates (> 90%).^47-50

In our study, day 8 PPR and day 21 SER were strong risk factors for LIF after four-drug induction therapy (P = .001). Other groups have identified day 8 PPR as a factor of poor prognosis.^{12-14,16,51,52} Early response is often evaluated on a day 14 or day 15 bone marrow aspirate^{12,14,16,51,53} or, occasionally, on day 21 or day 22 marrow.^52,54 It is of note that, in the FRALLE 93 trial, day 21 bone marrow was prospectively taken into account; patients with M2 or M3 bone marrow at day 21 received intensified induction therapy. Nevertheless, M2 or M3 bone marrow at day 21 remains a predictive factor of LIF but with a positive predictive value of only 17%.

Other features previously linked to LIF were not confirmed in our study, namely male sex,^55-58 age younger than 12 months or older than 10 years,^30,59-61 CNS disease at diagnosis,⁹ and French-American-British classification L2.^53,62

Our study is one of the rare studies to provide a multivariate analysis of prognostic factors of LIF.¹⁴ With a set of three simple initial parameters, we identified three categories of patients with low, intermediate, and high risk of LIF. This model, if validated in a separate cohort, could be used for modification of induction therapy in ALL. As mentioned earlier, combination of imatinib with chemotherapy in Ph1 patients is currently used in adult protocols and might become a standard even in children during induction therapy. Intensified induction in T-ALL patients at high risk of LIF could also be proposed.

Various salvage regimens were used in the FRALLE 93 study and yielded CR in 81% of the children (Table 4). A CR rate of 84% (26 of 31 patients) was obtained with the CAZED regimen, which contains conventional-dose cytarabine. Regimens with high-dose cytarabine without anthracycline but including other intercalating agents (mitoxantrone or amsacrine) gave a similar CR rate (11 of 14 patients). These results are similar to those obtained by Silverman et al,⁹ who reported a 91% CR rate but after one or more lines of salvage therapy (39% after one course). In contrast, our CR rate is higher than the 64% and 54% rates obtained by Rivera et al⁶³ and Giona et al,⁶⁴ respectively, with intermediate-dose cytarabine and idarubicin. Ochs et al³⁹ reported a 44% salvage rate with teniposide and conventional-dose cytarabine.

Twenty-three children received BMT in first CR after salvage therapy. The best 5-year OS rates were obtained with HLA genoidentical and autologous BMTs (50% for each). Among the 10 children who received genoidentical BMT, four experienced relapse (three died, one is in CR2), one died of toxicity, and five are still in CR1 64 to 106 months later. Four of eight children who received autologous BMT are still in CR1 after 54 to 109 months. Of note, patients treated with chemotherapy alone have an OS rate of 41.7% (SD = 14%). These survival rates are not statistically different. A higher 5-year OS rate was obtained after HLA genoidentical transplantation compared with unrelated donor transplant (50% [SD = 13%] v 15% [SD = 9%], respectively; P = .018). Others have reported a benefit for allogeneic BMT in LIF. Giona et al⁶⁴ reported a significantly higher disease-free survival rate after allogeneic BMT (43.3% [SD = 14.3%]) than after autologous BMT (12.7% [SD = 7.6%]) in patients (children and adults) in CR after a primary refractory or relapsed ALL (P = .01). Balduzzi et al⁶⁵ reported, in a prospective study, a disease-free survival rate of 56% after allogeneic transplantation with related donor compared with 26.5% after chemotherapy for children with LIF. Furthermore, survival after unrelated donor transplantation has increased in the recent era as a result of the improvements in donor selection and supportive care, potentially leading to better results in patients with LIF.

Minimal residual disease (MRD) can now be detected by flow cytometry or polymerase chain reaction amplification during treatment.^66-68 Patients with high MRD ( 10^–2) on the date of morphologic CR have a higher risk of death than patients with lower levels of MRD, a higher risk of relapse, a shorter continuous CR, and a survival rate of approximately 20% to 30%.^63,66-71 These results challenge the current definition of CR in this setting.⁷² Indeed, CR might better be defined as cytomorphologic and molecular or immunologic remission at the end of induction therapy. Patients with morphologically defined LIF and patients with a high level of MRD at the end of induction therapy can both be considered as poor early responders who need further intensification of the treatment. The molecular pathways involved in this treatment resistance are ill defined. Microarray technology helped to identify several sets of genes whose expression profiles are linked to the resistance to antileukemic drugs and to the treatment response.^73-75 This technology could be used to identify at-risk groups of patients and will stimulate the development of alternative treatment strategies.

To conclude, three risk groups for LIF can be identified at diagnosis based on the following three a priori parameters: Ph1 in BCP-ALL; T-cell phenotype; and, in T-ALL, the lack of mediastinal mass. These patients must be closely evaluated (at day 8 and day 15 or 21) for early response to potentially benefit from an early intensification of induction/consolidation therapy.

In children with LIF, salvage therapy may lead to CR in 80% of cases. Among these, 40% of the patients will be long-term survivors. Matched sibling transplantation in CR1 is likely to be the best option for these patients. Alternative treatments include intensified chemotherapy, autologous BMT, and nongenoidentical stem-cell transplantation.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Caroline Oudot, Marie-Françoise Auclerc, André Baruchel

Provision of study materials or patients: Christophe Piguet, Yves Perel, Virginie Gandemer, Marianne Debre, Christiane Vermylen, Brigitte Pautard, Claire Berger, Claudine Schmitt, Thierry Leblanc, Jean-Michel Cayuela, Gérard Socie, Gérard Michel, Guy Leverger, André Baruchel

Collection and assembly of data: Caroline Oudot, Marie-Françoise Auclerc

Data analysis and interpretation: Caroline Oudot, Marie-Françoise Auclerc, Vincent Levy, Raphaël Porcher, André Baruchel

Manuscript writing: Caroline Oudot, Vincent Levy, Thierry Leblanc, André Baruchel

Final approval of manuscript: Caroline Oudot, Vincent Levy, André Baruchel

	ACKNOWLEDGMENTS

 
We thank all the members of the FRALLE group and la Direction de Recherche Clinique de l’Assistance Publique des Hôpitaux de Paris.

	NOTES

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

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Submitted May 23, 2007; accepted November 29, 2007.

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