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Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 283-289 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.3927 Long-Term Results of the AIEOP-ALL-95 Trial for Childhood Acute Lymphoblastic Leukemia: Insight on the Prognostic Value of DNA Index in the Framework of Berlin-Frankfurt-Muenster–Based Chemotherapy
From the Pediatric Hematology Oncology, Ospedale dei Bambini G. Di Cristina, Palermo; Medical Statistics Unit and Department of Pediatrics, University of Milano-Bicocca, Milano; Ospedale San Gerardo, Monza; Pediatric Hematology Oncology, Torino; I Clinica Pediatrica, University of Napoli, Napoli; Pediatric Hematology Oncology, University of Pavia, Pavia; Pediatric Hematology Oncology, University of Catania, Catania; Pediatric Hematology, IRCCS Ospedale Bambino Gesù; Department of Hematology, University La Sapienza, Rome; Pediatric Hematology Oncology, University of Padua, Padua; Pediatric Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, I.G. Gaslini, Genua, Genua; Pediatric Hematology Oncology, Ospedale Pausilipon, Naples; Pediatric Hematology Oncology, University of Bologna, Bologna; and Pediatric Hematology Oncology, University of Bari, Bari, Italy Corresponding author: Giuseppe Basso, MD, Laboratorio di Oncoematologia Dipartimento di Pediatria, Università di Padova, Via Giustiniani, 3, 35128 Padova, Italy; e-mail: giuseppe.basso{at}unipd.it
Purpose Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica conducted the ALL-95 study for risk-directed, Berlin-Frankfurt-Muenster (BFM) –oriented therapy of childhood acute lymphoblastic leukemia, aimed at exploring treatment reduction in standard-risk patients (SR) and intensification during continuation therapy in intermediate-risk patients (IR) as randomized questions and treatment intensification in high-risk patients (HR). The prognostic value of DNA index was explored in this setting.
Patients and Methods A total of 1,744 patients were enrolled (115, SR; 1,385, IR; and 244, HR). SR patients (DNA index Results The event-free survival and overall survival probabilities at 10 years for the entire group were 72.5% (SE, 1.3) and 83.6% (SE, 0.9); 85.0% (SE, 3.4) and 95.5% (SE, 2.0) in SR, 75.1% (SE, 1.5) and 87.5% (SE, 0.9) in IR, and 51.0% (SE, 3.2) and 57.2% (SE, 3.3) in HR patients, respectively. Patients with a favorable DNA index had superior EFS in both IR (83.8% [2.7%] v 73.9% [1.7%]) and in HR (67.8% [9.4%] and 49.6% [3.5%]). Of the six patients with DNA index less than 0.8, only one remained in remission. Conclusion Favorable DNA index was associated with a better prognosis in IR and HR patients defined by presenting clinical criteria and treatment with a BFM-oriented chemotherapy.
More than 90% of expected cases of childhood acute lymphoblastic leukemia (ALL) in Italy are recruited by Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) and treated with Berlin-Frankfurt-Muenster (BFM) –oriented chemotherapy.1-3 In this AIEOP-ALL-95 study, patients were stratified according to age, WBC count, and DNA index (DI).4,5 Primary aims were to evaluate the impact of treatment reduction in hyperdiploid standard-risk (SR) patients; prognostic value of DI in intermediate-risk (IR) or high-risk (HR) patients; impact of randomly assigned vincristine (VCR) plus dexamethasone (DEXA) pulses during continuation therapy in IR; and the impact of intensification (full induction, repeated protocol II) in HR. The secondary aim was to assess the impact in IR of reduced high-dose methotrexate (HD-MTX) from 5 to 2 g/m2. We report long-term results of the AIEOP-ALL-95 study.
Patients younger than 18 years with newly diagnosed ALL were eligible (except for those with Down syndrome) and were stratified as SR, IR, or HR. SR patients were age 1 to 5 years, had WBC less than 20 x 109/L, DI  1.16 and less than 1.60, complete remission (CR) on day +43; and the absence of T-cell ALL, Philadelphia chromosome (Ph) –positive ALL [t(9,22) or BCR/ABL, t(4;11), or MLL/A4], extramedullary disease, poor response to prednisone (PPR; > 1,000 blasts/cm3 on day 8 after 7 days of prednisone and one injection of intrathecal MTX on day 1).5 HR patients had any of the following characteristics: PPR, Ph-positive ALL, infants (age < 1 year) with CD10– immunophenotype or t(4;11) translocation, or no CR on day +43. All of the remaining patients who were not classified according to criteria for SR or HR were classified as IR. The study was approved at participating institutions according to current bylaws. Written informed consent was obtained for all patients from legal guardians.
Diagnostic Studies For DI measurement, 300,000 to 500,000 mononuclear cells were stained by propidium iodide using an automated DNA-staining device (DNA-prep reagents; Coulter, Miami, FL) and analyzed after 2 hours by flow cytometry. DNA histograms obtained using semiautomatic cell cycle analysis software (Multicycle; Phoenix, San Diego, CA) allowed compensation for doublets and overlapping nuclei. DI was defined as the ratio between modal channel number of the G0/G1 peak of neoplastic and normal cells. Donor lymphocytes were used as normal controls; residual normal T lymphocytes in bone marrow samples, when present, served as internal controls.9 CR was defined as no physical signs of leukemia, no detectable leukemic cells on blood smears, bone marrow with active hematopoiesis and less than 5% leukemic blast cells, and normal CSF. Bone marrow aspiration was examined on day 43, at the end of phase IA: patients who failed to achieve CR were assigned to HR. Patients who achieved CR only after the following HR treatment elements (phase IB and consolidation) were defined as late responders; those with persistent leukemia (resistant) were considered to have experienced treatment failure.
Treatment
Hematopoietic stem-cell transplantation (HSCT) from matched familial donor (MFD) was indicated for HR patients with no CR day 43, Ph-positive ALL, infants with CD10– B lineage or t(4;11) translocation, or PPR with T-cell immunophenotype, WBC
Statistical Analysis Follow-up was updated as of December 31, 2005. Eighty (5.4%) patients lacked documented contact within previous 2 years, including 16 patients (1.1%) who were lost to follow-up.
Between May 1995 and August 2000, 1,861 patients were registered by 36 institutions: 74 were not eligible (second malignancy, n = 2; misdiagnosis, n = 14; Down syndrome, n = 37; pretreatment, n = 21), 43 were not assessable (inadequate information on diagnosis or treatment), and 1,744 were analyzed. Median follow-up was 7.3 years. Table 1 summarizes the main patient characteristics.
Twelve patients (0.7%) died during induction (infection, n = 5; brain hemorrhage, n = 3; other, n = 4; Table 2). The resistance rate was 0.9%. At a median of 2.3 years (range, 0.2 to 9.6 years), 390 patients experienced relapse (22.3%): 290 in bone marrow, 46 combined, and 54 extramedullary. Of 21 CNS relapses, 20 occurred less than 3 years from diagnosis; 24 testicular relapses were observed: they occurred after more than 1 year from diagnosis, including three occurring after more than 8 years. Of 27 deaths in remission (1.5%), 21 deaths occurred in patients treated with chemotherapy (infection, n = 17; cardiac failure, n = 2; car accident, n = 2 at 2.3 and 7.4 years after treatment), and six deaths occurred in 42 patients undergoing HSCT in first CR. Four patients developed second malignancy: acute myeloid leukemia at 2.3 years after diagnosis; T-cell lineage ALL 4.8 years after initial B-lineage ALL; non-Hodgkin's lymphoma at 5.5 years after diagnosis; and synovial sarcoma at 8 years after diagnosis.
Overall EFS and survival were 75.9% (SE, 1.0%) and 85.6% (SE, 0.8%) at 5 years, and 72.5% (SE, 1.3%) and 83.6% (SE, 0.9%) at 10 years, respectively (Appendix Fig A1, online only). A total of 115 patients (6.6%) were treated in SR, 1,385 patients (79.4%) were treated in IR, and 244 patients (14.0%) were treated in HR (Table 1). Protocol violations occurred for 52 patients allocated by clinical decision to SR (n = 13), IR (n = 29), and HR (n = 10). Five-year EFS in subgroups included males, 72.4% (SE, 1.5%); females, 79.9% (SE, 1.4%); and Ph-positive ALL, 28.3% (SE, 7.4%). Those who failed to achieve CR by day 43 had 5-year EFS as follows: 25.0% (SE, 6.0%); infants, 51.6% (SE, 9.0%); patients 10 to 17 years, 68.6% (SE, 2.6%); WBC 100 x 109/L, 58.1% (SE, 3.7%); T-ALL, 65.7% (SE, 3.4%); t(4;11), 61.1% (SE, 11.5%); and PPR, 54.4% (SE, 3.7%). Among patients with t(4;11) translocation, three of eight infants and eight of 10 children older than 1 year (eight in the IR group) are alive in continuous complete remission.
Results by Risk Group
Reduction of HD-MTX HD-MTX was administered at 2 g/m2 to B-precursor IR patients without extramedullary involvement. Their BFM risk factor14 could be calculated retrospectively, allowing comparison of 739 AIEOP-ALL-95 patients older than age 1 year with BFM risk factor 0.8 and less than 1.7, with that of 622 such patients treated in AIEOP-ALL-91,3 receiving otherwise similar chemotherapy except for HD-MTX 5 g/m2. EFS at 10 years was 73.0% (SE, 1.9%) in AIEOP-ALL-91 and 75.8% (SE, 2.1%) in AIEOP-ALL-95 (P = .16); cumulative incidences of relapse were 25.5% (SE, 1.8%) and 23.5% (SE, 2.1%). CNS relapses and CNS + BM relapses accounted for six and five patients in the AIEOP-ALL-91 compared with seven and eight patients in AIEOP-ALL-95.
DI: Association With Presenting Features and Impact on Outcome
Of six patients with marked hypodiploidy, four experienced relapse and one died in CR. Patients with favorable DI had 10-year EFS of 83.9% (SE, 2.1%) compared with 70.4% (SE, 1.5%) for remaining patients who, independently of the DI (mild hypodiploidy, near diploidy, or near tetraploidy), had similar outcomes. Of 33 patients with DI more than 1.6, 10 experienced relapse, one had secondary malignancy, and one was resistant. Among 1,322 IR patients (Fig 2), 187 with favorable DI had significantly better outcome: 10-year EFS was 83.8% (SE, 2.7%), compared with 73.9% (SE, 1.7%) in the remaining patients (P = .03).
To evaluate whether DI retained an independent prognostic value, we performed an analysis with the Cox regression model. Favorable DI was associated with a significant (P = .03) 30% reduction of risk of treatment failure. Significantly related to outcome were also age 1 to 5 years (hazard ratio [HR] = 0.61; P < .001), WBC less than 20 x 1009/L (HR = 0.70; P = .005), and female sex (HR = 0.76; P = .02). Interestingly, 25 of 232 HR patients presented with favorable DI; they qualified for HR as a result of PPR (n = 14), Ph-positive ALL (n = 5), t(4;11) in infants (n = 1), and resistance to phase IA (n = 5). Ten-year EFS in HR patients with favorable DI was 67.8% (SE, 9.4%) compared with 49.6% (SE, 3.5%) in the remaining 207 patients (P = .11; Fig 3) . Among five Ph-positive ALL patients with favorable DI, two experienced relapse and three remained in continuous complete remission (one after allogeneic HSCT) at 3.6, 6.9, and 8.6 years, respectively. Multivariate Cox analysis showed a significant relationship of favorable DI with outcome in HR patients (HR = 0.47; P = .04) even after adjusting by sex and HR features used for stratification.
Treatment Burden There was no difference between SR patients (who received only three drugs), and others in the induction IA group. The highest treatment burden was reported during consolidation in HR patients. In reinduction, protocol II was administered twice in HR patients. The first protocol II had figures similar to those reported during protocol II administered to non-HR patients, whereas the second protocol II in HR patients was associated with higher treatment burden (Appendix Table A2, online only).
With the use of BFM-based chemotherapy, patients enrolled onto AIEOP trials had a progressively improved cure rate of childhood ALL during the last 20 years. This was achieved by both improved supportive therapy and treatment intensification. Although the need for supportive therapy during induction was not significantly different for patients receiving or not receiving four doses of anthracyclines, consolidation phase in HR patients (based on three intensive polychemotherapy blocks) was more demanding. Unfortunately, its added value compared with usual HD-MTX BFM consolidation cannot be determined. Late intensification with protocol II was relatively feasible, although its short-term repetition in HR patients was associated with increased hospital stay and parenteral antimicrobial therapy. Feasibility of current intensive chemotherapy in the multicenter AIEOP network is confirmed also by the low rate of deaths during induction or remission observed in this study. Improved results in AIEOP-ALL-95 compared with previous AIEOP-ALL-91 are not fully explained by the reduced death rate during induction or resistance (Appendix Table A3, online only). Major contribution derives from an innovative, intensified approach in HR (consisting in entire induction phase IA + B and double delayed intensification), resulting in a better disease control compared with that of similar patients in AIEOP-ALL-91, as indicated in a preliminary report.13 Patients who benefited most were the PPR only; 51% EFS for infants is a respectable outcome for a difficult population. The subset (3%) of patients who failed to achieve CR after induction remained at worst prognosis. Despite achieving late morphologic remission (after phase IB or the subsequent chemotherapy blocks), they eventually experienced leukemia relapse, with only one fourth of them remaining disease free. Improved results were not extended to Ph-positive ALL, with 5-year EFS at 28.3%, whereas interesting results obtained by the few patients older than 1 year carrying t(4;11) translocation (eight of 10 patients in continuous CR), even when treated as IR patients, warrants confirmation on larger numbers of patients. Contribution of HSCT to first-line treatment of childhood ALL remains controversial. In this trial, HSCT was indicated in a small minority of patients and actually applied in 2.4%, thus there was little chance to influence the overall outcome. However, given careful selection and restriction to MFD, they may have had individual benefit, as shown by the recently reported international study in which these patients were included.15 The possible benefit of intensified continuation therapy in IR patients, explored by randomized application of VCR-DEXA pulses, was not confirmed by the large international I-BFM-SG study, which included a subset of ALL-95 IR patients.12 We report here on a complementary subset of such IR patients with more favorable features (WBC count < 20 x 109/L and age 1 to 5 years), randomly assigned in Italy outside the trial; no benefit was observed. Is traditional BFM 5 g/m2 HD-MTX10 superior to medium-dose to HD 2 g/m2? Despite lack of specific randomized studies, we tried to infer such information by comparing present AIEOP-ALL-95 and previous AIEOP-ALL-91 studies, using 5 and 2 g/m2, respectively, in IR patients. In this setting, reduced dosage was equally safe, provided extended intrathecal therapy during maintenance was used. The SR group in this study achieved a 10-year EFS of 85.0%, a result that might be considered not fully satisfactory in such a small, selected subpopulation of childhood ALL. Yet, because the usual cause of treatment failure was leukemia relapse, and most of the relapsed patients could be rescued by second-line treatment, a satisfactory 95.5% probability of 10-year survival was achieved.
The predictive value of DI, clearly documented especially by the Pediatric Oncology Group,4 has not been investigated extensively in BFM-based intensive chemotherapy regimens. Unfortunately, our data do not allow comparison with the prognostic role of specific trisomies. We document that, in the large group of patients treated on AIEOP-ALL-95 (achieving overall 5-year EFS of 75.9%), DI retained a clear, independent prognostic value. Dismal outcome of the 1% of patients with marked hypodiploidy (DI Although 5-year EFS is a conventional time point for evaluation of treatment outcome in childhood ALL, in this study we had the opportunity to report on an extended follow-up. This allowed us to document that EFS still decreased by approximately 3% between 5 and 10 years, mainly due to late relapses, occurring both in the marrow and in extramedullary sites. However, it is remarkable that none of the patients with favorable DI experienced late relapse (last relapse at 5.3 years from diagnosis), confirming a specific behavior. In particular, although CNS relapse occurred (all but one) within 3 years, testicular relapses spread over nine years. As expected, the relapse rate decreased earlier in HR patients than in IR patients, remaining in this latter group at the level of one per 100 patients at risk even after 7 years. This finding, in keeping with other reports,21,22 confirms that especially for non-HR patients, long follow-up is needed to evaluate treatment outcome and possibility of cure. Whether this is due to slow regrowth of silent leukemia or to the appearance of second leukemia in patients with genetic predisposition remains to be elucidated.23,24 In conclusion, progressive treatment intensification achieved in contemporary studies by most cooperative groups allowed reduced incidence of leukemia relapse, the most frequent cause for treatment failure. Extended use of intrathecal chemotherapy allowing minimized use of cranial radioprophylaxis, pursued by AIEOP since 1988, confirms a safe and effective approach. Improved supportive therapy, confirmed also by the low rate of deaths during induction or remission, supports the feasibility of AIEOP policy to deliver intensive chemotherapy in an extended network of more than 30 pediatric centers in the country, thus preventing obliged regional migrations observed in the last decades. This is associated with a relevant treatment burden, requiring the use of financial and human resources that has to be planned by health authorities. However, treatment reduction, although appealing, should be applied with great caution not to endanger the outstanding cure rate achieved so far, with more than 80% of patients with childhood ALL diagnosed in Italy during the second half of the 1990s having been cured. The contribution of HSCT in ALL front-line therapy remains limited, with its role focused on rescuing patients who have experienced a relapse. Wider and affordable application of modern techniques to monitor residual disease25 and the combined use of biologic markers heralding treatment response may help leukemia specialists to refine current chemotherapy programs. In this study, favorable DI was associated with better prognosis in IR and HR patients defined by clinical criteria and treated with BFM-oriented chemotherapy. Continuous effort put into genetic studies26 could provide novel insights for treatment of subsets of childhood ALL refractory to modern chemotherapy.
The author(s) indicated no potential conflicts of interest.
Conception and design: Maurizio Aricò, Giuseppe Basso, Giuseppe Masera, Valentino Conter Financial support: Giuseppe Basso, Giuseppe Masera Administrative support: Giuseppe Masera Provision of study materials or patients: Maurizio Aricò, Carmelo Rizzari, Elena Barisone, Andrea Biondi, Fiorina Casale, Franco Locatelli, Luca Lo Nigro, Matteo Luciani, Chiara Messina, Concetta Micalizzi, Rosanna Parasole, Andrea Pession, Nicola Santoro, Anna Maria Testi, Giuseppe Basso, Giuseppe Masera, Valentino Conter Collection and assembly of data: Daniela Silvestri, Giuseppe Basso Data analysis and interpretation: Maurizio Aricò, Maria Grazia Valsecchi, Carmelo Rizzari, Andrea Pession, Daniela Silvestri, Giuseppe Basso, Giuseppe Masera, Valentino Conter Manuscript writing: Maurizio Aricò, Maria Grazia Valsecchi, Carmelo Rizzari, Daniela Silvestri, Giuseppe Basso, Giuseppe Masera, Valentino Conter Final approval of manuscript: Maurizio Aricò, Maria Grazia Valsecchi, Carmelo Rizzari, Elena Barisone, Andrea Biondi, Fiorina Casale, Franco Locatelli, Luca Lo Nigro, Matteo Luciani, Chiara Messina, Concetta Micalizzi, Rosanna Parasole, Andrea Pession, Nicola Santoro, Anna Maria Testi, Daniela Silvestri, Giuseppe Basso, Giuseppe Masera, Valentino Conter
Supported by Associazione Italiana per la Ricerca sul Cancro, Ministero dell’Università e della Ricerca, Programmi di ricerca cofinanziati 2003 prot. 2003068942_001, Ric. Corr. Ospedale Bambino Gesù, Roma 2005-02P001576, Fondazione Tettamanti, Comitato M.L. Verga, and Fondazione Città della Speranza. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Rizzari C, Valsecchi MG, Arico M, et al: Outcome of very late relapse in children with acute lymphoblastic leukemia. Haematologica 89:427-434, 2004 22. Pui CH, Pei D, Sandlund JT, et al: Risk of adverse events after completion of therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 23:7936-7941, 2005 23. Aricò M, Germano G, del Giudice L, et al: Late relapse of childhood acute lymphoblastic leukemia and PCR-monitoring of minimal residual disease: How much time can elapse between "molecular" and clinical relapse? Haematologica 87:ELT19, 2002[Medline] 24. Konrad M, Metzler M, Panzer S, et al: Late relapses evolve from slow-responding subclones in t(12;21)-positive acute lymphoblastic leukemia: Evidence for the persistence of a preleukemic clone. Blood 101:3635-3640, 2003 25. van Dongen JJ, Seriu T, Panzer-Grumayer ER, et al: Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352:1731-1738, 1998[CrossRef][Medline] 26. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test; tests were two tailed. Cumulative incidence of relapse accounted for competing risks; the Gray test was used for comparison. The Cox model was applied for EFS with the covariates age (1 to 5 v 
0.8); 33 patients (2.0%) were near tetraploid (DI, 
