Publications by authors named "Benedetta Puccini"

37 Publications

Simplified Geriatric Assessment in Older Patients With Diffuse Large B-Cell Lymphoma: The Prospective Elderly Project of the Fondazione Italiana Linfomi.

J Clin Oncol 2021 Feb 12:JCO2002465. Epub 2021 Feb 12.

Division of Medical Oncology and Immune-related Tumors, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN), Italy.

Purpose: To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL).

Methods: We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050).

Results: We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age > 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases.

Conclusion: The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL.
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http://dx.doi.org/10.1200/JCO.20.02465DOI Listing
February 2021

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

Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial.

Lancet Haematol 2021 Jan 22;8(1):e34-e44. Epub 2020 Dec 22.

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

Background: Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population.

Methods: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m on day 1; intravenous doxorubicin 50 mg/m, vincristine 1·4 mg/m, and cyclophosphamide 750 mg/m on day 2; oral prednisone 100 mg/m on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m on day 1, intravenous rituximab 375 mg/m on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m every 12 h on days 1-3, intravenous rituximab 375 mg/m on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 10 cells per L or 10 mg per day for platelets 60-100 × 10 cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313).

Findings: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events.

Interpretation: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma.

Funding: Fondazione Italiana Linfomi and Celgene.
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http://dx.doi.org/10.1016/S2352-3026(20)30358-6DOI Listing
January 2021

Baseline metabolic tumor volume calculation using different SUV thresholding methods in Hodgkin lymphoma patients: interobserver agreement and reproducibility across software platforms.

Nucl Med Commun 2021 Mar;42(3):284-291

Nuclear Medicine Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence.

Aim: Although it is not yet used in clinical practice, metabolic tumor volume (MTV) assessed on the baseline FDG-PET has shown consistent prognostic value in various lymphoma types. The aim of our study was to compare interobserver agreement and reproducibility across platforms of MTV calculation using different SUV thresholding methods in a large series of patients with newly diagnosed Hodgkin lymphoma.

Materials And Methods: We retrospectively studied 121 patients. MTV at baseline FDG-PET was independently computed by three readers with three programs of semi-automatic segmentation, Fiji, LifeX, and Accurate. MTV measurement was performed with different thresholds: SUV >2.5, SUV >4, and SUV >41% of SUV max.

Results: At inter-observer agreement analysis all Intraclass Correlation Coefficients (ICCs) were excellent (ICC >0.9), except for Accurate SUV >41% of SUV max (ICC = 0.8). The highest correlations were obtained at the SUV >4 threshold. The second best was SUV >2.5 threshold. Regarding reproducibility across software, we found statistically significant differences between Fiji versus LifeX and Accurate at fixed thresholds and between LifeX and Accurate at SUV >41% of SUV max, while no significant differences emerged between LifeX and Accurate using fixed thresholds.

Conclusion: The three SUV thresholds studied are all suitable for MTV calculation in terms of reproducibility. The best reproducibility is achieved using fixed thresholds, both SUV >4 and SUV >2.5. If more than one software has to be used in a study, we suggest the use of fixed thresholds and the platforms LifeX and Accurate.
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http://dx.doi.org/10.1097/MNM.0000000000001324DOI Listing
March 2021

Treatment and prognosis of primary pulmonary lymphoma: A long-term follow-up study.

Eur J Haematol 2021 Jan 2;106(1):49-57. Epub 2020 Nov 2.

Haematology and Haematopoietic Stem Cells Transplant Unit, AO San Camillo-Forlanini, Rome, Italy.

Primary pulmonary lymphoma (PPL) is a rare disease with not well-defined optimal treatment. Outcomes and follow-up are variable in published data.

Objectives: To define the outcome and optimal treatment strategies in PPL.

Methods: We reviewed the medical records of 49 patients with PPL treated in three Italian Hematological Institutions between 2002 and 2018.

Results: Thirty-eight (77.5%) cases were indolent PPL, and 11 (22.5%) cases were aggressive PPL. The majority of patients were asymptomatic at diagnosis, early stages (stages IE-IIE), normal serum LDH, no bone marrow involvement, and low or low-intermediate risks of IPI. Local therapy ± immunotherapy or immuno-chemotherapy was possible in 18/49 (37%) patients. Twenty-eight (57%) patients were treated with immuno-chemotherapy after biopsy. Waiting and watching were reported in 3 (6%) patients. Overall, the CR and ORR were 83.7% and 95.9%. With a median follow-up of 62.5 months (range 0.8-199 months), the estimated 5- and 10-year OS rates were 85% and 72.3% for all patients, 89.2% and 80.3% for indolent PPL, and 70.7% and 47.1% for aggressive PPL. Aggressive PPL tended to have a high risk of progression in the first months (P = .056). No advantages were found for indolent PPL who received immuno-chemotherapy or more conservative approaches.

Conclusion: Our studies confirm the epidemiological and favorable survival of patients with PPL, suggesting a very conservative approach, particularly in indolent subtypes.
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http://dx.doi.org/10.1111/ejh.13507DOI Listing
January 2021

Treatment of very high-risk classical Hodgkin Lymphoma: cases' selection from real life and critical review of the literature.

Acta Biomed 2020 05 25;91(S-5):13-22. Epub 2020 May 25.

Hematology Unit, Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.

Over the last 4 decades, advances in radiation therapy and the addition of combination chemotherapy have significantly increased the cure rate of patients with HL, with a 5-year OS of about 90% . However, despite high rate of cure after first line of therapy, 5%-10% of HLs are refractory to the treatment, and 10-30% of patients have a disease relapse after a complete response (CR). Relapsed HL can be treated with salvage therapies with a long-lasting complete remission in 80% of cases. In recent years, novel drugs are available for the patients with relapsed/refractory HL, like Brentuximab Vedotin and immune checkpoint inhibitors. These drugs have been able to rescue a cohort of patients who subsequently could receive an allogeneic stem-cell transplant. Our cases have been chosen because they are representative of critical issues in the management of relapsed/refractory HL; our experiences are consistent with what reported by other Authors.
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http://dx.doi.org/10.23750/abm.v91iS-5.9911DOI Listing
May 2020

Aggressive Disease Course of Multiple Myeloma with Concomitant ALK-Negative Anaplastic Large Cell Lymphoma: A Case Report with an Unusual Presentation.

Case Rep Hematol 2020 16;2020:6309736. Epub 2020 Jan 16.

Haematology Unit, Careggi University Hospital, Florence, Italy.

ALK-negative anaplastic large cell lymphoma is a rare T-cell neoplasm with an aggressive course requiring prompt diagnostic work-up and treatment. Few cases of concomitant multiple myeloma and T-cell neoplasm are described in the literature, mainly regarding primary cutaneous anaplastic large cell lymphoma. We present the case of a 65-year-old man, simultaneously diagnosed with ALK-negative anaplastic large cell lymphoma with extranodal localization in the gastrocnemius muscle (stage 1AE) and IgG lambda multiple myeloma (ISS 2, Durie-Salmon stage 3A). Both diseases required therapeutic intervention due to the high proliferative index of lymphoma and the presence of bone lesions attributable to myeloma. The therapeutic program initially included chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone; CHOEP), radiotherapy on the leg, bortezomib, and then consolidation with autologous hematopoietic stem cell transplantation. Despite being on bortezomib treatment and waiting for transplantation, the patient experienced an early myeloma progression that turned out to be refractory to second-line lenalidomide-based treatment. To our knowledge, this is the first case of concurrent diagnosis of extranodal ALK-negative anaplastic large cell lymphoma of the muscle and multiple myeloma. Simultaneous onset can be challenging for clinicians as both diseases may have an aggressive course requiring multiple treatments with increased risk of toxicity and complicated management.
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http://dx.doi.org/10.1155/2020/6309736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201522PMC
January 2020

The classic prognostic factors in advanced Hodgkin's lymphoma patients are losing their meaning at the time of Pet-guided treatments.

Ann Hematol 2020 Feb 23;99(2):277-282. Epub 2019 Dec 23.

Policlinico S.Orsola-Malpighi, Istituto di Ematologia "Seragnoli", Bologna, Italy.

The International Prognostic Score (IPS) is the most commonly used risk stratification tool for patients with advanced Hodgkin lymphoma (HL). It incorporates seven clinical parameters independently associated with a poorer outcome: male sex, age, stage IV, hemoglobin level, white blood cell and lymphocyte counts, and albumin level. Since the development of the IPS, there have been significant advances in therapy and supportive care. Recent studies suggest that the IPS is less discriminating due to improved outcomes with ABVD therapy. The aim of the present study was to asses if classic prognostic factors maintain their prognostic meaning at the time of response-adapted treatment based on interim PET scans. We evaluated the prognostic significance of IPS in the 520 advanced stage HL patients enrolled in the PET-guided, HD0801 trial in which PET2-positive patients underwent a more intense treatment with an early stem-cell transplantation after 2 cycles of ABVD. We observed that in these patients, the IPS completely loses its prognostic value together with all the single parameters that contribute to the IPS. Furthermore, neutrophils, monocytes, lymphocytes, and the ratio among them also no longer had any predictive value. We believe that the substantial improvement in survival outcomes in PET2-positive patients treated with early autologous transplantation could explain the complete disappearance of the residual prognostic significance of the IPS.
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http://dx.doi.org/10.1007/s00277-019-03893-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976582PMC
February 2020

Clinical characteristics of interim-PET negative patients with a positive end PET from the prospective HD08-01 FIL study.

Ann Hematol 2020 Feb 23;99(2):283-291. Epub 2019 Dec 23.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

FDG-positron emission tomography (PET) performed early during therapy in advanced Hodgkin lymphoma patients has been confirmed as being important for progression-free survival. A group of patients with a negative interim-PET (i-PET) showed a positive end induction PET (e-PET). The aim of this study was to evaluate the clinical characteristics of patients with a positive e-PET as a secondary end point of the HD0801 study. A total of 519 patients with advanced-stage de novo Hodgkin lymphoma received initial treatment and underwent an i-PET. Patients with negative results continued the standard treatment. i-PET negative patients were then evaluated for response with an e-PET and those patients found to have a positive one were also then given a salvage therapy. Among 409 i-PET negative, 16 interrupted the therapy, 393 patients were evaluated with an e-PET, and 39 were positive. Sixteen out of 39 underwent a diagnostic biopsy and 15 were confirmed as HD. Seventeen out of 39 e-PET were reviewed according to the Deauville Score and, in sixteen, it was confirmed positive (10 DS 5, 6 DS 4). With the exception of high LDH value at diagnosis (p = 0.01; HR 95% CI 1.18-4.89), no clinical characteristics were significantly different in comparison with e-PET negative patients. Positive e-PET after a negative i-PET has a worse outcome when compared with i-PET positive patients salvaged with therapy intensification. It was not possible to identify clinical characteristics associated with a positive e-PET.
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http://dx.doi.org/10.1007/s00277-019-03889-3DOI Listing
February 2020

A Gene Expression-based Model to Predict Metabolic Response After Two Courses of ABVD in Hodgkin Lymphoma Patients.

Clin Cancer Res 2020 01 23;26(2):373-383. Epub 2019 Oct 23.

Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

Purpose: Early response to ABVD, assessed with interim FDG-PET (iPET), is prognostic for classical Hodgkin lymphoma (cHL) and supports the use of response adapted therapy. The aim of this study was to identify a gene-expression profile on diagnostic biopsy to predict iPET positivity (iPET).

Experimental Design: Consecutive untreated patients with stage I-IV cHL who underwent iPET after two cycles of ABVD were identified. Expression of 770 immune-related genes was analyzed by digital expression profiling (NanoString Technology). iPET was centrally reviewed according to the five-point Deauville scale (DS 1-5). An iPET predictive model was derived by multivariate regression analysis and assessed in a validation set identified using the same inclusion criteria.

Results: A training set of 121 and a validation set of 117 patients were identified, with 23 iPET cases in each group. Sixty-three (52.1%), 19 (15.7%), and 39 (32.2%) patients had stage I-II, III, and IV, respectively. Diagnostic biopsy of iPET cHLs showed transcriptional profile distinct from iPET. Thirteen genes were stringently associated with iPET. This signature comprises two functionally stromal-related nodes. Lymphocytes/monocytes ratio (LMR) was also associated to iPET. In the training cohort a 5-gene/LMR integrated score predicted iPET [AUC, 0.88; 95% confidence interval (CI), 0.80-0.96]. The score achieved a 100% sensitivity to identify DS5 cases. Model performance was confirmed in the validation set (AUC, 0.68; 95% CI, 0.52-0.84). Finally, iPET score was higher in patients with event versus those without.

Conclusions: In cHL, iPET is associated with a genetic signature and can be predicted by applying an integrated gene-based model on the diagnostic biopsy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2356DOI Listing
January 2020

Primary pulmonary lymphoma: imaging findings in 30 cases.

Radiol Med 2019 Dec 3;124(12):1262-1269. Epub 2019 Oct 3.

Department of Emergency Radiology, University Hospital Careggi, Largo Brambilla 3, 50123, Florence, Italy.

Purpose: To present our experience of cases of primary pulmonary lymphoma (PPL) found between January 2002 and July 2018, focusing on the radiological features and the differential diagnosis in order to contribute to the difficult role of the radiologist in the disease identification and to help the clinicians to reach the diagnosis.

Materials And Methods: CT scans of 30 patients (14 men and 16 women, aged 58-86, mean age 72 years) with PPL were retrospectively reviewed. All patients had a histopathological confirmation of the disease: MALT lymphoma (23 patients, 76.6%); diffuse large B-cell lymphoma-DLBCL (seven patients, 23.4%). All the staging CT scans were evaluated by three experienced radiologists dedicated to thoracic disease in order to radiologically define the predominant pattern of presentation.

Results: The following parenchymal patterns were observed: 11 patients with single/multiple nodules, five with masses/mass-like consolidations, 14 with consolidations with air bronchogram, 16 with ground-glass opacity, ten with angiogram sign, 22 with perilymphatic and/or peribronchovascular spread, 15 with associated lymphadenopathies, and 13 with pleural/chest wall involvement. The main characteristics of PPLs were the presence of consolidations and ground-glass opacities, with perilymphatic and/or bronchovascular spread.

Conclusion: All the characteristics of the work should alert the radiologist to consider lymphoma among the possible differential diagnoses, always correlating the results of the CT examination with appropriate clinical laboratory evaluations.
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http://dx.doi.org/10.1007/s11547-019-01091-zDOI Listing
December 2019

Chemotherapy-related nail toxicity.

Int J Hematol 2019 Nov 10;110(5):519-520. Epub 2019 Aug 10.

Haematology Unit, Careggi Hospital-University of Florence, Largo Brambilla 3, 50134, Florence, Italy.

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http://dx.doi.org/10.1007/s12185-019-02724-9DOI Listing
November 2019

The ion channels and transporters gene expression profile indicates a shift in excitability and metabolisms during malignant progression of Follicular Lymphoma.

Sci Rep 2019 06 13;9(1):8586. Epub 2019 Jun 13.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

The definition of the gene expression profile of genes encoding Ion Channels and Transporters (ICT-GEP) represents a novel and attracting aspect in cancer. We determined the ICT-GEP of Follicular Lymphoma (FL), and compared it with that of the more aggressive Diffuse Large B Cell Lymphoma (DLBCL). cDNA microarray data were collected both from patients enrolled for this study, and from public datasets. In FL the ICT-GEP indicated the overexpression of both the K channel encoding gene KCNN4, and SLC2A1, which encodes the Glut1 glucose transporter. SLC2A1 turned out to represent the hub of a functional network, connecting channels and transporters in FL. Relapsed FL patients were characterised by 38 differentially expressed ICT genes, among which ATP9A, SLC2A1 and KCNN4 were under-expressed, indicating a down-regulation of both excitability and glycolysis. A completely different profile of K channel encoding genes emerged in DLBCL accompanied by the over-expression of the fatty acid transporter-encoding gene SLC27A1 as well as of the metabolism regulator NCoR1. This indicates a change in excitability and a shift towards an oxidative metabolism in DLBCL. Overall, the ICT-GEP may contribute to identifying novel lymphoma biomarkers related to excitability and metabolic pathways, with particular relevance for drug resistant, relapsed FL.
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http://dx.doi.org/10.1038/s41598-019-44661-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565741PMC
June 2019

The use of Deauville 5-point score could reduce the risk of false-positive fluorodeoxyglucose-positron emission tomography in the posttherapy evaluation of patients with primary bone lymphomas.

World J Nucl Med 2018 Jul-Sep;17(3):157-165

Department of Hematology, University of Florence, Florence, Italy.

Primary bone lymphoma (PBL) is a rare disease. Little is reported about response evaluation procedures in these patients. Our aim was to evaluate response to therapy according to fluorodeoxyglucose-positron emission tomography (FDG-PET) results, and in particular to test the Deauville 5-point scale as compared to the visual evaluation of FDG-PET scans in PBL. In this single-center study, we diagnosed 31 consecutive patients with PBL, of which 24 were evaluated with end-of-treatment FDG-PET. Patients' ages ranged from 19 to 82 years. Six patients were treated with chemotherapy, 24 with chemotherapy and radiotherapy, and one patient with radiotherapy alone. Six patients were affected by a pathological fracture. Four patients died within the range of 3 to 36 months after diagnosis. The average follow-up of the remaining patients was 70 (24-173) months. Overall survival was 87% at 5 years. The only positive prognostic factor was complete remission after chemotherapy. According to visual criteria, end-of-treatment FDG-PET was evaluated in 24 patients and it was positive in 11 (46%) and negative in 13 patients. We organized a retrospective central-blinded revision of end-of-therapy FDG-PET scans using the 5-point Deauville Score (DS). We reviewed 17 out of 24 patients and obtained the following results: at the end of therapy, 12 patients with DS score 2, three patients with DS score 3, one patient with DS score 4, and none with DS score 5. Considering that all the 24 patients achieved complete remission after treatment, visual interpretation produced 11/24 false-positive results, and DS interpretation produced 1/17 false-positive results, thus significantly reducing the number of false positives. In PBL, the final evaluation at the end of therapy with FDG-PET should be evaluated using Deauville 5-point scale in order to significantly reduce the risk of false-positive scans.
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http://dx.doi.org/10.4103/wjnm.WJNM_42_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034538PMC
July 2018

Diffusion-Weighted and Perfusion-Weighted MRI to Evaluate Therapeutic Response in Lymphoma: A Comparison with FDG-PET/CT.

Acta Haematol 2018;139(2):74-76. Epub 2018 Jan 26.

Radiodiagnostic Unit No. 2, Department of Experimental and Clinical Biomedical Sciences, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

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http://dx.doi.org/10.1159/000485548DOI Listing
March 2019

Radiotherapy plus rituximab as first-line regimen for localized follicular lymphoma.

Leuk Lymphoma 2018 06 10;59(6):1420-1426. Epub 2017 Oct 10.

b Hematology Department , Azienda Ospedaliera Universitaria Careggi , Firenze , Italy.

Early-stage follicular lymphoma (FL) can be cured with involved-field radiotherapy (IF-RT); however, many patients relapse in non-irradiated areas. A combined association with chemotherapy could increase treatment efficacy, but toxic effects could be unacceptable. In vitro synergistic effect between rituximab (R) and RT has been observed, but clinical data are limited. We retrospectively analyzed 41 early-stage FL patients receiving R and IF-RT as first-line treatment. We administered R 375mg/m weekly for four courses, before or after IF-RT (median dose 24 Gy). Primary outcome was PFS, secondary endpoints were CR rate, OS and safety. All patients achieved CR, after a median follow-up of 46 months only three patients relapsed after 18, 26 and 42 months; estimated 5-year PFS was 90%. We suggest R in association with IF-RT could represent a feasible first-line treatment option for early-stage FL and could increase efficacy without additional toxicity compared to available data about RT alone.
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http://dx.doi.org/10.1080/10428194.2017.1387909DOI Listing
June 2018

Italian real-life experience with brentuximab vedotin: results of a large observational study of 40 cases of relapsed/refractory systemic anaplastic large cell lymphoma.

Haematologica 2017 11 3;102(11):1931-1935. Epub 2017 Aug 3.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Italy

Between November 2012 and July 2014, in accordance with national law 648/96, brentuximab vedotin was available in Italy for patients with relapsed systemic anaplastic large cell lymphoma outside a clinical trial context. A large Italian observational retrospective study was conducted on the use of brentuximab vedotin in everyday clinical practice to check whether clinical trial results are confirmed in a real-life context. The primary endpoint of this study was best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and safety profile. A total of 40 heavily pretreated patients were enrolled. Best response was observed after a median of four cycles in 77.5%: globally, 47.5% patients obtained a complete response, 64.2% in the elderly subset. The overall response rate was 62.5%. At the latest follow up, 15/18 patients are still in complete remission (3 with consolidation). The progression-free survival rate at 24 months was 39.1% and the disease-free survival rate at the same time was 54% (median not reached). All the long-term responders were aged <30 years at first infusion. The treatment was well tolerated even in this real-life context and no deaths were linked to drug toxicity. Brentuximab vedotin induces clinical responses quite rapidly, i.e. within the first four cycles of treatment in most responders, thus enabling timely use of transplantation. For patients ineligible for transplant or for those in whom a transplant procedure failed, brentuximab vedotin may represent a feasible effective therapeutic option in everyday clinical practice.
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http://dx.doi.org/10.3324/haematol.2017.171355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664397PMC
November 2017

Prognostic roles of absolute monocyte and absolute lymphocyte counts in patients with advanced-stage follicular lymphoma in the rituximab era: an analysis from the FOLL05 trial of the Fondazione Italiana Linfomi.

Br J Haematol 2015 May 29;169(4):544-51. Epub 2015 Mar 29.

Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

Recently, in an attempt to improve the discrimination power of the international prognostic index (IPI), patients with diffuse large B-cell lymphoma were evaluated to determine the prognostic roles of peripheral blood absolute monocyte count (AMC) and absolute lymphocyte count (ALC). Here, we analysed data of 428 patients with follicular lymphoma (FL) enrolled in a prospective, randomized trial (FOLL05 study) conducted by Fondazione Italiana Linfomi, to assess the impact of AMC and ALC on progression-free survival (PFS). All patients had been treated with one of three treatment combinations: (i) rituximab (R) plus cyclophosphamide, vincristine and prednisone; (ii) R plus cyclophosphamide, doxorubicin, vincristine and prednisone or (iii) R plus mitoxantrone and fludarabine. We showed that only AMC was a powerful predictor of PFS, and possibly overall survival, in patients with FL treated with combination chemotherapy regimens that contained R. The AMC can be used alone as a novel, simple factor that can predict survival outcome in patients with FL, independent of the immunochemotherapy regimen. It may therefore be widely used by clinicians, due to its simplicity and broad applicability. Additionally, it can be combined with other factors that determine the IPI or FLIPI, to increase the discriminating ability of these indices.
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http://dx.doi.org/10.1111/bjh.13332DOI Listing
May 2015

The prognostic value of positron emission tomography performed after two courses (INTERIM-PET) of standard therapy on treatment outcome in early stage Hodgkin lymphoma: A multicentric study by the fondazione italiana linfomi (FIL).

Am J Hematol 2015 Jun 10;90(6):499-503. Epub 2015 May 10.

Department of Hematology, Azienda Ospedaliera S. Croce E Carle, Cuneo, Italy.

This retrospective study included 246 patients with a new diagnosis of Hodgkin Lymphoma (HL) with a localized-stage (IA-IIA), consecutively admitted from January 2002 to December 2008, by twelve Italian hematological centers on behalf of Fondazione Italiana Linfomi (FIL). Patients were staged at baseline and after two cycles of chemotherapy with PET. All patients were treated with four cycles of ABVD followed by involved-field radiotherapy. No treatment change, based on PET-2 results was allowed. Endpoint of the study was the predictive role of PET-2 on 2-y failure-free survival (FFS). PET-2 was positive in 36 patients (15%) and negative in 210. After a mean follow-up of 46 (3-105) months 19/36 PET-2 positive patients progressed or relapsed and 17 achieved and maintained a CCR. The positive and negative predictive value of a PET2 was 53% and 95%, respectively. The sensibility, specificity and accuracy of PET2 were 65.5%, 92% and 89%, respectively. PET-2 positive scans were centrally reviewed according to the recently defined Deauville Criteria. Upon review the PPV and NPV was 73% and 96% overall. Factors with prognostic significance for progression in univariate analysis were a positive PET-2 (P = 0.000) and the presence of bulky disease (P < 0.01). In a multivariate analysis the only factor that affected negatively FFS was a positive PET-2 (P = 0.000). This study confirms that interim-PET could be considered a prognostic test also in early stage HL, but is unlikely to be a factor that will justify the change of therapeutical approach.
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http://dx.doi.org/10.1002/ajh.23994DOI Listing
June 2015

The use of anthracycline at first-line compared to alkylating agents or nucleoside analogs improves the outcome of salvage treatments after relapse in follicular lymphoma The REFOLL study by the Fondazione Italiana Linfomi.

Am J Hematol 2015 Jan 19;90(1):56-61. Epub 2014 Nov 19.

Division of Hematology, Spedali Civili, Brescia, Italy.

Follicular lymphoma (FL) patients experience multiple remissions and relapses and commonly receive multiple treatment lines. A crucial question is whether anthracyclines should be used at first-line or whether they would be better "reserved" for relapse and whether FL outcome can be optimized by definite sequences of treatments. Randomized trials can be hardly designed to address this question. In this retrospective multi-institutional study, time-to-next-treatment after first relapse was analyzed in 510 patients who had received either alkylating agents- or anthracycline- or nucleoside analogs-based chemotherapy with/without rituximab at first-line and different second-line therapies. After a median of 42 months, median time-to-next-treatment after relapse was 41 months (CI95%:34-47 months). After adjustment for covariates, first-line anthracycline-based chemotherapy with/without rituximab was associated with better time-to-next-treatment after any salvage than alkylating agents-based chemotherapy with/without rituximab or nucleoside analogs-based chemotherapy with/without rituximab (HR:0.74, P = 0.027). The addition of rituximab to first-line chemotherapy had no significant impact (HR:1.22, P = 0.140). Autologs stem cell transplantation performed better than any other salvage treatment (HR:0.53, P < 0.001). First-line anthracycline-based chemotherapy significantly improved time-to-next-treatment even in patients receiving salvage autologs stem cell transplantation (P = 0.041). This study supports the concept that in FL previous treatments significantly impact on the outcome of subsequent therapies. The outcome of second-line treatments, either with salvage chemoimmunotherapy or with autologs stem cell transplantation, was better when an anthracycline-containing regimen was used at first-line.
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http://dx.doi.org/10.1002/ajh.23872DOI Listing
January 2015

Comprehensive geriatric assessment is an essential tool to support treatment decisions in elderly patients with diffuse large B-cell lymphoma: a prospective multicenter evaluation in 173 patients by the Lymphoma Italian Foundation (FIL).

Leuk Lymphoma 2015 Apr 9;56(4):921-6. Epub 2014 Oct 9.

Department of Hematology, Spedali Civili , Brescia , Italy.

We performed a multicenter study to validate the concept that a simple comprehensive geriatric assessment (CGA) can identify elderly, non-fit patients with diffuse large B-cell lymphoma (DLBCL) in whom curative treatment is not better then palliation, and to analyze potential benefits of treatment modulation after further subdividing the non-fit category by CGA criteria. One hundred and seventy-three patients aged > 69 treated with curative or palliative intent by clinical judgement only were grouped according to CGA into fit (46%), unfit (16%) and frail (38%) categories. Two-year overall survival (OS) was significantly better in fit than in non-fit patients (84% vs. 47%; p < 0.0001). Survival in unfit and frail patients was not significantly different. Curative treatment slightly improved 2-year OS in unfit (75% vs. 45%) but not in frail patients (44% vs. 39%). CGA was confirmed as very efficient in identifying elderly patients with DLBCL who can benefit from a curative approach. Further efforts are needed to better tailor therapies in non-fit patients.
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http://dx.doi.org/10.3109/10428194.2014.953142DOI Listing
April 2015

Feasibility and safety of a reduced duration of therapy of colony-stimulating factor in a dose-dense regimen.

Support Care Cancer 2014 Sep 17;22(9):2557-61. Epub 2014 Apr 17.

Haematology Department, Azienda Ospedaliero Universitaria Careggi, Largo Brambilla, 3, 50139, Florence, Italy,

Purpose: The risk of febrile neutropenia (FN) in cancer patients receiving chemotherapy is mainly due to the type of chemotherapy regimen and the presence of specific risk factors in patients. The recent trend of using a dose-dense treatment schedule has enhanced the risk of FN. In the present prospective study, we evaluated the feasibility of a reduction of duration of therapy with colony-stimulating factor (G-CSF) in a dose-dense regimen.

Methods: Between June 2002 and December 2011, 107 patients with a new diagnosis of non-Hodgkin lymphoma (NHL) receiving dose-dense chemotherapy, every 14 days, were included in the study. The primary endpoint was defined as the completion of planned chemotherapy cycles as scheduled. Secondary endpoints were median number of administered G-CSF doses (vials), incidence of FN, hospitalization and toxicity.

Results: The planned chemotherapy cycles (primary endpoint) were completed by 84.1 % of patients. The median number of G-CSF (lenograstim) doses administered for each patient was 24 (range 10-35), which corresponds to a median of five vials (range 0-10) for each cycle. Grades 3-4 toxicities, related to G-CSF administration, included neutropenia and thrombocytopenia (14.0 and 1.9 %, respectively). No grades 3-4 bone pain was detected. The incidence of FN and hospitalization was 9.3 % (10/107) and 4.5 % (5/107), respectively.

Conclusions: Reduced dosage of G-CSF allows dose-dense chemotherapy scheduling, limits exposure to G-CSF and also represents an opportunity for cost savings.
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http://dx.doi.org/10.1007/s00520-014-2237-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118033PMC
September 2014

Rituximab plus liposomal pegylated doxorubicin in the treatment of primary cutaneous B-cell lymphomas.

Eur J Haematol 2014 Aug 4;93(2):129-36. Epub 2014 Apr 4.

Division of Haematology, University Hospital of Siena, Siena, Italy.

Background: In primary cutaneous B-cell lymphomas (PCBCL), radiotherapy - or surgery in a minority of cases - is the first-line treatment in follicle center lymphoma (PCFCL) and marginal zone B-cell lymphoma (PCMZL). Conversely, patients with multifocal skin involvement or relapsed/refractory disease deserve a systemic chemotherapy. In diffuse large B-cell lymphoma, leg type (PCLBCL-LT), due its poorer outcome, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like regimens are the most commonly used frontline, although hard to propose in elderly patients. In this regard, the association of rituximab (R) and pegylated liposomal doxorubicin (PLD) can be considered a promising, alternative approach.

Aims: Based on the favorable results reported with R and PLD in several recent trials, we decided to test efficacy and safety of this combination.

Methods: Twelve patients with PCBCL were treated with R plus PLD, and 7 had relapsed disease. Treatment plan consisted of 2 monthly cycles of R 375 mg/m(2) and PLD 20 mg/m(2) day 1;15, followed (in responders) by two cycles given only at day 1. All patients received prophylactic pyridoxine to prevent palmar-plantar erythrodysesthesia (PPE).

Results: Ten of 12 patients had a response (eight complete; two partial), remarkably 2/3 with PCLBCL-LT. Two patients did not respond (one progressive disease, PD, and one stable disease). Three patients died after a median follow-up of 56 months, two patients due to PD, and 1 due to a second neoplasm. Two out of 10 responders relapsed after 31 and 32 months, respectively. Hematological toxicity was negligible (one case of grade 2 neutropenia), as well as extra-hematological toxicity (two cases of grade 2 PPE).

Conclusions: These preliminary data suggest that R-PLD is effective and well tolerated in all subsets of PCBCL and may be offered frontline in indolent cases unsuitable for radiotherapy or surgery as well as in more aggressive cases with contraindications to CHOP-like regimens.
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http://dx.doi.org/10.1111/ejh.12315DOI Listing
August 2014

Identification of pharmacogenomic markers of clinical efficacy in a dose-dense therapy regimen (R-CHOP14) in diffuse large B-cell lymphoma.

Leuk Lymphoma 2014 Sep 24;55(9):2071-8. Epub 2014 Feb 24.

Sezione di Farmacologia Clinica e Oncologia, Dipartimento di Scienze della Salute, Università degli Studi di Firenze , Florence , Italy.

About 60% of patients with diffuse large B-cell lymphoma (DLBCL) may be cured by primary chemotherapy with an R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen. Most of the rest will die of the disease, mainly due to the occurrence of tumor drug resistance. Many efforts have been made to explain the molecular mechanisms of drug resistance in patients with cancer, including those with DLBCL. This exploratory study was designed to correlate the mRNA expression levels of candidate genes mainly involved in the doxorubicin pathway (ABCB1, GSTP1, TOPO2α, BCL2, PKCβII) with the outcome of 54 patients with DLBCL undergoing a dose-dense R-CHOP regimen. After multivariate analysis, high GSTP1 (p = 0.003) and TOPO2α (p = 0.02) gene expressions were associated with shorter overall survival and progression-free survival, respectively, suggesting that these genes may represent an unfavorable prognostic factor in the case of R-CHOP treatment. These biomarkers may be useful for selecting patients eligible for personalized chemotherapy after validation in an independent set.
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http://dx.doi.org/10.3109/10428194.2013.866665DOI Listing
September 2014

Primary lymphoma of bone: outcome and role of surgery.

Int Orthop 2013 Dec 24;37(12):2437-42. Epub 2013 Aug 24.

Orthopaedic Oncology Department, Careggi University Hospital, Largo Palagi 1, Firenze, Italy,

Purpose: Primary bone lymphoma is a rare disease. Little is reported about surgical procedures in these patients. We evaluated a single-centre consecutive series of 21 patients for results, prognostic factors and surgical treatment.

Methods: Patient ages ranged from 19 to 82 years. The most frequently affected site was the spine (six cases), followed by the ileum, femur and mandible (three cases each). Four patients were treated with chemotherapy and 17 with chemotherapy and radiation therapy. Six patients were affected by a pathological fracture. Surgery was performed in four patients (19%), in two cases before chemotherapy, in one case during chemotherapy and in one case after chemotherapy and radiotherapy. Five patients died within the range of three to 36 months after diagnosis. Average follow-up of the remaining patients was 62.8 (19-145) months.

Results: Overall survival was 74.2% at five years. The only positive prognostic factor was complete remission after chemotherapy. A trend for better survival was present for International Prognostic Index (IPI) score (P = 0.051), under 40 years of age (P = 0.10) and abnormal lactate dehydrogenase (LDH) values (P = 0.10), but it did not reach statistical significance.

Conclusions: Surgical treatment should be aimed at restoring function and eliminating pain while minimising delays in the chemotherapy schedule. When feasible, postponing surgery until after chemotherapy is advisable.
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http://dx.doi.org/10.1007/s00264-013-2055-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843197PMC
December 2013

Efficacy and safety of rituximab plus low-dose oral fludarabine and cyclophosphamide as first-line treatment of elderly patients with indolent non-Hodgkin lymphomas.

Leuk Lymphoma 2014 Apr 24;55(4):781-5. Epub 2014 Jan 24.

Unit of Hematology, University Hospital of Siena , Italy.

Indolent non-Hodgkin lymphomas (iNHLs) are B-cell neoplasms for which no consensus is available about optimal first-line therapy. Chemoimmunotherapy with fludarabine, cyclophospamide and rituximab is very effective, but may give severe hematological and non-hematological toxicity at standard doses, especially in elderly patients. In this phase II study, 25 untreated elderly patients with iNHL received rituximab (375 mg/m(2)) plus low-dose oral fludarabine (25 mg/m(2) for 4 consecutive days) and cyclophosphamide (150 mg/m(2) for 4 consecutive days) for four monthly cycles. Twenty-three patients were responsive (92%) and 12 patients achieved a complete remission (48%). Twenty-one patients (84%) were alive, median follow-up was 30 months and median event-free survival (EFS) was not reached. Patients who we previously treated with chemotherapy alone had a shorter EFS (median 20 months). Compliance was good, with mild toxicity. This regimen is effective for elderly patients with iNHL. The addition of rituximab results in long EFS without affecting toxicity.
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http://dx.doi.org/10.3109/10428194.2013.826354DOI Listing
April 2014

Bortezomib as salvage treatment for heavily pretreated relapsed lymphoma patients: a multicenter retrospective study.

Hematol Oncol 2013 Dec 29;31(4):179-82. Epub 2012 Oct 29.

Department of Hematology and Oncology 'L. and A. Seràgnoli', S. Orsola-Malpighi Hospital, University of Bologna, Italy.

Current treatments for non-Hodgkin lymphomas are not optimally effective. Among new agents, bortezomib seems to play a pivotal role in the regulation of several cell pathways involved in the development of lymphomas. After results were obtained with clinical trials, we aimed to observe treatment with bortezomib in everyday clinical practice. We performed a multicenter retrospective analysis to assess the efficacy of bortezomib in heavily pretreated (median number of previous therapies 4, range 2-6) lymphoma patients in an off-label setting. Bortezomib therapy was scheduled for 4-6 cycles (1.3 mg/m(2) biweekly). Data from 50 patients were collected: 22% had a complete remission, 26% obtained a partial response and the remaining 52% was non-responder. According to histotype, we observed an overall response rate (ORR) of 51.6% in mantle cell lymphomas, an ORR of 60% among follicular lymphoma patients, and an ORR of 50% in the indolent nonfollicular lymphomas. None of diffuse large B-cell lymphoma patients obtained a response. Extra-hematological toxicity was really mild, and peripheral neuropathy occurred in only 5 patients; hematological toxicity was grades 3-4 thrombocytopenia in nine patients and grades 3-4 neutropenia in only three patients. In conclusion, treatment with bortezomib as single agent resulted safe and effective in a subset of heavily pretreated lymphoma patients with usually poor outcome. New future hypotheses of investigation are indicated.
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http://dx.doi.org/10.1002/hon.2036DOI Listing
December 2013