Fludarabine plus alemtuzumab (FA) front-line treatment in young patients with chronic lymphocytic leukemia (CLL) and an adverse biologic profile

Mauro, Francesca Romana; Molica, Stefano; Laurenti, Luca; Cortelezzi, Agostino; Carella, Angelo Michele; Zaja, Francesco; Chiarenza, Annalisa; Angrilli, Francesco; Nobile, Francesco; Marasca, Roberto; Musolino, Caterina; Brugiatelli, Maura; Piciocchi, Alfonso; Vignetti, Marco; Fazi, Paola; Gentile, Giuseppe; Propris, Maria Stefania De; Starza, Irene Della; Marinelli, M; Chiaretti, Sabina; Giudice, Ilaria Del; Nanni, Mauro; Albano, Francesco; Cuneo, Antonio; Guarini, Anna; Foà, Robin

doi:10.1016/j.leukres.2013.11.009

Cited by 4 publications

(3 citation statements)

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“…TP53 encodes for the p53 protein, a transcription factor involved in essential cell functions, such as DNA repair, cell cycle control, apoptosis, aging, and stemness [ 1 , 2 ]. Aberrant p53 function, due to 17p deletion (del(17p)) and/or TP53 mutation, is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients [ 3 – 5 ]. Alterations of TP53 occur in about 10 % of untreated CLL patients [ 6 , 7 ], but up to 50 % in relapsed or refractory cases [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

TP53 gene mutation analysis in chronic lymphocytic leukemia by nanopore MinION sequencing

et al. 2016

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BackgroundThe assessment of TP53 mutational status is becoming a routine clinical practice for chronic lymphocytic leukemia patients (CLL). A broad spectrum of molecular techniques has been employed so far, including both direct Sanger sequencing and next generation sequencing. Oxford Nanopore Technologies recently released the MinION an USB-interfaced sequencer. In this paper we report our experience, with the MinION technology for the detection of the TP53 gene mutation in CLL patients.Twelve CLL patients at diagnosis were included in this study. All except one patient showed the TP53 gene deletion in Fluorescence in situ hybridization experiments.Patients were investigated for TP53 mutation by Sanger and by MinION sequencing.Analysis by Sanger was performed according with the IARC protocol.Analysis by MinION was performed adopting a strategy based on long template PCR, read error correction, and post variant calling filtering.ResultsDue to the high error rate of nanopore technology, sequence data were both used directly and before correction with two different in silico methods: ALEC and nanocorrect. A mean error rate of 15 % was detected before correction that was reduced to 4-5 % after correction.Analysis by Sanger sequencing was able to detect four patients mutated for TP53. MinION analysis detected one more mutated patient previously not detected from Sanger.ConclusionIn our hands, the Nanopore technology shows correlation with Sanger sequencing but more sensitive, manageable and less expensive, and therefore has proven to be a useful tool for TP53 gene mutation detection.Electronic supplementary materialThe online version of this article (doi:10.1186/s13000-016-0550-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

TP53 gene mutation analysis in chronic lymphocytic leukemia by nanopore MinION sequencing

et al. 2016

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“…Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with highly variable clinical manifestations, ranging from asymptomatic at the time of diagnosis to a progressive symptomatic disease that is poorly responsive to the common immuno-chemotherapeutic regimens [1–2]. Genomic sequencing studies have revealed a number of recurrently mutated genes in CLL [3–5].…”

Section: Introductionmentioning

confidence: 99%

Droplet digital PCR analysis of NOTCH1 gene mutations in chronic lymphocytic leukemia

Minervini

Anelli

et al. 2016

Oncotarget

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In chronic lymphocytic leukemia (CLL), NOTCH1 gene mutations (NOTCH1mut) have been associated with adverse prognostic features but the independence of these as a prognostic factor is still controversial. In our study we validated a c.7541-7542delCT NOTCH1 mutation assay based on droplet digital PCR (ddPCR); we also analyzed the NOTCH1mut allelic burden, expressed as fractional abundance (FA), in 88 CLL patients at diagnosis to assess its prognostic role and made a longitudinal ddPCR analysis in 10 cases harboring NOTCH1mut to verify the FA variation over time. Our data revealed that with the ddPCR approach the incidence of NOTCH1mut in CLL was much higher (53.4%) than expected. However, longitudinal ddPCR analysis of CLL cases showed a statistically significant reduction of the NOTCH1mut FA detected at diagnosis after treatment (median FA 11.67 % vs 0.09 %, respectively, p = 0.01); the same difference, in terms of NOTCH1mut FA, was observed in the relapsed cases compared to the NOTCH1mut allelic fraction observed in patients in complete or partial remission (median FA 4.75% vs 0.43%, respectively, p = 0.007). Our study demonstrated a much higher incidence of NOTCH1mut in CLL than has previously been reported, and showed that the NOTCH1mut allelic burden evaluation by ddPCR might identify patients in need of a closer clinical follow-up during the “watch and wait” interval and after standard chemotherapy.

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“…Alemtuzumab in combination with fludarabine achieved an ORR of 58·3% and a CR rate of 7·8% in patients with del(17p) younger than 60 years old. Absence of bulky lymphadenopathy, high β 2 ‐microglobulin levels and longer time interval from initial diagnosis were predictive of favourable PFS, which was similar to that in patients without the deletion: 51% vs. 60% survived after 3 years (Mauro et al , ). Another recent randomized trial showed that, while alemtuzumab combined with fludarabine and cyclophosphamide successfully prolonged PFS (but not OS) in patients with high risk cytogenetics, it failed to do so in the del(17p) subgroup (although the study was not adequately powered to conduct a complete subgroup analysis) (Geisler et al , ).…”

Section: Hitting Roadblocks: Inferior Chemotherapy Responses In Del(1mentioning

confidence: 72%

A new hope: novel therapeutic approaches to treatment of chronic lymphocytic leukaemia with defects inTP53

2014

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SummaryChronic lymphocytic leukaemia (CLL) is an indolent B-cell malignancy with heterogeneous outcomes. Chromosomal abnormalities in CLL are predictive of the natural disease course; del(11q) and del(17p) are recognized as high risk genetic lesions. Del(17p) is associated with an impaired function of TP53, a key tumour suppressor, and is particularly problematic. Such patients respond poorly to chemo-immunotherapy and have significantly shorter survival compared to patients with standard and low-risk cytogenetics. While TP53 pathway defects are rare at initial diagnosis, their frequency increases in relapsed CLL. Until very recently, this group of patients represented an unmet clinical need with few therapeutic options. However, the advent of targeted therapies has expanded the drug armamentarium and introduced new hope for these highly refractory patients. Agents that target B-cell receptor signalling, BH3-mimetics and others induce apoptosis of the neoplastic B-cells in a TP53-independent manner. Their use in the clinic is associated with remarkable activity in patients with del(17p). In this review we discuss the frequency and clinical significance of del(17p) and genetic mutations leading to disrupted TP53, the putative role of other TP53 homologues, and the results of key clinical trials involving both conventional chemotherapy and novel agents.

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Fludarabine plus alemtuzumab (FA) front-line treatment in young patients with chronic lymphocytic leukemia (CLL) and an adverse biologic profile

Cited by 4 publications

References 36 publications

TP53 gene mutation analysis in chronic lymphocytic leukemia by nanopore MinION sequencing

TP53 gene mutation analysis in chronic lymphocytic leukemia by nanopore MinION sequencing

Droplet digital PCR analysis of NOTCH1 gene mutations in chronic lymphocytic leukemia

A new hope: novel therapeutic approaches to treatment of chronic lymphocytic leukaemia with defects inTP53

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