Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study.

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 <100 and ≥ 1,500 IU/L, respectively. In this study cerebrospinal fluid asparagine levels were reduced during pegylated-asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum pegylated-asparaginase activity level resulting in complete cerebrospinal fluid asparagine depletion was identified. The consistency of the results found in the two independent data sets strengthen the observations of this study. Details of the treatment are available in the European Clinical Trials Database at https://www.clin-icaltrialsregister.eu/ctr-search/trial/2007-004270-43/IT.

B-ALL With t(5;14)(q31;q32); IGH-IL3 Rearrangement and Eosinophilia: A Comprehensive Analysis of a Peculiar IGH-Rearranged B-ALL.

Background: B-cell acute lymphoblastic leukemia associated with t(5;14)(q31;q32); IGH-IL3 is an exceptional cause of eosinophilia. The IGH enhancer on 14q32 is juxtaposed to the IL3 gene on 5q31, leading to interleukin-3 overproduction and release of mature eosinophils in the blood. Clinical, biological and outcome data are extremely scarce in the literature. Except for eosinophilia, no relevant common feature has been highlighted in these patients. However, it has been classified as a distinct entity in the World Health Organization classification. Cases Presentation: Eight patients with t(5;14)(q31;q32) treated by French or Austrian protocols were retrospectively enrolled. Array comparative genomic hybridization, multiplex ligation-dependent probe amplification or genomic PCR search for IKZF1 deletion were performed in 7. Sixteen patients found through an exhaustive search in the literature were also analyzed. For those 24 patients, median age at diagnosis is 14.3 years with a male predominance (male to female ratio = 5). Eosinophilia-related symptoms are common (neurologic in 26%, thromboembolic in 26% or pulmonary in 50%). Median white blood cells count is high (72 × 109/L) and linked to eosinophilia (median: 32 × 109/L). Peripheral blasts are present at a low level or absent (median: 0 × 109/L; range: 0-37 × 109/L). Bone marrow morphology is marked by a low blast infiltration (median: 42%). We found an IKZF1 deletion in 5 out of 7 analyzable patients Outcome data are available for 14 patients (median follow-up: 28 months): 8 died and 6 are alive in complete remission. Some of these features are concordant with those seen in patients with other IGH-rearranged B-cell acute lymphoblastic leukemias: young age at onset, male sex, low blast count, high incidence of IKZF1 deletion and intermediate prognosis. Conclusion: Based on shared epidemiological and biological features, B-cell acute lymphoblastic leukemia with t(5;14)(q31;q32) is a peculiar subset of IGH-rearranged B-cell acute lymphoblastic leukemia with an intermediate prognosis and particular clinical features related to eosinophilia.

High hyperdiploid acute lymphoblastic leukemia (ALL)-A 25-year population-based survey of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group.

BACKGROUND: Approximately 30% of childhood acute lymphoblastic leukemia (ALL) cases are high hyperdiploid (HD). Despite their low relative recurrence risk, this group accounts for the overall largest relapse proportion. PROCEDURE: To evaluate potential risk factors in our population-based cohort of patients with HD ALL enrolled in four Austrian ALL-BFM (Berlin-Frankfurt-Münster) studies from 1986 to 2010 (n = 210), we reviewed the clinical, laboratory, and cytogenetic data of the respective cases in relation to their outcome. RESULTS: The 5-year event-free (EFS) and overall survival (OS) of the entire group was 83.1 ± 2.7% and 92.0 ± 1.9%, respectively. Univariate analysis revealed that trisomy 17 was significantly associated with a better EFS and OS, whereas trisomy 10 and a modal chromosome number (MCN) > 53 chromosomes were significantly associated with a better OS. Except for the latter, findings remained valid in multivariate analysis. CONCLUSIONS: In line with previous studies, our retrospective analysis shows that MCN and specific trisomies are relevant prognostic indicators in an ALL-BFM cohort of patients with HD ALL. However, considering the current dominant role of minimal residual disease monitoring for prognostic stratification in ALL, including this particular subgroup, it is unlikely that this information is compelling enough to be utilized for refined risk classification in future ALL-BFM treatment protocols.

Safety and efficacy of intrathecal rituximab in children with B cell lymphoid CD20+ malignancies: An international retrospective study.

Central nervous system (CNS) involvement in patients with mature B non-Hodgkin lymphoma, post-transplantation proliferative disorder and acute lymphoblastic leukemia confers a significantly inferior prognosis as compared to patients without CNS disease. Intrathecal (IT) or intraventricular administration of rituximab is an option for this group of patients. We report 25 children with CNS involvement of CD20+ B lymphoid malignancies who received in total 163 IT/intraventricular rituximab doses. The median number of doses received by each patient was 6, with a median dose of 25 mg. The most common adverse events were Grades 1 and 2 peripheral neuropathies in five patients (20%), allergy in two patients, and headache in two patients. These events were self-limited, occurring in the 48 hours after treatment and resolving within 24 hr. Three patients presented with more severe though transient side effects, one with a Grade III neuropathy and two with seizure. Eighteen patients (72%) of those treated with IT/intraventricular rituximab, with or without other CNS directed treatment, achieved a CNS remission. This case series suggests that IT/intraventricular rituximab has therapeutic efficacy and relatively limited toxicity. Prospective trials of IT/intraventricular rituximab for patients with CNS involvement of CD20 + B lymphoid malignancies are warranted.

Outcome of children and adolescents with a second or third relapse of acute lymphoblastic leukemia (ALL): a population-based analysis of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) study group.

We analyzed outcome of a population-based cohort of 74 children with second and third acute lymphoblastic leukemia (ALL) relapse and aimed to identify prognostic factors. Duration of previous remission and site of relapse appeared of prognostic relevance as patients with a second remission duration >1.5 years and isolated extramedullary relapse did better. Neither patient with a second bone marrow relapse who underwent previous allogeneic transplantation nor patients with T-cell ALL survived. Overall, 7 of 74 (9%) patients are in long-term remission. Stem cell transplantation seemed to be the only curative option for systemic relapse of B-cell precursor ALL as all 4 surviving patients with a second/third relapse involving the bone marrow received a transplant. Conclusively, patients with a second ALL relapse are ideal candidates for phase I/II trials exploring new innovative drugs.

The inferior prognosis of adolescents with acute lymphoblastic leukaemia (ALL) is caused by a higher rate of treatment-related mortality and not an increased relapse rate--a population-based analysis of 25 years of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group.

Adolescents aged 15-18 years with acute lymphoblastic leukaemia (ALL) have been historically reported to have a poorer prognosis than younger children. We retrospectively analysed the characteristics and outcome of 67 adolescents included in a population-based series of 1125 non-infant cases that were enrolled into four Austrian ALL-BFM (Berlin-Frankfurt-Münster) multicentre trials at paediatric institutions within a 25-year period. Five-year event-free survival (EFS) and overall survival (OS) were 66 ± 6% and 76 ± 5% respectively, and thus lower than in younger children (83 ± 1%, 91 ± 1%; P < 0·001). This was not due to an increased cumulative incidence of relapse (CIR) (5-year CIR: 19 ± 5% vs. 13 ± 1%; P = 0·284), but due to an increased incidence of treatment-related death [5-year cumulative incidence of death (CID): 15 ± 4% vs. 3 ± 0%; P < 0·001] as a first event. Furthermore, while 44/67 (66%) non-high-risk adolescents had favourable 5-year EFS and OS rates (76 ± 7%, 89 ± 5%), 18/67 (27%) high-risk adolescents had an inferior outcome (5-year EFS: 56 ± 12%, OS 61 ± 11%, P < 0·05). Among the latter patients the CID was significantly higher than in younger high-risk children (22 ± 10% vs. 6 ± 2%; P = 0·020). Given that adolescent age is an independent risk factor for death as a first event, this specific age group may need particular vigilance when receiving intense BFM-type chemotherapy, as relapse-free survival is similar to younger children.

Feasibility and tolerability of bevacizumab in children with primary CNS tumors.

BACKGROUND: Bevacizumab, an antibody to the vascular endothelial growth factor, has demonstrated anti-cancer activity in a number of solid tumors. Fear of intratumoral hemorrhage, however, has slowed its introduction into the treatment of central nervous system (CNS) tumors. Currently, only a small number of children with gliomas received bevacizumab. METHODS: We retrospectively analyzed 30 patients who received bevacizumab between January 2007 and August 2009. The median age at start of bevacizumab treatment was 9.9 years (range: 1.5-18). Most patients had recurrent/progressive disease, 25 high-grade and 5 low-grade tumors. The median dose of bevacizumab was 9.5 mg/kg (range 5-15 mg/kg) every 2-3 weeks. In total, 478 courses were administered (median/patient 15.9, range: 2-52). The median duration of bevacizumab treatment was 10.0 months (range: 1.6-30.4). Twenty-nine of 30 patients received additional therapy concomitant to bevacizumab. RESULTS: No bevacizumab related intratumoral hemorrhage occurred in any of our 30 patients. Grade III hypertension was seen in two patients. One patient developed nephrotic syndrome requiring cessation of treatment. Grade III and I proteinuria were observed in one and five patients, respectively. New onset lymphopenia occurred in 12/30 and new onset hypothyroidism in 7/30 patients. Impaired wound healing was manageable. No immediate bevacizumab-related cardiotoxicity was observed as evidenced by echocardiography. CONCLUSIONS: Bevacizumab appears to be safe for children with primary CNS tumors. Adverse effects did occur but were manageable. No treatment-related death occurred. Long-term monitoring is advisable to detect lymphopenia and hypothyroidism. Hypertension occurred less frequently than in adult patients. Further prospective studies including more patients are warranted.

Long-term outcome of initially homogenously treated and relapsed childhood acute lymphoblastic leukaemia in Austria--a population-based report of the Austrian Berlin-Frankfurt-Münster (BFM) Study Group.

Relapsed acute lymphoblastic leukaemia (ALL) is the most common cause for a fatal outcome in paediatric oncology. Although initial ALL cure rates have improved up to 80%, the prognosis of recurrent ALL remains dismal with event-free-survival (EFS) rates about 35%. In order to analyse a population-based cohort with uniform treatment of initial disease, we examined the outcome of children suffering from relapsed ALL in Austria for the past 20 years and the validity of the currently used prognostic factors (e.g. time to and site of relapse, immunophenotype). Furthermore, we compared survival rates after chemotherapy alone with those after allogeneic stem cell transplantation (SCT). All 896 patients who suffered from ALL in Austria between 1981 and 1999 were registered in a prospectively designed database and treated according to trials ALL-Berlin-Frankfurt-Münster (BFM)-Austria (A) 81, ALL-A 84 and ALL-BFM-A 86, 90 and 95. Of these, 203 (23%) suffered from recurrent disease. One-hundred-and-seventy-two patients (85%) achieved second complete remission. The probability of 10-year EFS for the total group was 34 +/- 3%. Clinical prognostic markers that independently influenced survival were time to relapse, site of relapse and the immunophenotype. Additionally, a Cox regression model demonstrated that allogeneic SCT after first relapse was associated with a superior EFS compared with chemo/radiotherapy only (hazard ratio = 0.254; P = 0.0017).