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Originally published as JCO Early Release 10.1200/JCO.2008.18.6916 on January 5 2009 Publisher’s Note The February 20, 2009, article by Huguet et al, entitled, “Pediatric–Inspired Therapy in Adults With Philadelphia Chromosome—Negative Acute Lymphoblastic Leukemia: The GRAALL-2003 Study” (J Clin Oncol 27:911–918, 2009), was published in print with errors in Table 1. This article was also published online on January 5, 2009, with errors in Table 1. Under “Remission induction,” the term “corticosteroid prophase” was given, whereas it should have been “corticosteroid prephase.” The dose for L–asparaginase was given as, “6,000 U/m2/d on days 8, 10, 12, 18, 20, 22, 24, and 26,” and it should have been, “6,000 U/m2/d on days 8, 10, 12, 20, 22, 24, 26, and 28.” Also, the dose for cyclophosphamide (CPM) was given as, “750 mg/m2/d on days 1 and 8; 750 mg/m2 on day 15 in good early responders; 500 mg/m2/12 h on days 15 and 16 in poor early responders,” and should have been, “750 mg/m2/d on day 1; 750 mg/m2/d on day 15 in good early responders; 500 mg/m2/12 h on days 15 and 16 in poor early responders.” Under “Consolidation blocks 3, 6, and 9,” the dose for CPM was given as, “500 mg/m2 on days 29 and 30,” and should have been, “500 mg/m2/d on days 29 and 30.” Also, the dose for VP–16 was given as, “75 mg/m2m/d on days 29 and 30,“ and should have been, “75 mg/m2/d on days 29 and 30.” Under “Late intensification (between consolidation blocks 6 and 7),” the dose for lenograstim was not indicated for patients in complete remission after the first induction course, and should have been, “150 μg/m2/d if neutrophils < 0.5 G/L to myeloid recovery.” Under “Maintenance therapy,” the dose for prednisone (PDN) was given as, “40 mg/m2/d on days 1–14 monthly for 12 months,” and should have been, “40 mg/m2/d on days 1–7 monthly for 12 months.” Under “CNS therapy, Treatment of patients with initial CNS involvement,” the dose for triple IT injections was given as, “Eight between days 7 and 21 of induction; four during the first two consolidation blocks; one at day 29 of consolidation blocks 3 and 6,” and should have been, “Eight between days –7 and 21 of induction; four during the first two consolidation blocks; one at day 29 of consolidation blocks 3 and 6.” Also, the dose for cranial irradiation was given as, “15 Gy before SCT or 18 Gy before late intensification; 6–MP 60 mg/m2/d during irradiation,” and should have been, “15 Gy before SCT or 24 Gy before maintenance therapy initiation; 6–MP 60 mg/m2/d during irradiation.” Also under “CNS therapy,” the footnote for triple IT injections was given as: †Triple IT injections consisted of MTX 15 mg, Ara–C 40 mg, and PDN 40 mg. While it should have been: †Triple IT injections consisted of MTX 15 mg, Ara-C 40 mg, and methylprednisolone 40 mg. These corrections have been made online as of May 12, 2009. These corrections are not reflected in the February 20, 2009, print edition. An erratum for the print edition was published in the May 20, 2009, issue (J Clin Oncol 27:2574, 2009). © 2009 American Society of Clinical Oncology.
Pediatric-Inspired Therapy in Adults With Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia: The GRAALL-2003 StudyFrom the Departments of Hematology, Hôpital Purpan, Toulouse; Hôpital Haut-Lévèque, Bordeaux; Hôpital Saint-Louis, Hôpital Necker, and Hôpital Pitié-Salpêtriere, Assistance Publique–Hôpitaux de Paris, Paris; Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon; Hotel Dieu, Nantes; Hôpital de la Timone, Marseille; Hôpital Larrey, Angers; Hôpital Brabois, Nancy, France; Hôpital Universitaire, Geneva, Switzerland; and Cliniques Universitaires Saint-Luc, Brussels, Belgium. Corresponding author: Hervé Dombret, MD, Department of Hematology, Hôpital Saint-Louis, 1 Ave Claude Vellefaux, 75010 Paris, France; e-mail: herve.dombret{at}sls.aphp.fr.
Purpose Retrospective comparisons have suggested that adolescents or teenagers with acute lymphoblastic leukemia (ALL) benefit from pediatric rather than adult chemotherapy regimens. Thus, the aim of the present phase II study was to test a pediatric-inspired treatment, including intensified doses of nonmyelotoxic drugs, such as prednisone, vincristine, or L-asparaginase, in adult patients with ALL up to the age of 60 years. Patients and Methods Between 2003 and 2005, 225 adult patients (median age, 31 years; range, 15 to 60 years) with Philadelphia chromosome–negative ALL were enrolled onto the Group for Research on Adult Acute Lymphoblastic Leukemia 2003 protocol, which included several pediatric options. Some adult options, such as allogeneic stem-cell transplantation for patients with high-risk ALL, were nevertheless retained. Results were retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience in 712 patients age 15 to 55 years. Results Complete remission rate was 93.5%. At 42 months, event-free survival (EFS) and overall survival (OS) rates were 55% (95% CI, 48% to 52%) and 60% (95% CI, 53% to 66%), respectively. Age remained an important bad prognostic factor, with 45 years of age as best cutoff. In older versus younger patients, there was a higher cumulative incidence of chemotherapy-related deaths (23% v 5%, respectively; P < .001) and deaths in first CR (22% v 5%, respectively; P < .001), whereas the incidence of relapse remained stable (30% v 32%, respectively). Complete remission rate (P = .02), EFS (P < .001), and OS (P < .001) compared favorably with the previous LALA-94 experience. Conclusion These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.
In children with acute lymphoblastic leukemia (ALL), current therapies yield complete remission (CR) rates of 98% and event-free survival (EFS) rates of 70% to 80% at 5 years.1 In adults, even if the CR rate reaches 85% to 90%, therapeutic results remain less satisfactory, with a disease-free survival (DFS) rates of only 30% to 40% at 5 years.1 The largest adult trial conducted by the British Medical Research Council (MRC) and Eastern Cooperative Oncology Group (ECOG) has recently reported a 90% CR rate with a 5-year overall survival (OS) rate of 43% in patients with Philadelphia chromosome (Ph)–negative ALL.2 In a study that retrospectively compared two trials, one designed for children and the other for adults, we have reported that adolescents and young adults age 15 to 20 years old markedly benefited from a pediatric approach.3 Comparable results have been reported in four similar studies.4–7 However, whether pediatric or pediatric-inspired treatments might also improve the outcome of adults older than age 20 years remained unresolved. The main concern was the perceived worse tolerance of higher cumulative doses of chemotherapy. Thus, the aim of the present phase II study conducted by the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) was to test the efficacy and tolerability of a pediatric-inspired therapy in adults with Ph-negative ALL up to the age of 60 years. When retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience,8 results suggest that this strategy might be associated with a highly significant improvement in patient outcome, even if a worse treatment tolerance is observed in patients older than 45 years.
Study Design and Population The GRAALL-2003 study was conducted in 70 centers in France, Belgium, and Switzerland. Patients age 15 to 60 years old were eligible if they had newly diagnosed Ph-negative ALL with L1 or L2 morphology according to the French-American-British classification. Ineligibility criteria were severe cardiac disease; renal or hepatic dysfunction; HIV, human T-lymphotropic virus, hepatitis B virus, or hepatitis C virus infection; and pregnancy. A total of 225 consecutive patients were entered onto the study between November 2003 and November 2005. Written informed consent was obtained from all patients or from the parents of those younger than 18 years old before enrollment. The study was approved in March 2003 by the Institutional Review Board of Hôpital Purpan, Toulouse II, France, and conducted in accordance with the Declaration of Helsinki.
Diagnosis of ALL
Response Criteria
Risk Classification and Stratification
Treatments
Statistical Considerations Binary variables were compared with the Fisher's exact test. The Mann-Whitney U test was used for median comparisons. OS and EFS were calculated from the date of prephase initiation. Events accounting for EFS were failure of CR induction, relapse, and death in first CR. DFS was calculated from the CR date. Events accounting for DFS were relapse and death in CR. Failure time data were estimated using the Kaplan-Meier method13 and then compared using the log-rank test.14 Cumulative incidence estimations took into account competing risks and were compared by the Gray test.15 All deaths related to treatment toxicity during induction or later but not after SCT were collectively defined as chemotherapy-related deaths. In multivariate analyses, outcome comparisons were adjusted with the Cox model16 and tested using the likelihood-ratio test. All calculations were performed using the STATA/SE software, version 9.0 (STATA Corp, College Station, TX) and the R software, version 1.5.1 (The R Development Core Team, A Language and Environment Copyright, 2002; University of Auckland, Auckland, New Zealand). Outcome was updated as of December 15, 2007. The median follow-up time of surviving patients was 37 months.
Patient Characteristics The median age was 31 years (range, 15 to 60 years; Table 2). One hundred forty-nine patients had B-cell precursor (BCP) ALL, whereas 76 patients had T-lineage ALL. Median age was 34 years in the B-lineage subgroup and 29 years in the T-lineage subgroup (P = .23 by Mann-Whitney U test). Median WBC was significantly higher in the T-lineage subgroup compared with the B-lineage subgroup (P < .001 by Mann-Whitney U test).
Response to Initial Therapy Overall, 57 patients (25%) had CsR-ALL, and 90 patients (40%) had ChR-ALL (Appendix Table A1, online only). Ninety-nine (89%) of the 111 poor early responders received the planned HyperC induction reinforcement. The reason for not administering this sequence was early death in one patient and toxic adverse event in the remaining 11 patients. None of the patients with corticosteroid-sensitive or chemotherapy-sensitive ALL received HyperC reinforcement. The overall CR rate was 93.5% (210 patients). The rate of CR patients who did not require the salvage course was not lower in poor early responders compared with good early responders (89% v 93%, respectively; P = .48 by Fisher's exact test). Fourteen patients (6%) died during induction, four of them after the HyperC sequence. No patient died during salvage therapy. The causes of induction death were sepsis (nine patients), CNS thrombosis and/or hemorrhage (four patients), and liver failure (one patient). The incidence of induction death was significantly higher in the B-lineage subgroup (P = .038 by Fisher's exact test).
Risk Groups
General Outcome
There was a trend toward a better outcome in patients with T-ALL. At 42 months, EFS was estimated to be 62% (95% CI, 50% to 72%) in T-ALL patients and 52% (95% CI, 42% to 59%) in BCP-ALL patients (P = .09 by log-rank test). This was mainly related to a higher CR rate in the T-ALL subset versus BCP-ALL patients (99% v 91%, respectively; P = .02). Once CR was achieved, 42-month DFS was estimated to be 57% (95% CI, 48% to 65%) in BCP-ALL patients and 63% (95% CI, 51% to 73%) in T-ALL patients (P = .37 by log-rank test). Of note, using this response-adapted induction, a poor early response still had a negative impact on DFS in patients with BCP-ALL (P = .004 by log-rank test) but not in those with T-ALL (P = .23 by log-rank test).
Impact of Risk Classification When censoring the 71 patients who received transplantation in first CR at transplant time, 42-month EFS, overall survival, and DFS were 55% (95% CI, 47% to 63%), 60% (95% CI, 51% to 68%), and 59.5% (95% CI, 51% to 67%), respectively. Using the GRAALL classification, DFS was 52% (95% CI, 40% to 63%) in high-risk patients v 68% (95% CI, 55% to 78%) in standard-risk patients (P = .05 by log-rank test). However, the difference in OS rate from CR among the standard- and high-risk GRAALL subgroups did not reach the significance level (60% v 72% at 42 months, respectively; P = .08). Using the MRC-ECOG classification, DFS was 54% (95% CI, 42% to 64%) in high-risk patients v 67% (95% CI, 53% to 77%) in standard-risk patients (P = .06 by log-rank test). In the MRC-ECOG standard-risk subgroup, EFS and OS were 64% (95% CI, 51% to 74%) and 76% (95% CI, 63% to 85%), respectively, after censoring at transplantation time those patients who received transplantation.
Impact of Age
Older patients did not tolerate the planned treatment as well as younger patients, especially L-asparaginase, leading to a lower cumulative dose and delay in consolidation initiation in CR patients (Table 4). However, the incidence of severe drug-related adverse events was not significantly higher in the older subgroup.
Historical Comparison With the LALA-94 Trial We then retrospectively compared the GRAALL-2003 results with those observed in patients with Ph-negative ALL treated in the former French LALA-94 adult trial (Table 5).8 Because older patients were not included in the LALA-94 trial, the 214 GRAALL-2003 patients  age 55 years old were compared with the 712 LALA-94 patients with Ph-negative ALL. Main baseline characteristics were well balanced between both trial cohorts, except for more patients with CNS disease in the LALA-94 cohort and more patients with t(4;11) and/or MLL-AF4 rearrangements in the GRAALL-2003 cohort. Significant increases in CR, EFS, and OS rates and a significant decrease in cumulative incidence of relapse were observed in the GRAALL-2003 trial (Table 5, Fig A2A, online only). The gain in EFS was observed in patients older than 45 years as well as in younger patients (Appendix Fig A2B). However, this translated significantly into a longer OS in the younger age subgroup (66% v 44% at 42 months in GRAALL-2003 v LALA-4, respectively; P < .001 by log-rank test) but not in the subgroup of patients older than 45 years (42% v 30% at 42 months in GRAALL-2003 v LALA-4, respectively; P = .13 by log-rank test). Of importance, because indications of SCT in first CR differed among both trials, the historical inferiority of the LALA-94 protocol was still observed and even more marked when censoring all SCT patients at transplantation time in both trials (data not shown).
Results presented here strongly suggest that an intensified protocol might yield significantly better results than former protocols in adults with Ph-negative ALL. This intensified approach incorporated several pediatric options including increased cumulative dosages and cautious observance of dose-intensity. The doses of nonmyelotoxic drugs (prednisone, vincristine, and L-asparaginase) were in the range of most pediatric regimens. The HyperC induction sequence might also have played a role, particularly in adults with T-ALL in whom the HyperC, vincristine, doxorubicin, and dexamethasone regimen previously yielded an excellent CR rate.17 Late intensification, which has rarely been tested in adults,18,19 was relatively well tolerated and might also have contributed. Not only the doses, but also the schedules and modalities of administration of the different drugs may have impacted therapeutic results. In this regard, a short delay between remission induction and consolidation has been evidenced as a prominent favorable prognostic factor in both childhood and adult ALL.20,21 In addition to this pediatric-like chemotherapy backbone, the GRAALL-2003 protocol retained treatment options currently used in adults, including cranial irradiation, early intensive administration of growth factors, and larger indication of allogeneic SCT in first CR. Actually, given the poor outcome observed so far in adults with the disease, the issue of long-term effects was less of a concern than in children. If these promising results could be confirmed in larger studies and/or with a longer follow-up, they will probably impact on the clinical management of these patients in the future. In younger patients with low peripheral-blood count ALL corresponding to the standard-risk MRC-ECOG group,2 such new intensified approaches might be associated with long-term DFS rates of 65% to 70% in patients who have not received transplantation, raising again the issue of the place of allogeneic SCT in first CR in these relatively good-risk patients. However, the age issue will certainly remain the most important one. Although the toxicity of the GRAALL-2003 chemotherapy was acceptable in younger adults up to 45 years of age, older patients did not tolerate both induction and postremission treatments as well. Even if they still drew a benefit from this intensified approach compared with the historical experience, the cumulative incidence of chemotherapy-related deaths of 23% is clearly too high (Fig A1, online only). Dose adaptations and reduced intensity conditioning SCT might be evaluated in these older adults. A more radical option currently being tested by several other groups would be to use unmodified pediatric protocols in adult patients Even if preliminary results look interesting,22,23 the main issue obviously relates to the upper age limit because it remains uncertain whether adults older than 20 to 25 years of age will tolerate such unmodified pediatric approaches as well as teenagers. Thus, currently, we propose using unmodified pediatric protocols in teenagers and adapted pediatric-inspired protocols in younger adults. To reduce treatment-related toxicity in patients older than 45 years, we are currently recommending systemic anti-infectious prophylaxis during induction and delayed intensification. Testing reduced-intensity conditioning rather than standard myeloablative SCT in these patients could be another option.
The author(s) indicated no potential conflicts of interest.
Conception and design: Françoise Huguet, Thibaut Leguay, Emmanuel Raffoux, Xavier Thomas, Kheira Beldjord, Eric Delabesse, Patrice Chevallier, Agnes Buzyn, André Delannoy, Yves Chalandon, Jean-Paul Vernant, Marina Lafage-Pochitaloff, Agnès Chassevent, Véronique Lhéritier, Elizabeth Macintyre, Marie-Christine Béné, Norbert Ifrah, Hervé Dombret Administrative support: Véronique Lhéritier Provision of study materials or patients: Françoise Huguet, Thibaut Leguay, Emmanuel Raffoux, Xavier Thomas, Patrice Chevallier, Agnes Buzyn, André Delannoy, Yves Chalandon, Jean-Paul Vernant, Norbert Ifrah, Hervé Dombret Collection and assembly of data: Françoise Huguet, Kheira Beldjord, Eric Delabesse, Agnes Buzyn, Marina Lafage-Pochitaloff, Agnès Chassevent, Véronique Lhéritier, Elizabeth Macintyre, Marie-Christine Béné, Norbert Ifrah, Hervé Dombret Data analysis and interpretation: Françoise Huguet, Kheira Beldjord, Eric Delabesse, Agnes Buzyn, André Delannoy, Yves Chalandon, Jean-Paul Vernant, Marina Lafage-Pochitaloff, Agnès Chassevent, Elizabeth Macintyre, Marie-Christine Béné, Norbert Ifrah, Hervé Dombret Manuscript writing: Françoise Huguet, Elizabeth Macintyre, Marie-Christine Béné, Norbert Ifrah, Hervé Dombret Final approval of manuscript: Françoise Huguet, Thibaut Leguay, Emmanuel Raffoux, Xavier Thomas, Kheira Beldjord, Eric Delabesse, Patrice Chevallier, Agnes Buzyn, André Delannoy, Yves Chalandon, Jean-Paul Vernant, Marina Lafage-Pochitaloff, Agnès Chassevent, Véronique Lhéritier, Elizabeth Macintyre, Marie-Christine Béné, Norbert Ifrah, Hervé Dombret
The following centers and investigators participated in the GRAALL-2003 trial: France: Aix en Provence – Cailleres, Da Silva; Amiens – Damaj, Royer, Dubus, Capiod, Marolleau; Angers – Francois, Hunault, Ifrah, Marie, Genevieve, Baranger, Chassevent, Blanchet; Annecy – Corront, Cadoux; Avignon – Boulat, Derre; Bayonne – Banos, Bauduer, Burtin; Besançon – Brion, Deconninck, Garnache Ottou, Ferrand; Blois – Rodon; Bobigny – Gardin, Fenaux, Beve, Boulalam, Eclache, Fenaux; Bordeaux – Boiron, Leguay, Pigneux, Bilhou-Nabera, Perry, Lacombe, Tabrizi, Lippert, Marit; Brest – Guillerme, Berthou, Lecalvez, De Braekeleer, Ugo; Caen – Reman, Lepesant, Salaun, Plessis, Naguib, Leporrier; Clamart – De Revel, Samson, Desangles; Clermont-Ferrand – Chaleteix, Villemagne, Latiere, Berger, Giollant, Tchirkov, Tournilhac; Colmar – Audhuy, Raby, Bauly, Moskochenko; Creteil – Kuentz, Maury, Pautas, Cordonnier, Beaune, Jouault, Bories, Reyes; Dijon – Caillot, Casanovas, Grandjean, Menadier, Favre-Audry, Mugneret, Teyssier; Grenoble – Garban, Bulabois, Gressin, Rolland, Jacob, Lefebvre, Leroux, Callanan, Cahn; Lens – Stalnikiewicz, Poulain; Lille – Darre, De Botton, Lepelley, Lai, Soenen, Preudhomme, Grardel, Bauters; Limoges – Turlure, Bordessoule, Chaury, Trimoreau, Gachard; Lyon – Le, Nicolini, Tavernier, Thiebaut, Thomas, Lheritier, Girard, Wattel, Tigaud, Hayette, Michallet; Marseille – Vey, Charbonnier, Stoppa, Mouton, Sainty, Moziconacci, Arnoulet, Lafage-Pochitaloff, Blaise; Meaux – Frayfer, Mossafa; Montpellier – Fegueux, Quittet, Grosjean, Taib, Taviaux, Dupont, Rossi; Mulhouse – Arkam, Ojeda Uribe, Iglarz, Drenou, Jeandidier, Isaac; Nancy – Witz, Bene, Witz, Gregoire, Monhoven; Nantes – Chevallier, Delaunay, Milpied, Vigouroux, Moreau, Harousseau, Saulquin, Garand, Talmant, Avet-Loiseau; Nice – Gratecos, Legros, Sirvent, Touitou, Ticchioni, Raynaud; Nîmes – Jourdan, Nicolas, Brun, Chiesa; Orléans – Alexis, Legac, Schoenwald; Paris Cochin – Dreyfus, Khelfaoui, Pucard, Viguie; Paris Necker – Buzyn, Couderc, Asnafi, Valensi, Radford-Weiss, Delabesse, Macintyre, Varet; Paris Pitié-Salpétrière – Dhedin, Aliammar, Merle-Beral, Nguyen-Khac, Davi, Leblond, Vernant; Paris Saint-Antoine – Isnard, Negadi, Perot, Van den Akker, Laporte, Gorin; Paris Saint-Louis – Raffoux, Treilhou, Maarek, Daniel, Soulier, Cayuela, Miclea, de Labarthe, Dombret; Perpignan – Valantin, Sanhes; Poitiers – Renaud, Larchee, Cividin, Brizard, Chomel, Guilhot; Reims – Himberlin, Baury, Daliphard, Luquet, Cornillet-Lefebvre, Delmer; Rennes – Escoffre-Barbe, Lamy, Picouleau, Roussel, Henry, Ly Sunnaram, Fest; Rouen – Lepretre, Contentin, Jardin, Lenain, Tilly, Tallon, Lenormand, Stamatoullas-Bastard, Penther, Bastard; Saint-Cloud – Glaisner, Janvier, Bourgignat; Saint-Etienne – Cornillon, Jaubert, Guyotat, Marchand, Campos, Nadal, Flandrin; Strasbourg – Bilger, Fohrer, Lioure, Ame, Eischen, Leymarie, Gervais, Herbrecht; Toulouse – Huguet, Recher, Daniel, Kuhlein, Dastugue, Demas, Attal; Toulon – De Jaurreguiberry; Tours – Delain, Delepine, Degene, Barin, Colombat; Valenciennes – Fernandes, Poulain, Daudignon; Versailles – Choquet, Rousselot, Taksin, Pousset, Terre, Castaigne; Villejuif – Arnaud, Bayle, Bourhis, Auger, Bernheim. Belgium: UCL Saint-Luc – Ferrant, Costantini, Libouton, Poirel; Gilly – Mineur; Jolimont – Delannoy, Tacal, Rack; UCL Mont Godine – Bosly, Crasson; Michaux, Vandenbeghe, Hagemeijer. Switzerland: Basel – Gratwohl, Meili, Heim; Geneva – Chalandon, Passweg, Trembleau, Cabrol; Lausanne – Spertini, Abbal, Jotterand, Porter
We thank F. Daniel and M.-E. Llau from the Regional Clinical Research Office of Toulouse and A. Praire, M.D. Lorenzi, B. Gauthier, F. Perry, R. Delépine, and D. Djordjijevic for their help in data monitoring. We are indebted to S. Chevret, MD, PhD, G. Socié, MD, PhD, and A. Baruchel, MD, for their valuable advice. This article is dedicated to all pediatricians dealing with childhood acute lymphoblastic leukemia around the world.
Written on behalf of the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). GRAALL includes the former France-Belgium Group for Lymphoblastic Acute Leukemia in Adults, the French Western-Eastern Group for Lymphoblastic Acute Leukemia, and the Swiss Group for Clinical Cancer Research. GRAALL participating centers and investigators are listed in the Appendix. Supported by the Regional Clinical Research Office, Toulouse, France, and by grants from the Programme Hospitalier de Recherche Clinique (PHRC ID No. 0200701) in France and the Swiss Federal Government in Switzerland. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
30 x 109/L for B-lineage ALL, clinical and/or morphologic CNS involvement, t(4;11) and/or MLL-AF4 fusion transcript, t(1;19) and/or E2A-PBX1 fusion transcript, and low hypodiploidy (30 to 39 chromosomes or DNA index < 0.85) and/or near-triploidy (60 to 78 chromosomes or DNA index of 1.30 to 1.69).
