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L L Nigro,
E Mirabile,
M Tumino,
C Caserta,
G Cazzaniga,
C Rizzari,
D Silvestri,
B Buldini,
E Barisone,
F Casale, [......],
C Micalizzi,
A Pession,
R Parasole,
N Santoro,
G Masera, G Basso,
M Aricò,
M G Valsecchi,
A Biondi,
V Conter
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2013; · 8.30 Impact Factor
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Marta Pillon,
Gloria Tridello,
Maria P Boaro,
Chiara Messina,
Maria C Putti,
Stefania Varotto,
Maria G Petris,
Sara Scrimin,
Luigi Zanesco,
Angelo Rosolen, Giuseppe Basso
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ABSTRACT: The aim of this study was to assess life goal achievements in long-term survivors (LTS) receiving cranial radiotherapy (CRT) as central nervous system (CNS) prophylaxis for acute lymphoblastic leukemia (ALL) during childhood, compared to healthy individuals. Participants in this study were 141 LTS treated in our center from 1961 to 1990. Questionnaires were mailed to LTS. Analyses were stratified by age classes comparing LTS and a matched healthy population living in the same geographic area, as well as comparing patients treated with 24 Gy vs. 18 Gy CRT. Survivors reached the same educational level as controls. Significant differences were noted according to age and CRT dose. LTS had similar employment rates to those of controls, but lower marriage rates. Most respondents described their life positively, but as worse in the 24 Gy group. This study highlights the good life satisfaction of our LTS despite the long-term effects of the disease and its treatment.
Leukemia & lymphoma 07/2012; · 2.40 Impact Factor
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C Palmi,
E Vendramini,
D Silvestri,
G Longinotti,
D Frison,
G Cario,
C Shochat,
M Stanulla,
V Rossi,
A M Di Meglio, [......],
G Fazio,
A Leszl,
M Schrappe, G Basso,
A Biondi,
S Izraeli,
V Conter,
M G Valsecchi,
G Cazzaniga,
G Te Kronnie
[show abstract]
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ABSTRACT: Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has achieved an 80% cure rate as a result of a risk-adapted therapy largely based on minimal residual disease (MRD) monitoring. However, relapse is still the most frequent adverse event, occurring mainly in the patients with intermediate MRD levels (intermediate risk, IR), emphasizing the need for new prognostic markers. We analyzed the prognostic impact of cytokine receptor-like factor 2 (CRLF2) over-expression and P2RY8-CRLF2 fusion in 464 BCP-ALL patients (not affected by Down syndrome and BCR-ABL negative) enrolled in the AIEOP-BFM ALL2000 study in Italy. In 22/464 (4.7%) samples, RQ-PCR showed CRLF2 over-expression (20 times higher than the overall median). P2RY8-CRLF2 fusion was detected in 22/365 (6%) cases, with 10/22 cases also showing CRLF2 over-expression. P2RY8-CRLF2 fusion was the most relevant prognostic factor independent of CRLF2 over-expression with a threefold increase in risk of relapse. Significantly, the cumulative incidence of relapse of the P2RY8-CRLF2+ patients in the IR group was high (61.1%±12.9 vs 17.6%±2.6, P<0.0001), similar to high-risk patients in AIEOP-BFM ALL2000 study. These results were confirmed in a cohort of patients treated in Germany. In conclusion, P2RY8-CRLF2 identifies a subset of BCP-ALL patients currently stratified as IR that could be considered for treatment intensification.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2012; 26(10):2245-53. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2012; 26(7):1717-9. · 8.30 Impact Factor
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M G Loudin,
J Wang,
H-C Eastwood Leung,
S Gurusiddappa,
J Meyer,
G Condos,
D Morrison,
A Tsimelzon,
M Devidas,
N A Heerema,
A J Carroll,
S E Plon,
S P Hunger, G Basso,
A Pession,
D Bhojwani,
W L Carroll,
K R Rabin
[show abstract]
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ABSTRACT: Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-DS (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only 2 NDS cases (3.1%) (Fisher's exact P=0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters and enrichment of highly methylated genes for specific pathways and transcription factor-binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2011; 25(10):1555-63. · 8.30 Impact Factor
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M Blink,
T D Buitenkamp,
M M van den Heuvel-Eibrink,
A A Danen-van Oorschot,
V de Haas,
D Reinhardt,
J-H Klusmann,
M Zimmermann,
M Devidas,
A J Carroll, G Basso,
A Pession,
H Hasle,
R Pieters,
K R Rabin,
S Izraeli,
C M Zwaan
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2011; 25(8):1365-8. · 8.30 Impact Factor
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M Pigazzi,
R Masetti,
S Bresolin,
A Beghin,
A Di Meglio,
S Gelain,
L Trentin,
E Baron,
M Giordan,
A Zangrando,
B Buldini,
A Leszl,
M C Putti,
C Rizzari,
F Locatelli,
A Pession,
G Te Kronnie, G Basso
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2011; 25(3):560-3. · 8.30 Impact Factor
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[show abstract]
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ABSTRACT: Activation of the Notch pathway occurs commonly in T acute lymphoblastic leukemia (T-ALL) because of mutations in Notch1 or Fbw7 and is involved in the regulation of cell proliferation and survival. Deregulated Notch3 signalling has also been shown to promote leukemogenesis in transgenic mice, but the targets of Notch3 in human T-ALL cells remain poorly characterized. Here, we show that Notch3 controls levels of mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1). In a model of T-ALL cell dormancy, both Notch3 activation and MKP-1 expression were upregulated in aggressive compared with dormant tumors, and this inversely correlated with the levels of phosphorylated p38 and extracellular signal-regulated kinase1/2 (ERK1/2) MAPKs, two canonical MKP-1 targets. We demonstrate that MKP-1 protein levels are regulated by Notch3 in T-ALL cell lines because its silencing by RNA interference or treatment with γ-secretase inhibitors induced strong MKP-1 reduction whereas activation of Notch3 signalling had the opposite effect. Furthermore, MKP-1 has an important role in T-ALL cell survival because its attenuation by short hairpin RNA significantly increased cell death under stress conditions. This protective function has a key role in vivo, as MKP-1-deficient cells showed impaired tumorigenicity. These results elucidate a novel mechanism downstream of Notch3 that controls the survival of T-ALL cells.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2011; 25(4):588-98. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2010; 25(1):173-4. · 8.30 Impact Factor
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V Conter,
M Aricò, G Basso,
A Biondi,
E Barisone,
C Messina,
R Parasole,
G De Rossi,
F Locatelli,
A Pession, [......],
C Micalizzi,
M Citterio,
C Rizzari,
D Silvestri,
R Rondelli,
L Lo Nigro,
O Ziino,
A M Testi,
G Masera,
M G Valsecchi
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ABSTRACT: 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.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2009; 24(2):255-64. · 8.30 Impact Factor
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M Bardini,
R Spinelli,
S Bungaro,
E Mangano,
L Corral,
I Cifola,
G Fazio,
M Giordan, G Basso,
G De Rossi,
A Biondi,
C Battaglia,
G Cazzaniga
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ABSTRACT: The pathogenesis of infant acute lymphoblastic leukemia (ALL) is still not well defined. Short latency to leukemia and very high concordance rate for ALL in Mixed-Lineage Leukemia (MLL)-positive infant twins suggest that the MLL rearrangement itself could be sufficient for overt leukemia. Attempts to generate a suitable mouse model for MLL-AF4-positive ALL did not thoroughly resolve the issue of whether cooperating mutations are required to reduce latency and to generate overt leukemia in vivo. In this study, we applied single-nucleotide polymorphism array technology to perform genomic profiling of 28 infant ALL cases carrying t(4;11) to detect MLL-cooperating aberrations hidden to conventional techniques and to gain new insights into infant ALL pathogenesis. In contrast to pediatric, adolescent and adult ALL cases, the MLL rearrangement in infant ALL is associated with an exceptionally low frequency of copy-number abnormalities, thus confirming the unique nature of this disease. By contrast, additional genetic aberrations are acquired at disease relapse. Small-segmental uniparental disomy traits were frequently detected, mostly constitutional, and widely distributed throughout the genome. It can be argued that the MLL rearrangement as a first hit, rather than inducing the acquisition of additional genetic lesions, has a major role to drive and hasten the onset of leukemia.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2009; 24(1):169-76. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2009; 24(1):232-5. · 8.30 Impact Factor
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V H J Van der Velden,
L Corral,
M G Valsecchi,
M W J C Jansen,
P De Lorenzo,
G Cazzaniga,
E R Panzer-Grümayer,
M Schrappe,
A Schrauder,
C Meyer,
R Marschalek,
L L Nigro,
M Metzler, G Basso,
G Mann,
M L Den Boer,
A Biondi,
R Pieters,
J J M Van Dongen
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ABSTRACT: Acute lymphoblastic leukemia (ALL) in infants younger than 1 year is a rare but relatively homogeneous disease ( approximately 80% MLL gene rearranged, approximately 70% CD10-negative) when compared with childhood and adult ALL. Several studies in children and adults with ALL have shown that minimal residual disease (MRD) status is a strong and independent prognostic factor. We therefore evaluated the prognostic significance of MRD in infant ALL. Ninety-nine infant patients treated according to the Interfant-99 protocol were included in this study. MRD was analyzed by real-time quantitative PCR analysis of rearranged immunoglobulin genes, T-cell receptor genes and MLL genes at various time points (TP) during therapy. Higher MRD levels at the end of induction (TP2) and consolidation (TP3) were significantly associated with lower disease-free survival. Combined MRD information at TP2 and TP3 allowed recognition of three patients groups that significantly differed in outcome. All MRD-high-risk patients (MRD levels > or =10(-4) at TP3; 26% of patients) relapsed. MRD-low-risk patients (MRD level <10(-4) at both TP2 and TP3) constituted 44% of patients and showed a relapse-rate of only 13%, whereas remaining patients (MRD-medium-risk patients; 30% of patients) had a relapse rate of 31%. Comparison between the current Interfant-06 stratification at diagnosis and the here presented MRD-based stratification showed that both stratifications recognized different subgroups of patients. These data indicate that MRD diagnostics has added value for recognition of risk groups in infant ALL and that MRD diagnostics can be used for treatment intervention in infant ALL as well.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2009; 23(6):1073-9. · 8.30 Impact Factor
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ABSTRACT: Treatment response is a strong outcome predictor for childhood acute lymphoblastic leukemia (ALL). Here, we evaluated the predictive impact of flow cytometric blast quantification assays (absolute blast count, BC, and blast reduction rate, BRR) in peripheral blood (pB) and/or bone marrow (BM) at early time points of induction therapy (days 0, 8 and 15) on the remission status in the AIEOP-BFM-ALL 2000 protocol. At the single parameter level (905 patients), the strongest predictive parameter for the remission status as a dichotomous minimal residual disease (MRD) parameter (positive/negative) has been provided by the BC at day 15 in BM (cutoff: 17 blasts/microl; 50 vs 15%; odds ratio: 5.6; 95% confidence interval: 4.1-7.6, P<0.001), followed by the BRR at day 15 in BM and by the BC at day 8 in pB (odds ratios: 3.8 and 2.6, respectively). In the multiple regression analysis (440 patients), BC in pB (d0 and d8) and in BM (d15) as well as BRR at day 8 in pB provided significantly contributing variables with an overall correct prediction rate of 74.8%. These data show that the quantitative assessment of early response parameters, especially absolute BCs at day 15 in BM, has a predictive impact on the remission status after induction therapy.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2008; 23(3):528-34. · 8.30 Impact Factor
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ABSTRACT: The inducible cyclic AMP (cAMP) early repressor (ICER) and cAMP response element-binding protein (CREB) are transcriptional regulators of the cAMP-mediated signaling pathway. CREB has been demonstrated to be upregulated in the majority of childhood leukemias contributing to disease progression, whereas ICER, its endogenous repressor, was found to be downregulated. Our research focus has been the function of restored ICER expression. ICER exogenously expressed in cell lines decreases CREB protein level and induces a lowered clonogenic potential in vitro. It decreases the ability of HL60 to invade the extramedullary sites and to promote bone marrow angiogenesis in nonobese diabetic-severe combined immunodeficient mice, demonstrating its potential effects on tumor progression. ICER represses the majority of 96 target genes upregulated by CREB. It binds CRE promoters and controls gene expression restoring the normal regulation of major cellular pathways. ICER is subjected to degradation through a constitutively active form of the extracellular signal-regulated protein kinase, which drives it to the proteasome. We propose that ICER is downregulated in HL60 to preserve CREB overexpression, which disrupts normal myelopoiesis and promotes blast proliferation. These findings define the function of ICER as a tumor suppressor in leukemia. Unbalanced CREB/ICER expression needs to be considered a pathogenetic feature in leukemogenesis. The molecular characterization of this pathway could be useful for novel therapeutic strategies.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2008; 22(12):2217-25. · 8.30 Impact Factor
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ABSTRACT: The aim of the study was to analyze the impact of minimal residual disease (MRD) after reinduction therapy on the outcome of children with relapsed 'high-risk' acute lymphoblastic leukemia (ALL). Sixty patients with isolated or combined marrow relapse were studied. All patients belonged to the S3 or S4 groups, as defined by the Berlin-Frankfurt-Münster stratification for relapsed ALL. MRD was studied by real-time quantitative PCR after the first, second and third chemotherapy course (time points 1 (TP1), 2 (TP2) and 3 (TP3), respectively). MRD results, not used for treatment refinement, were categorized as negative (NEG MRD), positive not-quantifiable (POS-NQ MRD) when MRD level was below quantitative range (a level <10(-4)) or positive within quantitative range (POS MRD) when MRD level was >or=10(-4). With a median observation time of 15 months, overall 3-year event-free survival (EFS) was 27%. The 3-year EFS was 73, 45 and 19% for patients with NEG-MRD, POS NQ-MRD and POS-MRD at TP1, respectively (P<0.05). The prognostic predictive value of MRD was statistically confirmed in multivariate analysis. MRD quantitation early and efficiently differentiates patients who benefit from conventional treatment, including allogeneic hematopoietic stem cell transplantation, from those needing innovative, experimental therapies.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2008; 22(12):2193-200. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2008; 22(4):858-61. · 8.30 Impact Factor
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T Flohr,
A Schrauder,
G Cazzaniga,
R Panzer-Grümayer,
V van der Velden,
S Fischer,
M Stanulla, G Basso,
F K Niggli,
B W Schäfer,
R Sutton,
R Koehler,
M Zimmermann,
M G Valsecchi,
H Gadner,
G Masera,
M Schrappe,
J J M van Dongen,
A Biondi,
C R Bartram
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ABSTRACT: Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets (< or =10(-4)), 671 (20%) patients revealed only one sensitive target, 217 (6%) patients had targets with lower sensitivity, and 88 (3%) patients had no targets. MRD-based risk group assignment was feasible in 2594 (78%) patients: 40% were classified as MRD-SR (two sensitive targets, MRD negativity at both time points), 8% as MRD-HR (MRD > or =10(-3) at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2008; 22(4):771-82. · 8.30 Impact Factor
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Leukemia 06/2007; 21(5):1122-4. · 9.56 Impact Factor
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Leukemia 05/2007; 21(4):838-42. · 9.56 Impact Factor
