-
Inge van der Sluis, Anja Möricke,
Gabriele Escherich,
Arend von Stackelberg,
Wolfgang Holter,
Thomas Klingebiel,
Christian Flotho,
Sabine Legien,
Wim Tissing,
Marc Bierings,
Cecile Guimbal-Schmolck,
Uwe Pichlmeier,
Hans-Jürgen Kühnel,
Rob Pieters
[show abstract]
[hide abstract]
ABSTRACT: The pharmacokinetics, pharmacodynamics, efficacy and safety of a new recombinant E.coli-asparaginase preparation was evaluated in infants (< 1 year of age) with de novo acute lymphoblastic leukemia. Twelve patients were treated according to the INTERFANT-06 protocol and received up to 10,000 U/m2; recombinant asparaginase as intravenous infusion on days 15, 18, 22, 25, 29 and 33 of remission induction treatment. The asparaginase dose was individually adjusted by protocol to 67% of the calculated dose for infants < 6 months, and to 75% of the calculated dose for infants aged 6-12 months. The trough serum asparaginase activities observed were above 20, 50, or 100 U/L in 86%, 71%, and 51% of measured samples, respectively. Looking only at the data assessed 3 days after asparaginase infusion these percentages were 91%, 84%, and 74% respectively. Asparagine was completely depleted in serum in all but one patient who was the youngest in the study. No anti-asparaginase-antibodies were detected during this treatment phase. Observed adverse reactions are known as possible and labeled side effects of asparaginase treatment and chemotherapy. We conclude that the asparaginase dose regimen used in infants is safe and provides complete asparagine depletion for the desired time period in nearly all patients. Measured asparaginase trough serum levels justify the higher doses used in infants compared to older children and show that the 3 days intervals are preferred over 4 days intervals. (This trial was registered at www.clinicaltrialsregister.eu as EudraCT number 2008-006300-27).
Haematologica 06/2013; · 6.42 Impact Factor
-
Petra Dörge,
Barbara Meissner,
Martin Zimmermann, Anja Moericke,
Andre' Schrauder,
Jean-Pierre Bourquin,
Denis Schewe,
Jochen Harbott,
Andrea Teigler-Schlegel,
Richard Ratei,
Wolf Dieter Ludwig,
Rolf Köhler,
Claus R Bartram,
Martin Schrappe,
Martin Stanulla,
Gunnar Cario
[show abstract]
[hide abstract]
ABSTRACT: IKZF1 gene deletions have been associated with a poor outcome in pediatric precursor B-cell acute lymphoblastic leukemia. To assess the prognostic relevance of IKZF1 deletions for patients treated on Berlin-Frankfurt-Munster Study Group trial ALL-BFM 2000, we screened 694 diagnostic acute lymphoblastic leukemia samples by Multiplex Ligation-Dependent Probe Amplification. Patients whose leukemic cells beared IKZF1 deletions had a lower 5-year event-free survival (0.69+/-0.05 vs. 0.85+/-0.01; p<0.0001) compared to those without, mainly due to a higher cumulative incidence of relapses (0.21+/-0.04 vs. 0.10+/-0.01; p=0.001). Although IKZF1 deletions were significantly associated with the P2RY8-CRLF2 rearrangement, their prognostic value was found independent from this association. Thus, IKZF1 deletion is an independent predictor of treatment outcome and strong candidate marker for integration in future treatment stratification strategies on ALL-BFM protocols.
Haematologica 08/2012; · 6.42 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Acute leukaemias of ambiguous lineage (ALAL) represent a rare type of leukaemia, expressing both myeloid and lymphoid markers. This study retrospectively analyzed data from 92 children (biphenotypic n = 78, bilineal n = 6, lineage switch n = 8) with ALAL registered in the Berlin-Frankfürt-Münster (BFM) acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) studies between 1998 and 2006 (2.4% of all cases with acute leukaemia). Our cohort of ALAL patients was characterized by comparatively high median age (8.9 years), high median white blood cell count (14.9 x 10(9)/l), as well as frequent hyperleucocytosis (18.5%) and central nervous system involvement (24.1%). The most frequent cytogenetic abnormalities were ETV6/RUNX1 fusion (16%) and trisomy 8 (14.6%). Complete remission rate was significantly lower than in ALL-BFM patients (91.8% vs. 99.1%, P < 0.001), but comparable to AML-BFM patients (87.9%). Event-free survival (EFS) and overall survival (OS) of ALAL patients were low, at 62 +/- 5%. 5-year probability of EFS was significantly worse than in ALL patients (80 +/- 1%, P < 0.001), but better than for AML patients (49 +/- 2%, P = 0.027). Our data suggest that an intensive therapy regimen including stem cell transplantation may be favourable for bilineal or lineage switch cases, whereas patients with ETV6/RUNX1 fusion, lymphoid morphology and patients with expression of cyCD22 and cyCD79a should be treated with an ALL-directed therapy.
British Journal of Haematology 04/2010; 149(1):84-92. · 4.94 Impact Factor
-
Gunnar Cario,
Martin Zimmermann,
Renja Romey,
Stefan Gesk,
Inga Vater,
Jochen Harbott,
André Schrauder, Anja Moericke,
Shai Izraeli,
Takashi Akasaka,
Martin J S Dyer,
Reiner Siebert,
Martin Schrappe,
Martin Stanulla
[show abstract]
[hide abstract]
ABSTRACT: High-level expression of the cytokine receptor-like factor 2 gene, CRLF2, in precursor B-cell acute lymphoblastic leukemia (pB-ALL) was shown to be caused by a translocation involving the IGH@ locus or a deletion juxtaposing CRLF2 with the P2RY8 promoter. To assess its possible prognostic value, CRLF2 expression was analyzed in 555 childhood pB-ALL patients treated according to the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster 2000 (ALL-BFM 2000) protocol. Besides CRLF2 rearrangements, high-level CRLF2 expression was seen in cases with supernumerary copies of the CRLF2 locus. On the basis of the detection of CRLF2 rearrangements, a CRLF2 high-expression group (n = 49) was defined. This group had a 6-year relapse incidence of 31% plus or minus 8% compared with 11% plus or minus 1% in the CRLF2 low-expression group (P = .006). This difference was mainly attributable to an extremely high incidence of relapse (71% +/- 19%) in non-high-risk patients with P2RY8-CRLF2 rearrangement. The assessment of CRLF2 aberrations may therefore serve as new stratification tool in Berlin-Frankfurt-Münster-based protocols by identifying additional high-risk patients who may benefit from an intensified and/or targeted treatment.
Blood 04/2010; 115(26):5393-7. · 9.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although deletions of cell cycle regulatory gene loci have long been reported in various malignancies, little is known regarding their relevance in pediatric T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (TALL). The current study focused on loss of heterozygosity (LOH) analyses of the CDKN2A/B (chromosome 9p), ATM (chromosome 11q) and p53 (chromosome 17p) gene loci. Frequencies of LOH were compared in 113 pediatric T-LBL and 125 T-ALL who were treated uniformly according to ALL-BFM strategies. Furthermore, LOH findings were correlated with clinical characteristics and tested for their prognostic relevance. LOH at 9p was detected in 47% of T-LBL and 51% of T-ALL, and was associated with male gender in both. In T-ALL, LOH at 9p was associated with favorable initial treatment response. A tendency for favorable event-free-survival was observed in LOH 9p positive T-LBL. The frequency of LOH at chromosomes 11q and 17p was 5% or less for both diseases.
Haematologica 08/2009; 95(1):158-62. · 6.42 Impact Factor
-
Birgit Burkhardt, Anja Moericke,
Wolfram Klapper,
Franziska Greene,
Janina Salzburg,
Christine Damm-Welk,
Martin Zimmermann,
Konstantin Strauch,
Wolf-Dieter Ludwig,
Martin Schrappe,
Alfred Reiter
[show abstract]
[hide abstract]
ABSTRACT: Deletions on chromosome 6q are frequently reported in hematological malignancies. However, their biological or prognostic impact has not yet been clarified. This study analyzed loss of heterozygosity (LOH) at chromosome 6q and compared the LOH findings in pediatric precursor T lymphoblastic lymphoma (T-LBL) with the LOH findings in precursor-T lymphoblastic leukemia (T-ALL). For LOH analyses, a set of 25 microsatellite-markers on 6q14-q24 were examined. All patients were treated uniformly according to ALL-BFM-type treatment-strategy. A total of 1671 markers were successfully analyzed from 108 T-LBL patients. LOH was detected in 21 T-LBL patients. There was clear association between LOH at 6q and an increased risk of relapse. In comparison, 3109 markers were successfully analyzed from 127 T-ALL-patients. LOH was detected in 16 patients, but was not associated with increased relapse-rate. The localization of the common LOH regions identified for T-LBL and T-ALL samples did not overlap. Therefore patterns of LOH at 6q and the prognostic impact of LOH differ between T-ALL and T-LBL. These results hint at biologic differences between the two diseases.
Leukemia & lymphoma 04/2008; 49(3):451-61. · 2.40 Impact Factor
-
The Lancet 05/2007; 369(9568):1232. · 38.28 Impact Factor
