Publications by authors named "Francesca R Mauro"

48 Publications

Efficacy of idelalisib and rituximab in relapsed/refractory chronic lymphocytic leukemia treated outside of clinical trials. A report of the Gimema Working Group.

Hematol Oncol 2021 Mar 19. Epub 2021 Mar 19.

Department of Medical Sciences, Hematology Section, University of Ferrara, Cona - Ferrara, Italy.

Because the efficacy of new drugs reported in trials may not translate into similar results when used in the real-life, we analyzed the efficacy of idelalisib and rituximab (IR) in 149 patients with relapsed/refractory chronic lymphocytic leukemia treated at 34 GIMEMA centers. Median progression-free survival (PFS) and overall survival were 22.9 and 44.5 months, respectively; performance status (PS) ≥2 and ≥3 previous lines of therapy were associated with shorter PFS and overall survival (OS). 48% of patients were on treatment at 12 months; the experience of the centers (≥5 treated patients) and PS 0-1 were associated with a significantly longer treatment duration (p = 0.015 and p = 0.002, respectively). TP53 disruption had no prognostic significance. The overall response rate to subsequent treatment was 49.2%, with median OS of 15.5 months and not reached in patients who discontinued, respectively, for progression and for toxicity (p < 0.01). Treatment breaks ≥14 days were recorded in 96% of patients and adverse events mirrored those reported in trials. In conclusion, this real-life analysis showed that IR treatment duration was longer at experienced centers, that the ECOG PS and ≥3 lines of previous therapy are strong prognostic factor and that the overall outcome with this regimen was superimposable to that reported in a randomized trial.
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http://dx.doi.org/10.1002/hon.2861DOI Listing
March 2021

COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus.

Leukemia 2020 09 9;34(9):2354-2363. Epub 2020 Jul 9.

Struttura Semplice Dipartimentale di Ematologia, Presidio Ospedaliero Santa Chiara, Trento, Italy.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79-7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.
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http://dx.doi.org/10.1038/s41375-020-0959-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347048PMC
September 2020

International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia.

Blood 2020 05;135(21):1859-1869

University of Texas MD Anderson Cancer Center, Houston, TX.

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.
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http://dx.doi.org/10.1182/blood.2019003453DOI Listing
May 2020

Frontline treatment with the combination obinutuzumab ± chlorambucil for chronic lymphocytic leukemia outside clinical trials: Results of a multinational, multicenter study by ERIC and the Israeli CLL study group.

Am J Hematol 2020 06 14;95(6):604-611. Epub 2020 Mar 14.

Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a "real-world" setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a "real-world" setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.
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http://dx.doi.org/10.1002/ajh.25766DOI Listing
June 2020

Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations.

Br J Haematol 2020 06 16;189(5):853-859. Epub 2020 Feb 16.

Haematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.

In chronic lymphocytic leukaemia (CLL), caution is warranted regarding the clinical implications of immunoglobulin variable heavy chain region (IGHV) rearrangements with a 'borderline' (BL) percentage of mutations (i.e. 97-97·9% IGHV identity). We analysed the IGHV mutational status in 759 untreated CLL patients (cohort 1). BL-CLL (n = 36, 5%) showed a time to first treatment (TFT) similar to that of M-CLL (n = 338) and significantly longer than that of UM-CLL (n = 385), despite the enrichment in subset #2 cases. In fact, CLLs belonging to subset #2 (n = 15/759, 2%) were significantly more frequent among BL-CLLs (n = 5/36, 14%), with a brief TFT. TFT of BL-CLL remained comparable to that of M-CLL also considering the 327 CLL patients evaluated at diagnosis. These findings were then validated in an independent cohort 2 of 759 newly diagnosed CLL patients (BL-CLL: n = 11, 1·4%) and in all newly diagnosed patients from cohorts 1 and 2 (n = 1 086, 84% stage A; BL-CLL: n = 47, 4·3%). BL-CLL at diagnosis showed a biological profile comparable to that of M-CLL with a low frequency of unfavourable prognostic markers, except for a significant enrichment in subset #2. Our data suggest that the prognosis of BL-CLL is good and similar to that of M-CLL, with the exception of subset #2 cases.
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http://dx.doi.org/10.1111/bjh.16434DOI Listing
June 2020

Biological and clinical implications of mutations in chronic lymphocytic leukemia.

Haematologica 2020 31;105(2):448-456. Epub 2020 Jan 31.

Division of Hematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy.

is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of mutations are largely unexplored. Furthermore, little is known about the prognostic impact of mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in -mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, -mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, <0.001) similar to cases harboring mutations (median progression-free survival: 2.6 years, <0.0001). mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, =0.004) in multivariate analysis adjusted for mutation, 17p deletion and mutation status. If validated, mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.
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http://dx.doi.org/10.3324/haematol.2019.219550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012473PMC
April 2021

Olaptesed pegol (NOX-A12) with bendamustine and rituximab: a phase IIa study in patients with relapsed/refractory chronic lymphocytic leukemia.

Haematologica 2019 10 16;104(10):2053-2060. Epub 2019 May 16.

Haematology Clinic, Department of Internal Medicine, University of Genoa, and Ospedale Policlinico S. Martino, Clinica Ematologica, Genoa, Italy

Olaptesed pegol (NOX-A12) is a pegylated structured L-oligoribonucleotide that binds and neutralizes CXCL12, a chemokine tightly regulating the life cycle of chronic lymphocytic leukemia cells. The resulting inhibition of CXCR4 and CXCR7 signaling reduces the protective activity of the bone marrow and lymph node microenvironment. CXCL12 inhibition mobilizes chronic lymphocytic leukemia cells into the circulation and prevents their homing into the protective niches. In this phase I/II study, 28 patients with relapsed/refractory chronic lymphocytic leukemia were treated with olaptesed pegol in combination with bendamustine and rituximab. Combination treatment was preceded by single escalating pilot doses of olaptesed pegol in the first ten patients for evaluation of safety and pharmacokinetics. Peak concentrations and systemic exposure of olaptesed pegol were dose-linear; plasma elimination was monophasic with a 53.2 h half-life. A rapid increase in circulating chronic lymphocytic leukemia cells was observed already 1 h after administration of olaptesed pegol and lasted for at least 72 h. Single-agent treatment was well tolerated and no dose-limiting toxicity was observed. The combination regimen yielded an overall response rate of 86%, with 11% of patients achieving a complete response and 75% a partial response. Notably, all ten high-risk patients, including four with a 17p deletion, responded to treatment. The median progression-free survival was 15.4 (95% confidence interval: 12.2, 26.2) months while the median overall survival was not reached with >80% of patients alive after a median follow-up of 28 months. Olaptesed pegol was well tolerated and did not result in additional toxicity when combined with bendamustine and rituximab (). Further clinical development of this novel CXCL12 inhibitor is thus warranted.
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http://dx.doi.org/10.3324/haematol.2018.205930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886437PMC
October 2019

Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib.

Br J Haematol 2019 02 18;184(3):392-396. Epub 2018 Oct 18.

Department of Cellular Biotechnologies and Haematology, "Sapienza" University, Rome, Italy.

TP53-disrupted chronic lymphocytic leukaemia (CLL) patients show a suboptimal long-term response to ibrutinib. We hereby report that ibrutinib-induced in vitro apoptosis and proliferation inhibition were significantly lower in TP53-mutated (TP53-M) CLL cells compared to TP53 wild-type cells. Contrariwise, venetoclax effectively killed TP53-M cells. Gene expression profile analysis of TP53-M cells revealed a downmodulation of B-cell receptor (BCR)-related genes and an upmodulation of genes with anti-apoptotic/pro-survival activity, suggesting that the survival and proliferation of TP53-M cells are less dependent on the BCR pathway. These observations further support the use of drug combinations for the optimal management of TP53-M CLL patients.
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http://dx.doi.org/10.1111/bjh.15613DOI Listing
February 2019

Balancing efficacy and toxicity of targeted agents currently used for the treatment of patients with chronic lymphocytic leukemia.

Expert Rev Hematol 2018 08 18;11(8):601-611. Epub 2018 Jul 18.

a Hematology, Department of Cellular Biotechnologies and Hematology , Sapienza University and Policlinico Umberto 1 , Rome , Italy.

Introduction: In recent years, innovative mechanism-based drugs have enriched the therapeutic armamentarium for patients with chronic lymphocytic leukemia (CLL) and are widely used in the clinical practice. These small molecules targeting the B-cell receptor signaling pathway and the BCL-2 anti-apoptotic protein offer new chemo-free options to both unfit patients and high-risk patients who show a poor response to chemoimmunotherapy. Nonetheless, treatment with ibrutinib, idelalisib and venetoclax is associated with unique side effects. Awareness, prevention and the appropriate management of these specific toxicities are of crucial importance for a successful treatment. Areas covered: The purpose of this review is to discuss the most relevant studies on small molecules in CLL, with particular attention to the emerging toxicity profile of these agents and to the factors that should be considered to address the most appropriate treatment approach for each patient. Expert opinion: The increased knowledge on the biology of CLL has translated into the development of targeted agents that are highly effective and produce deep responses. Toxicities potentially associated with these agents should be known for an optimal management of CLL patients.
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http://dx.doi.org/10.1080/17474086.2018.1495557DOI Listing
August 2018

In chronic lymphocytic leukaemia with complex karyotype, major structural abnormalities identify a subset of patients with inferior outcome and distinct biological characteristics.

Br J Haematol 2018 04 2;181(2):229-233. Epub 2018 Apr 2.

Haematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Ferrara, Italy.

Complex karyotype (CK) is a negative prognostic factor in chronic lymphocytic leukaemia (CLL). However, CK is a heterogeneous cytogenetic category. Unbalanced rearrangements were present in 73·3% of 90 CLL patients with CK (i.e. ≥3 chromosome aberrations in the same clone), and were associated with a shorter overall survival (P = 0·025) and a shorter time to first treatment (P = 0·043) by multivariate analysis. Patients with unbalanced rearrangements presented a distinct mRNA expression profile. In conclusion, CLL patients with unbalanced rearrangements might represent a subset of very high-risk CLL patients with distinct clinical and biological characteristics.
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http://dx.doi.org/10.1111/bjh.15174DOI Listing
April 2018

Venetoclax: a chance for patients with chronic lymphocytic leukaemia previously treated with ibrutinib.

Lancet Oncol 2018 01 12;19(1):7-8. Epub 2017 Dec 12.

Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome, Italy.

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http://dx.doi.org/10.1016/S1470-2045(17)30910-5DOI Listing
January 2018

Clinical relevance of hypogammaglobulinemia, clinical and biologic variables on the infection risk and outcome of patients with stage A chronic lymphocytic leukemia.

Leuk Res 2017 06 27;57:65-71. Epub 2017 Feb 27.

Hematology Section, Cosenza Hospital, Cosenza, Italy.

The prognostic effect of hypogammaglobulinemia (HGG), clinical and biologic characteristics on the infection risk and outcome has been retrospectively analyzed in 899 patients with stage A chronic lymphocytic leukemia (CLL). Low levels of IgG were recorded in 19.9% of patients at presentation, low levels of IgM and/or IgA in 10.4% and an additional 20% of patients developed HGG during the course of the disease. Before the start of any treatment, 160 (12.9%) patients experienced at least one grade ≥3 infection requiring a systemic anti-infective treatment and/or hospitalization. While IgG levels at diagnosis were not associated with an increased risk of grade ≥3 infection or with an adverse outcome, a significantly increased rate of grade ≥3 infections was recorded in patients with unmutated IGHV (p=0.011) and unfavorable FISH aberrations (p=0.009). Late onset HGG, more frequently recorded in patients with Rai stage I-II (p=0.001) and unmutated IGHV (p=0.001), was also associated with a higher rate of severe infections (p=0.002). These data indicate that, stage A patients with clinical and biologic characteristics of a more aggressive disease develop more frequently late onset HGG, grade ≥3 infections and require a closer clinical monitoring.
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http://dx.doi.org/10.1016/j.leukres.2017.02.011DOI Listing
June 2017

Another treatment option for relapsed or refractory chronic lymphocytic leukaemia.

Lancet Oncol 2017 03 28;18(3):270-271. Epub 2017 Jan 28.

Department of Cellular Biotechnologies and Haematology, Sapienza University, Rome 00161, Italy. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(16)30667-2DOI Listing
March 2017

Fludarabine, cyclophosphamide and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia. A multicenter phase I-II GIMEMA trial.

Leuk Lymphoma 2017 07 23;58(7):1640-1647. Epub 2016 Nov 23.

a Department of Cellular Biotechnologies and Hematology, Hematology , Sapienza University , Rome , Italy.

The activity and safety of a regimen combining lenalidomide with fludarabine and cyclophosphamide (FC) was investigated in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Treatment consisted of six monthly courses of the FC regimen combined with 14 days of lenalidomide given at the starting dose of 2.5 mg during course 1. The maximum tolerated dose of lenalidomide was 5 mg. Forty patients were assessed for response, 66% were IGHV unmutated, 45% showed deletion 11q or 17p. The overall response and complete remission rates were 62.5% and 22.5%, respectively, the median progression-free and overall survival (OS) were 19 and 45 months, respectively. Grade 3-4 granulocytopenia was observed in 65% of cases, severe infections in 7.5%, the lenalidomide-related toxicity was mild. In conclusion, the results of this study demonstrate that low-dose lenalidomide associated with the FC schedule is an effective treatment for R/R patients with CLL, associated with an acceptable safety profile.
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http://dx.doi.org/10.1080/10428194.2016.1258698DOI Listing
July 2017

Management of elderly and unfit patients with chronic lymphocytic leukemia.

Expert Rev Hematol 2016 Dec 21;9(12):1165-1175. Epub 2016 Nov 21.

a Hematology, Department of Cellular Biotechnologies and Hematology , Policlinico Umberto 1 and Sapienza University , Rome , Italy.

Introduction: About 75% of patients with chronic lymphocytic leukemia (CLL) are more than 65 years at the time of diagnosis. Treatment of the elderly remains complicated due to multiple factors, such as comorbidities, decline in functional reserve and fitness. Since chronological age by itself cannot properly predict life expectancy and treatment tolerance, an accurate assessment of the fitness status is of crucial importance for an optimal treatment choice. Areas covered: This review will discuss the most relevant aspects concerning the issues experienced in the management of elderly/unfit patients with CLL. The most frequently observed age-related toxicities, fitness assessments, supportive care measures and treatment options for elderly patients and for patients who are deemed unfit will be discussed. Literature search methodology included examination of PubMed index. Expert commentary: During the last decade, different trials focusing on elderly/unfit patients have investigated more tolerable chemoimmunotherapy schedules and, more recently, the activity and safety of chemo-free regimens. Chlorambucil combined with an anti-CD20 monoclonal antibody has shown clinical activity with a relatively good profile of toxicity. The recent introduction of the B-cell receptor antagonists, ibrutinib and idelalisib, and other targeted drugs in development (e.g. venetoclax), is broadening the therapeutic armamentarium of elderly CLL patients.
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http://dx.doi.org/10.1080/17474086.2016.1254544DOI Listing
December 2016

Combination of bendamustine and rituximab as front-line therapy for patients with chronic lymphocytic leukaemia: multicenter, retrospective clinical practice experience with 279 cases outside of controlled clinical trials.

Eur J Cancer 2016 06 27;60:154-65. Epub 2016 Apr 27.

Hematology Unit, Department of Onco-Hematology, Guglielmo da Saliceto Hospital, Piacenza, Italy.

Recently, encouraging results in terms of safety and efficacy have been obtained using bendamustine-rituximab (BR) in untreated chronic lymphocytic leukaemia (CLL) patients enrolled in a phase II study. Here, we report a retrospective international multicenter study of CLL patients treated with BR as front-line therapy. The cohort included 279 patients with progressive CLL from 33 centers (29 Italian, 3 Israeli and 1 German) who received at least 1 cycle of BR as first-line treatment during the 2008-2014 period. The primary objective of this study was to evaluate the efficacy and safety of BR administered as front-line therapy, outside of controlled clinical trials. Median age was 70 years (range, 43-86 years); 62.4% were males and 35.8% had Binet stage C. Forty-two patients (15.2%) were unfit (cumulative illness rating scale [CIRS] score ≥7), and 140 (50.2%) had creatinine clearance ≤70 ml/min. Fluorescent in situ hybridisation analysis, available for 192 cases, showed that 21 (10.9%) had del11q and 18 (9.4%) del17p. The overall response rate (ORR) was 86.4%, with a complete remission rate of 28%. Patients with del17p had an ORR of 66.7%. After median follow-up of 24 months, the 2-year progression-free survival (PFS) was 69.9%; CIRS ≥7, immunoglobulin heavy-chain variable-region (IGHV) unmutated status, del17p and BR dose intensity <80% were independently associated with shorter PFS. Grade III or IV neutropenia, thrombocytopenia, and anaemia were observed in 25.9%, 15.4%, and 15.1% of patients, respectively. Twenty-four patients (8.6%) had severe infections. BR is also an effective and safe regimen for untreated CLL patients, outside of controlled clinical trials.
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http://dx.doi.org/10.1016/j.ejca.2016.03.069DOI Listing
June 2016

Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia.

Blood 2015 Oct 14;126(16):1921-4. Epub 2015 Aug 14.

Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Ferrara, Italy;

Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant treatment advancement in chronic lymphocytic leukemia (CLL). In the new scenario of targeted agents, there is an increasing interest in identifying patients who gain the maximum benefit from FCR. In this observational multicenter retrospective analysis of 404 CLL patients receiving frontline FCR, the combination of three biomarkers that are widely tested before treatment (IGHV mutation status, 11q deletion and 17p deletion; available in 80% of the study cohort) allowed to identify a very low-risk category of patients carrying mutated IGHV genes but neither 11q or 17p deletion that accounted for 28% of all cases. The majority of very low-risk patients (71%) remained free of progression after treatment and their hazard of relapse decreased after 4 years from FCR. The life expectancy of very low-risk patients (91% at 5 years) was superimposable to that observed in the matched normal general population, indicating that neither the disease nor complications of its treatment affected survival in this favorable CLL group. These findings need a prospective validation and may be helpful for the design of clinical trials aimed at comparing FCR to new targeted treatments of CLL, and, possibly, for optimized disease management.
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http://dx.doi.org/10.1182/blood-2015-05-647925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743433PMC
October 2015

Prospective validation of predictive value of abdominal computed tomography scan on time to first treatment in Rai 0 chronic lymphocytic leukemia patients: results of the multicenter O-CLL1-GISL study.

Eur J Haematol 2016 Jan 31;96(1):36-45. Epub 2015 Mar 31.

Hematology Unit, Department of Onco-Hematology, A.O. of Cosenza, Cosenza, Italy.

Objective: We performed an external and multicentric validation of the predictive value of abdominal computed tomography (aCT) on time to first treatment (TTFT) in early stage chronic lymphocytic leukemia (CLL) patients.

Methods: aCT was performed at diagnosis in 181 Rai 0 patients enrolled in the O-CLL1-GISL trial (clinicaltrial.gov ID:NCT00917549).

Results: Fifty-five patients showed an abnormal aCT. Patients with an abnormal aCT showed a significantly shorter TTFT than those with normal aCT (P < 0.0001). At multivariate analysis, aCT (P = 0.011), β-2 microglobulin (P = 0.019), and CD38 expression (P = 0.047) correlated with TTFT. Following IWCLL 2008 criteria, 112 (61.9%) cases remained at Rai 0, while 69 (38.1%) satisfied the criteria of clinical monoclonal B-cell lymphocytosis (cMBL). Reclassified Rai 0 patients with an abnormal aCT showed a significantly shorter TTFT than those with a normal aCT (P < 0.0001). At multivariate analysis, only aCT (P = 0.011) correlated with TTFT. Eleven cMBL cases (15.9%) showed an abnormal aCT and were reclassified as small lymphocytic lymphomas (SLL); nonetheless, TTFT was similar for cMBLs and SLLs.

Conclusion: Our results confirm the ability of the abnormal aCT to predict progression in early stage cases.
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http://dx.doi.org/10.1111/ejh.12545DOI Listing
January 2016

Increased chronic lymphocytic leukemia proliferation upon IgM stimulation is sustained by the upregulation of miR-132 and miR-212.

Genes Chromosomes Cancer 2015 Apr 2;54(4):222-34. Epub 2015 Feb 2.

Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy.

To assess the involvement of microRNAs (miRNAs) in B-cell receptor (BCR) stimulation, we first evaluated miRNA profiling following IgM cross-linking in chronic lymphocytic leukemia (CLL) cells and in normal B lymphocytes. Second, we combined miRNA and gene expression data to identify putative miRNA functional networks. miRNA profiling showed distinctive patterns of regulation after stimulation in leukemic versus normal B lymphocytes and identified a differential responsiveness to BCR engagement in CLL subgroups according to the immunoglobulin heavy chain variable region mutational status and clinical outcome. The most significantly modulated miRNAs in stimulated CLL are miR-132 and miR-212. Notably, these miRNAs appeared regulated in progressive but not in stable CLL. Accordingly, gene profiling showed a significant transcriptional response to stimulation exclusively in progressive CLL. Based on these findings, we combined miRNA and gene expression data to investigate miR-132 and miR-212 candidate interactions in this CLL subgroup. Correlation analysis pointed to a link between these miRNAs and RB/E2F and TP53 cascades with proproliferative effects, as corroborated by functional analyses. Finally, basal levels of miR-132 and miR-212 were measured in an independent cohort of 20 unstimulated CLL cases and both showed lower expression in progressive compared to stable patients, suggesting an association between the expression of these molecules and disease prognosis. Overall, our results support a model involving miR-132 and miR-212 upregulation in sustaining disease progression in CLL. These miRNAs may therefore provide new valuable strategies for therapeutic intervention.
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http://dx.doi.org/10.1002/gcc.22236DOI Listing
April 2015

Italian external and multicentric validation of the MD Anderson Cancer Center nomogram and prognostic index for chronic lymphocytic leukaemia patients: analysis of 1502 cases.

Br J Haematol 2014 Oct 11;167(2):224-32. Epub 2014 Jul 11.

UOC Ematologia di Cosenza, Cosenza, Italy.

We performed an external and multicentric validation of the nomogram and prognostic index (PI) proposed by the MD Anderson Cancer Center to prognostically stratify chronic lymphocytic leukaemia (CLL) patients in 1502 CLL cases. All six parameters involved in the nomogram and PI (age, sex, absolute lymphocyte count, number of lymph node groups, Rai stage and β2-microglobulin) were independently associated with survival. The nomogram was accurate in predicting survival (c-index = 0·82). According to the PI, 38·7% of patients were at low-risk, 58·3% at intermediate-risk and 3% at high-risk. The estimated median survival times were: not reached for low-risk, 13·4 years for intermediate-risk and 3·4 years for high-risk. The estimated median and 5-year survival by PI were similar to those originally reported. The PI remained a predictor of survival when analysis was limited to 847 Rai stage 0 (P < 0·0001) and 151 clinical monoclonal B-cell lymphocytosis (cMBL) cases (P = 0·033). Finally, the PI allowed prediction of time to therapy in all patients (P < 0·0001), in Rai 0 (P < 0·0001) and in cMBL cases (P = 0·044). Our results confirm the ability of the PI to predict prognosis, even in early stage disease cases. The study also extended the utility of the PI to cMBL cases.
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http://dx.doi.org/10.1111/bjh.13032DOI Listing
October 2014