Publications by authors named "Annalisa Chiarenza"

55 Publications

A brief rituximab, bendamustine, mitoxantrone (R-BM) induction followed by rituximab consolidation in elderly patients with advanced follicular lymphoma: a phase II study by the Fondazione Italiana Linfomi (FIL).

Br J Haematol 2021 Jan 21. Epub 2021 Jan 21.

SC Ematologia AOU Città della Salute e della Scienza di Torino, Torino, Italy.

Treatment for follicular lymphoma (FL) in the elderly is not well standardized. A phase II, multicentre, single arm trial was conducted in this setting with a brief chemoimmunotherapy regimen. Treatment consisted in four monthly courses of rituximab, bendamustine and mitoxantrone (R-BM) followed by 4 weekly rituximab as consolidation; rituximab maintenance was not applied because the drug was not licensed at the time of enrolment. The primary endpoint was the complete remission rate (CR). Seventy-six treatment-naive FL patients (aged 65-80 and a "FIT" score, according to the Comprehensive Geriatric Assessment) were enrolled. CR was documented in 59/76 patients (78%), partial remission in 12 (16%) and stable/progressive disease in five (6%) with an overall response rate in 71/76 (94%). Median follow-up was 44 months with 3-year progression-free-survival (PFS) and overall-survival of 67% and 92% respectively. Nine deaths occurred, three of progressive disease. The regimen was well tolerated and the most frequent severe toxicity was neutropenia (18% of the cycles). Bcl-2/IGH rearrangement was found in 40/75 (53%) of evaluated patients. R-BM was highly effective in clearing polymerase chain reaction-detectable disease: 29/31 (96%) evaluated patients converted to bcl-2/IGH negativity at the end of treatment. A brief R-BM regimen plus rituximab consolidation is effective and safe in "FIT" elderly, treatment-naïve, FL patients, inducing high CR and molecular remission rates with prolonged PFS.
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http://dx.doi.org/10.1111/bjh.17283DOI Listing
January 2021

Comparison of ibrutinib and idelalisib plus rituximab in real-life relapsed/resistant chronic lymphocytic leukemia cases.

Eur J Haematol 2020 Dec 30. Epub 2020 Dec 30.

Biothecnology Research Unit, AO of Cosenza, Cosenza, Italy.

Objectives: To compare the capacity of ibrutinib (IB) and idelalisib-rituximab (IDELA-R) of prolonging overall survival (OS) as in CLL patients, previously treated with chemotherapy only.

Methods: A real-life cohort of 675 cases has been identified and investigated in the database of the groups participating in the study.

Results: At an unadjusted univariate analysis, a significant death risk reduction was observed favoring IB (IDELA-R vs IB HR = 0.5, 95% CI = 0.36-0.71) although with some limitations due to the non-randomized and retrospective nature of the study and to the lower number of patients in the IDELA-R group (112 cases) related to the current prescribing practice. To overcome the potential problem of confounding by indication, we adjusted the association between the type of therapy and mortality for all variables significantly associated with OS at Cox univariate analysis. Furthermore, those variables, differently distributed between the two study groups, were introduced into the multivariate Cox model to improve the effectiveness of the analysis. By introducing all these variables into the multiple Cox regression model, we confirmed the protective effect of IB vs IDELA-R (HR = 0.67, 95% CI = 0.45-0.98, P = .04) independent of potential confounders.

Conclusions: Although our analysis presents some constraints, that is, the unavailability of additional potential confounders, and the retrospective nature of the study, this observation may be of help for the daily clinical practice, particularly in the absence of randomized trials comparing the two schedules.
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http://dx.doi.org/10.1111/ejh.13573DOI Listing
December 2020

SF3B1-mutated chronic lymphocytic leukemia shows evidence of NOTCH1 pathway activation including CD20 downregulation.

Haematologica 2020 10 29;Online ahead of print. Epub 2020 Oct 29.

Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN), Italy.

Chronic lymphocytic leukemia (CLL) is characterized by a low CD20 expression, in part explained by an epigenetic-driven downregulation triggered by mutations of the NOTCH1 gene. In the present study, by taking advantage of a wide and well-characterized CLL cohort (n=537), we demonstrate that CD20 expression is downregulated in SF3B1-mutated CLL in an extent similar to NOTCH1-mutated CLL. In fact, SF3B1-mutated CLL cells show common features with NOTCH1-mutated CLL cells, including a gene expression profile enriched of NOTCH1-related gene sets and elevated expression of the active intracytoplasmic NOTCH1. Activation of the NOTCH1 signaling and down-regulation of surface CD20 in SF3B1-mutated CLL cells correlate with over-expression of an alternatively spliced form of DVL2, a component of the Wnt pathway and negative regulator of the NOTCH1 pathway. These findings are confirmed by separately analyzing the CD20-dim and CD20-bright cell fractions from SF3B1-mutated cases as well as by DVL2 knock-out experiments in CLL-like cell models. Altogether, the clinical and biological features that characterize NOTCH1-mutated CLL may also be recapitulated in SF3B1-mutated CLL, contributing to explain the poor prognosis of this CLL subset and providing the rationale for expanding novel agents-based therapies to SF3B1-mutated CLL.
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http://dx.doi.org/10.3324/haematol.2020.261891DOI Listing
October 2020

Impaired nodal shrinkage and apoptosis define the independent adverse outcome of NOTCH1 mutated patients under ibrutinib therapy in chronic lymphocytic leukaemia.

Haematologica 2020 07 30. Epub 2020 Jul 30.

Cinical and Experimental Hematology Unit, CRO, IRCCS, Aviano (PN), Italy.

The introduction of agents inhibiting the BCR-associated kinases such as ibrutinib has dramatically changed treatments algorithms of chronic lymphocytic leukaemia (CLL) as well as the role of different adverse prognosticators. We evaluated the efficacy of ibrutinib as single agent, in a real-life context, on 180 patients with CLL mostly pre-treated, recruited from three independent cohorts from Italy. Patients received 420 mg oral ibrutinib once daily until progression or occurrence of unacceptable side effects. Seventy-three patients discontinued ibrutinib for progression or for adverse events. NOTCH1 mutations (M) were correlated with a reduced redistribution lymphocytosis, calculated at 3 months on ibrutinib (p=0.022). Moreover, NOTCH1 mutated patients showed inferior nodal response at 6 months on ibrutinib compared to NOTCH1 wild type patients (p<0.0001). Significant shorter progression free survival (PFS) and overall survival (OS) were observed in NOTCH1 mutated patients (p=0.00002 and p=0.001). Interestingly, NOTCH1 M plus lower bax/bcl-2 ratio identified a CLL subset showing the worst PFS and OS (p=0.0002 and p=0.005). In multivariate analysis of PFS and OS, NOTCH1 M were confirmed an independent prognosticator (p=0.00006 and p=0.0039). In conclusion, NOTCH1 M are strongly associated with lower bax/bcl-2 ratio, consistent with a defective apoptosis, lower redistribution lymphocytosis and lower nodal shrinkage under ibrutinib treatment, this last responsible for partial responses, subsequent relapses, shorter PFS and OS. The therapeutic options for NOTCH1 mutated patients could be represented by either new small molecules combination approaches or from antibodies targeting NOTCH1.
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http://dx.doi.org/10.3324/haematol.2020.251488DOI Listing
July 2020

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.

Università Vita-Salute San Raffaele and IRCC Ospedale San Raffaele, Milan, 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

Brentuximab vedotin in association with bendamustine in refractory or multiple relapsed Hodgkin lymphoma. A retrospective real-world study.

Eur J Haematol 2020 Jun 13;104(6):581-587. Epub 2020 Mar 13.

Department of Oncology, Hematology and BMT Unit, Casa di Cura La Maddalena, Palermo, Italy.

Objective And Methods: In order to assess the efficacy of brentuximab vedotin (Bv) in combination with bendamustine (B) in multiple relapsed or refractory (RR) classic Hodgkin lymphoma (cHL), medical records of 47 patients treated with BvB in second relapse or beyond were reviewed.

Results: The median number of previous treatments was 2 (1-4). Bv was given at 1.8 mg/kg on day 1 and bendamustine at 90 mg/m on days 1 and 2 of a 21-day cycle. The median number of BvB cycles was 4 (2-7), and all patients were evaluable for efficacy. The CR and OR rates were 49% and 79%, respectively; 67% of responding patients and 2 in stable disease proceeded to a SCT procedure. After a median follow-up of 19 months (5-47), median PFS was 18 months (95%CI: 23-29), and the 2-year OS was 72%. Significantly longer PFS and OS were observed in patients attaining a major clinical response to treatment and in those who received consolidation with SCT. Fifteen (32%) patients experienced severe (G > 2) toxicity. The main toxicities were neutropenia (23%), gastrointestinal (10%), peripheral sensory neuropathy (11%), and infection (4%).

Conclusion: Our real-world results suggest that BvB is an effective third-line rescue and bridge-to-transplant regimen for RR-cHL patients.
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http://dx.doi.org/10.1111/ejh.13400DOI Listing
June 2020

CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression.

Blood 2020 04;135(15):1244-1254

Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy.

CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The cutoff value for the extensively validated 30% of positive CLL cells is able to separate CLL patients into 2 subgroups with different prognoses, but it does not consider the pattern of CD49d expression. In the present study, we analyzed a cohort of 1630 CLL samples and identified the presence of ∼20% of CLL cases (n = 313) characterized by a bimodal expression of CD49d, that is, concomitant presence of a CD49d+ subpopulation and a CD49d- subpopulation. At variance with the highly stable CD49d expression observed in CLL patients with a homogeneous pattern of CD49d expression, CD49d bimodal CLL showed a higher level of variability in sequential samples, and an increase in the CD49d+ subpopulation over time after therapy. The CD49d+ subpopulation from CD49d bimodal CLL displayed higher levels of proliferation compared with the CD49d- cells; and was more highly represented in the bone marrow compared with peripheral blood (PB), and in PB CLL subsets expressing the CXCR4dim/CD5bright phenotype, known to be enriched in proliferative cells. From a clinical standpoint, CLL patients with CD49d bimodal expression, regardless of whether the CD49d+ subpopulation exceeded the 30% cutoff or not, experienced clinical behavior similar to CD49d+ CLL, both in chemoimmunotherapy (n = 1522) and in ibrutinib (n = 158) settings. Altogether, these results suggest that CD49d can drive disease progression in CLL, and that the pattern of CD49d expression should also be considered to improve the prognostic impact of this biomarker in CLL.
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http://dx.doi.org/10.1182/blood.2019003179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228464PMC
April 2020

Monocytic Myeloid Derived Suppressor Cells in Hematological Malignancies.

Int J Mol Sci 2019 Nov 1;20(21). Epub 2019 Nov 1.

Division of Hematology, AOU "Policlinico-Vittorio Emanuele", 95125 Catania, Italy.

In the era of novel agents and immunotherapies in solid and liquid tumors, there is an emerging need to understand the cross-talk between the neoplastic cells, the host immune system, and the microenvironment to mitigate proliferation, survival, migration and resistance to drugs. In the microenvironment of hematological tumors there are cells belonging to the normal bone marrow, extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and neoplastic cells themselves. In this context, myeloid suppressor cells are an emerging sub-population of regulatory myeloid cells at different stages of differentiation involved in cancer progression and chronic inflammation. In this review, monocytic myeloid derived suppressor cells and their potential clinical implications are discussed to give a comprehensive vision of their contribution to lymphoproliferative and myeloid disorders.
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http://dx.doi.org/10.3390/ijms20215459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862591PMC
November 2019

A laboratory-based scoring system predicts early treatment in Rai 0 chronic lymphocytic leukemia.

Haematologica 2020 Jun 3;105(6):1613-1620. Epub 2019 Oct 3.

Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy

We present a laboratory-based prognostic calculator (designated CRO score) to risk stratify treatment-free survival in early stage (Rai 0) chronic lymphocytic leukemia (CLL) developed using a training-validation model in a series of 1,879 cases from Italy, the United Kingdom and the United States. By means of regression analysis, we identified five prognostic variables with weighting as follows: deletion of the short arm of chromosome 17 and unmutated immunoglobulin heavy chain gene status, 2 points; deletion of the long arm of chromosome 11, trisomy of chromosome 12, and white blood cell count >32.0x10/microliter, 1 point. Low-, intermediate- and high-risk categories were established by recursive partitioning in a training cohort of 478 cases, and then validated in four independent cohorts of 144 / 395 / 540 / 322 cases, as well as in the composite validation cohort. Concordance indices were 0.75 in the training cohort and ranged from 0.63 to 0.74 in the four validation cohorts (0.69 in the composite validation cohort). These findings advocate potential application of our novel prognostic calculator to better stratify early-stage CLL, and aid case selection in risk-adapted treatment for early disease. Furthermore, they support immunocytogenetic analysis in Rai 0 CLL being performed at the time of diagnosis to aid prognosis and treatment, particularly in today's chemofree era.
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http://dx.doi.org/10.3324/haematol.2019.228171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271568PMC
June 2020

Biological and clinical implications of mutations in chronic lymphocytic leukemia.

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

Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

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
January 2020

Outcome of transformed follicular lymphoma worsens according to the timing of transformation and to the number of previous therapies. A retrospective multicenter study on behalf of Fondazione Italiana Linfomi (FIL).

Br J Haematol 2019 05 21;185(4):713-717. Epub 2019 Feb 21.

Haematology, ASST Spedali Civili di Brescia, Brescia, Italy.

Optimal treatment for transformed follicular lymphoma (tFL) is not fully defined. Clinical characteristics and treatments that impact on post-transformation outcome of 176 biopsy-proven tFL were analysed. Transformation occurred at initial diagnosis in 52% (Group 1) and after a FL diagnosis in 48% (Group 2). Five-year overall survival was 84% for Group 1 and 51% for Group 2 (P < 0·001). In Group 1, 5-year progression-free survival was superior after rituximab maintenance compared to observation only (94% vs. 53%, P = 0·024). In Group 2, an inverse trend was found between survival and both a higher number of pre-transformation treatment lines and a short time-to-transformation.
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http://dx.doi.org/10.1111/bjh.15816DOI Listing
May 2019

Immune off-target effects of Brentuximab Vedotin in relapsed/refractory Hodgkin Lymphoma.

Br J Haematol 2019 05 15;185(3):468-479. Epub 2019 Feb 15.

Section of Haematology, Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania, Italy.

Hodgkin Lymphoma (HL) is associated with deep microenvironment re-shaping and myeloid dysfunction. Given that only limited data are available regarding the role of Brentuximab Vedotin (BV) as single agent in transplant-naive relapsed/refractory (R/R) patients and its off-target effects on immune system, we evaluated the amount of regulatory T-cells (T-regs), myeloid-derived suppressor cells (MDSC) subpopulations, and their functional marker, serum arginase-1 (s-Arg-1), in peripheral blood of 15 consecutive R/R HL patients. After a median of four BV cycles, the overall response rate (complete response + partial response) was 47%, with 4 (27%) complete metabolic remissions. BV reduced the absolute number of three MDSC subtypes and s-Arg-1 levels. Patients with baseline s-Arg-1 ≥200 ng/ml had inferior progression-free survival at 36 months compared to those with low s-Arg-1. T-regs dysfunction was recovered by BV: absolute T-regs count was increased after treatment with BV, independently of metabolic response achieved, with a significant reduction of CD30 T-regs. Our data disclose off-target effects of BV in the microenvironment that could explain its deep and durable clinical efficacy.
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http://dx.doi.org/10.1111/bjh.15801DOI Listing
May 2019

Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: a GIMEMA, ERIC and UK CLL FORUM study.

Haematologica 2018 07 19;103(7):1209-1217. Epub 2018 Apr 19.

Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.

We performed an observational study on the efficacy of ben-damustine and rituximab (BR) as first salvage regimen in chronic lymphocytic leukemia (CLL). In an intention-to-treat analysis including 237 patients, the median progression-free survival (PFS) was 25 months. The presence of del(17p), unmutated IGHV and advanced stage were associated with a shorter PFS at multivariate analysis. The median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival (OS) was 74.5 months. Advanced disease stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within Named Patient Programs in the United Kingdom and in Italy was carried out with OS as objective end point. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, there was no difference in OS between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an efficacious first salvage regimen in CLL in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in patients without 17p deletion.
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http://dx.doi.org/10.3324/haematol.2018.189837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029555PMC
July 2018

Prognostic meaning of neutrophil to lymphocyte ratio (NLR) and lymphocyte to monocyte ration (LMR) in newly diagnosed Hodgkin lymphoma patients treated upfront with a PET-2 based strategy.

Ann Hematol 2018 Jun 14;97(6):1009-1018. Epub 2018 Feb 14.

Department of General Surgery and Medical-Surgical Specialties, Haematology Section, University of Catania, Catania, Italy.

Recent reports identify NLR (the ratio between absolute neutrophils counts, ANC, and absolute lymphocyte count, ALC), as predictor of progression-free survival (PFS) and overall survival (OS) in cancer patients. We retrospectively tested NLR and LMR (the ratio between absolute lymphocyte and monocyte counts) in newly diagnosed Hodgkin lymphoma (HL) patients treated upfront with a PET-2 risk-adapted strategy. NLR and LMR were calculated using records obtained from the complete blood count (CBC) from 180 newly diagnosed HL patients. PFS was evaluated accordingly to Kaplan-Meier method. Higher NLR was associated to advanced stage, increased absolute counts of neutrophils and reduced count of lymphocytes, and markers of systemic inflammation. After a median follow-up of 68 months, PFS at 60 months was 86.6% versus 70.1%, respectively, in patients with NLR ≥ 6 or NLR < 6. Predictors of PFS at 60 months were PET-2 scan (p < 0.0001), NLR ≥ 6.0 (p = 0.02), LMR < 2 (p = 0.048), and ANC (p = 0.0059) in univariate analysis, but only PET-2 was an independent predictor of PFS in multivariate analysis. Advanced-stage patients (N = 119) were treated according to a PET-2 risk-adapted protocol, with an early switch to BEACOPP regimen in case of PET-2 positivity. Despite this strategy, patients with positive PET-2 still had an inferior outcome, with PFS at 60 months of 84.7% versus 40.1% (negative and positive PET-2 patients, respectively, p < 0.0001). Independent predictors of PFS by multivariate analysis were PET-2 status and to a lesser extend NLR in advanced stage, while LMR maintained its significance in early stage. By focusing on PET-2 negative patients, we found that patients with NLR ≥ 6.0 or LMR < 2 had an inferior outcome compared to patients with both ratios above the cutoff (78.7 versus 91.9 months, p = 0.01). We confirm NLR as predictor of PFS in HL patients independently from stage at diagnosis. Integration of PET-2 scan, NLR and LMR can result in a meaningful prognostic system that needs to be further validated in prospective series including patients treated upfront with PET-2 adapted-risk therapy.
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http://dx.doi.org/10.1007/s00277-018-3276-yDOI Listing
June 2018

Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia.

J Exp Med 2018 02 4;215(2):681-697. Epub 2018 Jan 4.

Clinical and Experimental Onco-Hematology Unit, CRO Aviano National Cancer Institute, Aviano, Italy

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.
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http://dx.doi.org/10.1084/jem.20171288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789417PMC
February 2018

Long-Term Results of the FOLL05 Trial Comparing R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Symptomatic Follicular Lymphoma.

J Clin Oncol 2018 03 2;36(7):689-696. Epub 2017 Nov 2.

Stefano Luminari, Angela Ferrari, and Francesco Merli, Azienda Ospedaliera Arcispedale Santa Maria Nuova-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Reggio Emilia; Stefano Luminari, Martina Manni, Alessandra Dondi, Vittoria Tarantino, Luigi Marcheselli, and Massimo Federico, University of Modena and Reggio Emilia, Modena, Italy; Annalisa Chiarenza, Azienda Ospedaliera Universitaria Policlinico-Vittorio Emanuele, University of Catania, Catania; Chiara Rusconi, Azienda Socio Sanitaria Territoriale (ASST) -Grande Ospedale Metropolitano Niguarda; Andrés J.M. Ferreri, IRCCS San Raffaele Scientific Institute, Milano; Alessandra Tucci, ASST-Spedali Civili di Brescia, Brescia; Umberto Vitolo, Città della Salute e della Scienza University and Hospital, Torino; Sofia Kovalchuk, University of Florence, Florence; Emanuele Angelucci, Ospedale Policlinico San Martino, Genova; Alessandro Pulsoni, Sapienza University of Rome, Rome; Luca Arcaini, Fondazione IRCCS Policlinico San Matteo, Pavia; Francesco Angrilli, Spirito Santo Hospital, Pescara; Gianluca Gaidano, University of Eastern Piedmont, Novara; Caterina Stelitano, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria; Giovanni Bertoldero, Ospedale di Mirano, Mirano; Nicola Cascavilla, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo; Flavia Salvi, Ospedale SS Antonio e Biagio, Alessandria; and Daniele Vallisa, Guglielmo da Saliceto Hospital, Piacenza, Italy.

Purpose The FOLL05 trial compared R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-FM (rituximab plus fludarabine and mitoxantrone) regimens without rituximab maintenance as initial therapy for patients with advanced-stage follicular lymphoma (FL). A previous analysis with a median follow-up of 34 months showed a superior 3-year time to treatment failure, the primary study end point, with R-CHOP and R-FM versus R-CVP and showed R-CHOP to have a better risk-benefit ratio in terms of toxicity than R-FM. We report a post hoc analysis of this trial after a median follow-up of 7 years. Patients and Methods Of the 534 enrolled patients, 504 were evaluable. At the time of analysis, the median follow-up was 84 months (range, 1 to 119 months). Results The 8-year time to treatment failure and progression-free survival rates were 44% (95% CI, 39% to 49%) and 48% (95% CI, 43% to 53%), respectively. The hazard ratio for progression-free survival adjusted by FL International Prognostic Index 2 versus R-CVP was 0.73 for R-CHOP (95% CI, 0.54 to 0.98; P = .037) and 0.67 for R-FM (95% CI, 0.50 to 0.91; P = .009). The 8-year overall survival (OS) rate was 83% (95% CI, 79% to 87%), with no significant differences among study arms. Overall, we observed a higher risk of dying as a result of causes unrelated to lymphoma progression with R-FM versus R-CVP. Conclusion With an 83% 8-year OS rate, long-term follow-up of the FOLL05 trial confirms the favorable outcome of patients with advanced-stage FL treated with immunochemotherapy. The three study arms had similar OS but different activity and toxicity profiles. Patients initially treated with R-CVP had a higher risk of lymphoma progression compared with those receiving R-CHOP, as well as a higher risk of requiring additional therapy.
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http://dx.doi.org/10.1200/JCO.2017.74.1652DOI Listing
March 2018

The prognostic value of the myeloid-mediated immunosuppression marker Arginase-1 in classic Hodgkin lymphoma.

Oncotarget 2016 10;7(41):67333-67346

Division of Hematology, AOU "Policlinico - Vittorio Emanuele", University of Catania, Catania, Italy.

Purpose: Neutrophilia is hallmark of classic Hodgkin Lymphoma (cHL), but its precise characterization remains elusive. We aimed at investigating the immunosuppressive role of high-density neutrophils in HL.

Experimental Design: First, N-HL function was evaluated in vitro, showing increased arginase (Arg-1) expression and activity compared to healthy subjects. Second, we measured serum level of Arg-1 (s-Arg-1) by ELISA in two independent, training (N = 40) and validation (N = 78) sets.

Results: s-Arg-1 was higher in patients with advanced stage (p = 0.045), B-symptoms (p = 0.0048) and a positive FDG-PET scan after two cycles of chemotherapy (PET-2, p = 0.012). Baseline levels of s-Arg-1 > 200 ng/mL resulted in 92% sensitivity and 56% specificity to predict a positive PET-2.Patients showing s-Arg-1 levels > 200 ng/mL had a shorter progression free survival (PFS). In multivariate analysis, PET-2 and s-Arg-1 at diagnosis were the only statistically significant prognostic variables related to PFS (respectively p = 0.0004 and p = 0.012).Moving from PET-2 status and s-Arg-1 level we constructed a prognostic score to predict long-term treatment outcome: low s-Arg-1 and negative PET-2 scan (score 0, N = 63), with a 3-Y PFS of 89.5%; either positive PET-2 or high s-Arg-1 (score 1, N = 46) with 3-Y PFS of 67.6%, and both positive markers (score 2, N = 9) with a 3-Y PFS of 37% (p = 0.0004).

Conclusions: We conclude that N-HL are immunosuppressive through increased Arg-1 expression, a novel potential biomarker for HL prognosis.
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http://dx.doi.org/10.18632/oncotarget.12024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341879PMC
October 2016

Mesenchymal Stem Cells (MSC) Regulate Activation of Granulocyte-Like Myeloid Derived Suppressor Cells (G-MDSC) in Chronic Myeloid Leukemia Patients.

PLoS One 2016 8;11(7):e0158392. Epub 2016 Jul 8.

Division of Hematology, A.O.U. Policlinico-OVE, Catania, University of Catania, Catania, Italy.

It is well known that mesenchymal stem cells (MSC) have a role in promotion of tumor growth, survival and drug-resistance in chronic myeloid leukemia (CML). Recent reports indicated that a subpopulation of myeloid cells, defined as granulocyte-like myeloid-derived suppressor cells (G-MDSC) is increased in these patients. So far, the role of MSC in MDSC expansion and activation into the BM microenvironment remains unexplored. To address this question, here we use a specific experimental model in vitro, co-culturing MSC with peripheral blood mononucleated cells (PBMC) from normal individuals, in order to generate MSC-educated G-MDSC. Although MSC of healthy donors (HD) and CML patients were able to generate the same amount of MDSC, only CML-MSC-educated G-MDSC exhibited suppressive ability on autologous T lymphocytes. In addition, compared with HD-MSC, CML-MSC over-expressed some immunomodulatory factors including TGFβ, IL6 and IL10, that could be involved in MDSC activation. CML-MSC-educated G-MDSC expressed higher levels of ARG1, TNFα, IL1β, COX2 and IL6 than G-MDSC isolated from co-culture with HD-MSC. Our data provide evidence that CML-MSC may play a critical role in tumor microenvironment by orchestrating G-MDSC activation and regulating T lymphocytes-mediated leukemia surveillance, thus contributing to CML immune escape.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158392PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938578PMC
July 2017

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.

UOC Ematologia, Ospedale Annunziata, Cosenza, Italy. Electronic address:

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

Granulocyte-like myeloid derived suppressor cells (G-MDSC) are increased in multiple myeloma and are driven by dysfunctional mesenchymal stem cells (MSC).

Oncotarget 2016 Dec;7(52):85764-85775

Division of Hematology, A.O.U. Policlinico-OVE, Catania, University of Catania, Italy.

Granulocytic-Myeloid-derived suppressor cells (G-MDSC) are increased in Multiple Myeloma (MM) patients but the mechanisms of G-MDSC generation are still unknown. There are many evidences of the role of mesenchymal stem cells (MSC) in promoting MM cell growth, survival and drug-resistance. We here used a specific experimental model in vitro to evaluate the ability of MSC to induce G-MDSC. We found that although MSC derived from healthy donors (HD), MGUS and MM were able to generate the same amount of MDSC, only MM-MSC-educated G-MDSC exhibited suppressive ability. In addition, in comparison with MSC derived from HD, MM-MSC produce higher amount of immune-modulatory factors that could be involved in MDSC induction. Compared to G-MDSC obtained from co-culture models with MSC from healthy subjects, both MGUS and MM-MSC-educated G-MDSC showed increase of immune-modulatory factors. However, only MM-MSC educated G-MDSC 1) up-regulated immune-suppressive factors as ARG1 and TNFα, 2) expressed higher levels of PROK2, important in angiogenesis and inflammatory process, and 3) showed ability to digest bone matrix.Our data demonstrate that MM-MSC are functionally different from healthy subjects and MGUS-MSC, supporting an evolving concept regarding the contribution of MM-MSC to tumor development and progression.
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http://dx.doi.org/10.18632/oncotarget.7969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349872PMC
December 2016