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We analyzed the long-term outcome of 4865 patients treated in Studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia (ALL) of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Treatment was characterized by progressive intensification of systemic therapy and reduction of cranial radiotherapy. A progressive improvement of results with reduction of isolated central nervous system relapse rate was obtained. Ten-year event-free survival increased from 53% in Study 82 to 72% in Study 95, whereas survival improved from 64 to 82%. Since 1991, all patients were treated according to Berlin-Frankfurt-Muenster (BFM) ALL treatment strategy. In Study 91, reduced treatment intensity (25%) yielded inferior results, but intensification of maintenance with high-dose (HD)-L-asparaginase (randomized) allowed to compensate for this disadvantage; in high-risk patients (HR, 15%), substitution of intensive polychemotherapy blocks for conventional BFM backbone failed to improve results. A marked improvement of results was obtained in HR patients when conventional BFM therapy was intensified with three polychemotherapy blocks and double delayed intensification (Study 95). The introduction of minimal residual disease monitoring and evaluation of common randomized questions by AIEOP and BFM groups in the protocol AIEOP-BFM-ALL 2000 are expected to further ameliorate treatment of children with ALL.

SummaryThe safety and efficacy of the combination clofarabine/cyclophosphamide/etoposide were evaluated in children with advanced acute lymphoblasticleukaemia (ALL). The study enrolled 25 paediatric patients (median age12AE5 years) with either refractory (n = 17; 68%) or multiple relapsed (n =8;32%) ALL to receive clofarabine 40 mg/m 2 , cyclophosphamide 400 mg/m 2 and etoposide 150 mg/m 2 , daily for 5 consecutive days. No patient died fromtreatment-related complications. The most common adverse events werefebrile neutropenia, mucositis and reversible liver toxicity; no case of liverveno-occlusive disease was reported. The overall remission rate was 56%: 13patients (52%) achieved complete remission (CR) and one (4%) CR withoutplatelet recovery (CRp). In seven of the 13 (54%) patients achieving CR,remissions were of sufficient duration to allow patients to receive allogeneichaematopoietic stem cell transplantation. The probability of CR/CRp wasgreater in the 17 patients with B cell precursor ALL than in the eight withT-ALL (76% vs. 12%, respectively, P

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 ≥ 1.16 and < 1.60; age, 1 to 5 years; and WBC < 20,000, non–T-immunophenotype, with no high-risk features) received a reduced induction therapy (no anthracyclines); IR patients were randomly assigned to receive or not receive vincristine and dexamethasone pulses during maintenance; HR therapy was based on a conventional BFM schedule intensified with three chemotherapy blocks followed by a double reinduction phase. 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.

B-cell precursor (BCP) acute lymphoblastic leukemia (BCP-ALL) in infants (ie, children age

Importance: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Objective: To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. Design, Setting, and Participants: In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow

Background: Adolescents (aged 10–17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years. Methods: We retrospectively analysed outcomes of 1094 adolescents with ALL, aged 10–17 years, treated within the AIEOP-BFM ALL 2000 trial, overall and by the age groups 10–14 and 15–17 years. Findings: Compared with younger children (aged 1–9 years, n = 3647), adolescents had a statistically inferior 5-year event-free survival (EFS) [74.6% (1.3) vs. 84.4% (0.6)] and overall survival (OS) [83.4% (1.1) vs. 92.7% (0.4); p < 0.001]. Clinical and biological disease characteristics did not differ between the two subgroups of adolescents, including minimal residual disease (MRD) results during initial therapy, except for ETV6-RUNX1 frequency and gender. With a median follow-up of 8.8 years, the 5-year EFS and OS were 76.2% (1.5) and 84.9% (1.3), respectively, for those aged 10–14 years and 70.0% (2.8) and 78.8% (2.5) for those aged 15–17 years (p = 0.06; 0.05). There was no significant difference in the cumulative incidence of relapses [17.8% (1.4) and 18.3% (2.4); p = 0.98], while the incidence of treatment-related deaths as a first event was 2.6% (0.6) versus 7.4% (1.6) (p < 0.001) with, in particular, a higher incidence in the high-risk arm. Interpretation: Further prospective studies and biological investigations are required to define optimal treatment for adolescents, in particular for those aged 15–17 years. Newer agents (immunotherapy, targeted therapy) in early treatment phases of patients at higher risk of treatment failure could replace most toxic treatment elements, with the aim of reducing both toxicity and the risk of relapses.

Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 μmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 μmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 μmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels

Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% ( P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% ( P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% ( P = .06). Patients with ETV6-RUNX1–positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively ( P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response.

Aim: We have previously reported an association of dihydrofolate reductase promoter polymorphisms with reduced event-free survival in childhood acute lymphoblastic leukemia (ALL) patients treated with Dana Farber Cancer Institute protocol. Here, we assessed whether these associations are applicable to other protocol, based on different methotrexate doses. Methods: Genotypes for six tag polymorphisms and resulting haplotypes were analyzed for an association with ALL outcome. Results: The association was found with the polymorphisms A-680C, A-317G and C-35T in high-risk group patients. Carriers of haplotype *1 had a remarkably higher risk of events compared with noncarriers and a lower probability of event-free survival (21.4 vs 81.3%). Conclusion: The role of DHFR variants in predicting the outcome of childhood ALL extends beyond single-treatment protocol and can be useful biomarker in personalizing treatment.

To the editor: Reinduction therapy (also known as delayed intensification, DI) is an essential part of childhood acute lymphoblastic leukemia (ALL) treatment.[1][1],[2][2] In Berlin-Frankfurt-Munster (BFM) studies, it includes same/similar drugs as those employed in induction therapy. The Children

Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Munster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m(2) per day) or prednisone (60 mg/m(2) per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov (BFM: NCT00430118, AIEOP: NCT00613457).

Citation: D’Angio' M, Valsecchi MG, Testi AM, Conter V, Nunes V, Parasole R, Colombini A, Santoro N, Varotto S, Caniglia M, Silvestri D, Consarino C, Levati L, Magrin E, Locatelli F, Basso G, Foa' R, Biondi A, and Cazzaniga G . Clinical features and outcome of SIL/TAL1-positive T-cell acute lymphoblastic leukemia in children and adolescents. A 10 year experience of the AIEOP group. Haematologica. 2014; 99:xxx doi:10.3324/haematol.2014.112151

Approximately 10–15% of pediatric patients with acute lymphoblastic leukemia (ALL) have a T-cell phenotype. The prognosis of these patients has improved over the last years, owing to the use of more intensive treatment strategies. Characterization of molecular alterations with prognostic impact in T-ALL may be of great help for an early identification of patients at high risk (HR) of failure in whom more intensive treatments, including allogeneic hematopoietic stem cell transplantation, may be considered.

Background Acute lymphoblastic leukemia (ALL) in infants is a relatively rare disease with peculiar biological features and worse outcome in comparison to ALL in older children. Infant ALL is characterized by a high frequency of MLL gene rearrangements, mainly CD10-negative B-cell precursor ALL (BCP-ALL) immunophenotype and high tumor burden at diagnosis. Even with new therapeutic approaches event-free survival (EFS) in this subgroup of patients does not exceed 50%. Although flow cytometric (FCM) minimal residual disease (MRD) detection at day 15 of remission induction is well established for patients' stratification in older children treated with the AIEOP-BFM-2009 protocol, the prognostic value of FCM MRD in infant ALL is not fully known yet. Aim of the present study was to evaluate the prognostic significance of FCM MRD measurement in infants with ALL treated with Interfant-99 and Interfant-06 protocols in AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) centers in Italy. Patients and methods Between May 1999 and December 2011, 120 consecutive infants aged 0 to 365 days with newly diagnosed ALL were treated in AIEOP centers with the Interfant99 and the on-going Interfant-06 protocols. Among these patients, 51 (42.5%) with available day 15 follow-up bone marrow samples were included in this study on FCM MRD. In 39 (76.5%) cases, different types of MLL gene rearrangements were identified by fluorescence in situ hybridization (FISH), while 12 (23.5%) patients had germline MLL. MRD detection was performed by 4-6-color FCM. Median follow-up time was 3.5 years (range: 1 month – 7.5 years). Outcome was estimated by evaluating the probability of EFS and the cumulative incidence of relapse (CIR). Analysis of prognostic relevance of FCM MRD in combination with other criteria used for stratifying patients enrolled in the Interfant-06 protocol was performed with the Cox model on the cause-specific hazard of relapse. Results and discussion We classified infants according to the AIEOP-BFM day 15 stratification into three risk groups: 14 patients (27.5%) were considered at standard risk (SR: MRD less than 0.1%), 9 patients (15.7%) at high risk (HR: MRD 10% or more), and the majority of infants (29, 56.9%) at intermediate risk (IR: MRD 0.1% to 10%). As the 14 SR patients had 3-year EFS and CIR significantly better than other patients, we considered two major groups of patients with different outcome: SR group (MRD Conclusion Day 15 FCM MRD proved to be a suitable variable predicting treatment failure and can be used as an alternative or in combination with Interfant-06 stratification criteria to identify SR patients. Disclosures: Popov: Alexion: Research Funding.

Venous thromboembolic events (VTEs) are frequent complications of childhood acute lymphoblastic leukemia (ALL) treatment. The aim of the study was to evaluate the rate of symptomatic VTEs in children with ALL and the predictive value of clinical and biological factors and routine monitoring of coagulation parameters in identifying children at a higher risk of this complication.Between September 2000 and July 2006, 2042 children (≥1 and younger than 18 y) with newly diagnosed ALL were enrolled in Italy in the AIEOP (Italian Association of Pediatric Hematology and Oncology)-BFM (Berlin-Frankfurt-Muenster) ALL 2000 trial. Patients with symptomatic VTEs (deep venous thromboses or cerebral venous thromboses) were identified after a careful review of clinical records. The impact of coagulation derangement at the onset of VTEs was evaluated by a nested case-control study.Forty-eight (2.4%) children presented with a VTE. The rate of VTEs was higher in male patients (P=0.001); patients randomized to receive dexamethasone tended to have a higher rate of VTE compared with those who received prednisone (P=0.10). The coagulation derangement at the onset of VTE was not associated with VTE occurrence. The prevalence of a factor V Leiden G1691A mutation and the prothrombin G20210A variant was higher in children with VTE than that expected in the general population.