Città della Pieve, Italy
Città della Pieve, Italy

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Vitolo U.,Hematology | Chiappella A.,Hematology | Franceschetti S.,University of Piemonte Orientale | Carella A.M.,University of Genoa | And 21 more authors.
The Lancet Oncology | Year: 2014

Background: Up to 40% of elderly patients with untreated diffuse large B-cell lymphoma (DLBCL) given a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP21) relapse or develop refractory disease. Lenalidomide has high activity in relapsed or refractory aggressive B-cell lymphomas. In phase 2 of the REAL07 trial, we aimed to establish the safety and efficacy of the combination of lenalidomide and R-CHOP21 in elderly patients with untreated DLBCL. Methods: REAL07 was an open-label, multicentre trial that was done in 13 centres in Italy and one in Germany. Eligible patients were aged 60-80 years; had newly diagnosed, untreated, CD20-positive, Ann Arbor stage II-IV DLBCL or grade 3b follicular lymphoma; had an Eastern Cooperative Oncology Group performance status of 0-2; had an International Prognostic Index (IPI) risk of low-intermediate, intermediate-high, or high; and were fit according to comprehensive geriatric assessment. Participants were to receive 15 mg oral lenalidomide on days 1-14 of six 21-day cycles, and standard doses of R-CHOP21 chemotherapy (375 mg/m2 intravenous rituximab, 750 mg/m2 intravenous cyclophosphamide, 50 mg/m2 intravenous doxorubicin, and 1·4 mg/m2 intravenous vincristine on day 1, and 40 mg/m2 oral prednisone on days 1-5). The primary endpoint was frequency of overall response (complete response [CR] and partial response [PR]), which was assessed by 18F-fluorodeoxyglucose (18F-FDG) PET at the end of the treatment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00907348. Findings: 49 patients were included in phase 2: nine had been enrolled into phase 1 between Oct 23, 2008, and June 4, 2009, and had received the maximum tolerated dose of 15 mg lenalidomide; and 40 were enrolled into phase 2 between April 28, 2010, and June 3, 2011. 45 patients (92%, 95% CI 81-97) achieved a response (42 [86%] CR; three [6%] PR). Three patients (6%) did not respond and one (2%) died for reasons unrelated to treatment or disease. 277 (94%) of 294 planned cycles of lenalidomide and R-CHOP21 were completed. Grade 3-4 neutropenia was reported in 87 cycles (31%), grade 3-4 leukopenia in 77 (28%), and grade 3-4 thrombocytopenia in 35 (13%). No grade 4 non-haematological adverse events were reported. No patients died during the study as a result of toxic effects. Interpretation: Lenalidomide with R-CHOP21 is effective and safe in elderly patients with untreated DLBCL. Funding: Fondazione Italiana Linfomi and Celgene. © 2014 Elsevier Ltd.


Palanca-Wessels M.C.A.,Fred Hutchinson Cancer Research Center | Czuczman M.,Roswell Park Cancer Institute | Salles G.,University of Lyon | Assouline S.,Jewish General Hospital | And 17 more authors.
The Lancet Oncology | Year: 2015

Background: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). Methods: In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m2. Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. Findings: Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Interpretation: Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Funding: Genentech. © 2015 Elsevier Ltd.


Krop I.E.,Dana-Farber Cancer Institute | Lin N.U.,Dana-Farber Cancer Institute | Blackwell K.,Duke University | Guardino E.,Genentech | And 6 more authors.
Annals of Oncology | Year: 2015

Background: We characterized the incidence of central nervous system (CNS) metastases after treatment with trastuzumab emtansine (T-DM1) versus capecitabine-lapatinib (XL), and treatment efficacy among patients with pre-existing CNS metastases in the phase III EMILIA study. Patients and methods: In EMILIA, patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer previously treated with trastuzumab and a taxane were randomized to T-DM1 or XL until disease progression. Patients with treated, asymptomatic CNS metastases at baseline and patients developing postbaseline CNS metastases were identified retrospectively by independent review; exploratory analyses were carried out. Results: Among 991 randomized patients (T-DM1 = 495; XL = 496), 95 (T-DM1 = 45; XL = 50) had CNS metastases at baseline. CNS progression occurred in 9 of 450 (2.0%) and 3 of 446 (0.7%) patients without CNS metastases at baseline in the T-DM1 and XL arms, respectively, and in 10 of 45 (22.2%) and 8 of 50 (16.0%) patients with CNS metastases at baseline. Among patients with CNS metastases at baseline, a significant improvement in overall survival (OS) was observed in the T-DM1 arm compared with the XL arm [hazard ratio (HR) = 0.38; P = 0.008; median, 26.8 versus 12.9 months]. Progression-free survival by independent review was similar in the two treatment arms (HR = 1.00; P = 1.000; median, 5.9 versus 5.7 months). Multivariate analyses demonstrated similar results. Grade ≥3 adverse events were reported in 48.8% and 63.3% of patients with CNS metastases at baseline administered T-DM1 and XL, respectively; no new safety signals were observed. Conclusion: In this retrospective, exploratory analysis, the rate of CNS progression in patients with HER2-positive advanced breast cancer was similar for T-DM1 and for XL, and higher overall in patients with CNS metastases at baseline compared with those without CNS metastases at baseline. In patients with treated, asymptomatic CNS metastases at baseline, T-DM1 was associated with significantly improved OS compared with XL. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Coiffier B.,Hematology | Osmanov E.A.,Cancer Research Center | Hong X.,Fudan University | Scheliga A.,Instituto Nacional Of Cancer | And 15 more authors.
The Lancet Oncology | Year: 2011

Background: Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. Methods: In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m2, administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845. Findings: Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [<1%] patient and 12 [4%] patients, respectively), nausea or vomiting (two [<1%] patients and 10 [3%] patients, respectively) and thrombocytopenia (two [<1%] patients and 10 [3%] patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients [2%]) and pyrexia (six patients [2%]) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment. Interpretation: Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients. Funding: Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc. © 2011 Elsevier Ltd.


Filippi A.R.,University of Turin | Piva C.,University of Turin | Giunta F.,Nuclear Medicine | Bello M.,Nuclear Medicine | And 8 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2013

Purpose To investigate the role of radiation therapy (RT) in patients affected with primary mediastinal B-cell lymphoma (PMBCL) with residual 18fluorodeoxyglucose positron emission tomography ( 18FDG-PET)-positive disease after rituximab chemotherapy (R-CT). Methods and Materials Thirty-seven patients treated with R-CT and RT, all with 18FDG-PET scan at diagnosis and before RT, were included. All 18FDG-PET scans were reviewed, and responses were classified according to the Deauville 5-point scoring system. Outcomes measures were overall survival (OS) and progression-free survival (PFS), estimated for the whole cohort and for subgroups according to 18FDG-PET score after R-CT. Results The median follow-up time was 40.9 months. Three patients were assigned to Deauville score 1 (8.1%), 9 to score 2 (24.3%), 7 to score 3 (19%), 14 to score 4 (37.8%), and 4 to score 5 (10.8%). After RT, all patients with score 3-4 experienced a complete response (CR). Among patients with score 5, 1 was in CR (25%), 2 had persistent positivity (50%), and 1 showed progressive disease (25%). A total of 4 patients experienced progression or relapse: 1 of 33 (3%) with scores 1-4, and 3 of 4 (75%) with score 5. The 3-year OS and PFS of the whole cohort were 89.8% and 88.7%, respectively. OS was significantly different between scores 1-3 and scores 4-5 (100% vs 77% at 3 years, P<.05). Patients with a score of 5 had a significantly worse outcome than did all other patients (OS at 2 years, 33.3% vs 100%). Conclusions Approximately 50% of PMBCL patients show residual disease at 18FDG-PET scan after R-CT. RT is able to convert to CR approximately 85% of these patients, but those with a Deauville score of 5 (10%) appear at high risk of progression and death, and they might be candidates for intensified programs. © 2013 Elsevier Inc.


Xiong Q.,Cardiovascular Division | Xiong Q.,Center for Magnetic Resonance Research | Ye L.,Cardiovascular Division | Zhang P.,Cardiovascular Division | And 10 more authors.
Circulation | Year: 2013

Background-: The use of cells derived from human induced pluripotent stem cells as cellular therapy for myocardial injury has yet to be examined in a large-animal model. Methods and Results-: Immunosuppressed Yorkshire pigs were assigned to 1 of 3 groups: A myocardial infarction group (MI group; distal left anterior descending coronary artery ligation and reperfusion; n=13); a cell-treatment group (MI with 4×10 vascular cells derived from human induced pluripotent stem cells administered via a fibrin patch; n=14); and a normal group (n=15). At 4 weeks, left ventricular structural and functional abnormalities were less pronounced in hearts in the cell-treated group than in MI hearts (P<0.05), and these improvements were accompanied by declines in scar size (10.4±1.6% versus 8.3±1.1%, MI versus cell-treatment group, P<0.05). The cell-treated group displayed a significant increase in vascular density and blood flow (0.83±0.11 and 1.05±0.13 mL·min·g, MI versus cell-treatment group, P<0.05) in the periscar border zone (BZ), which was accompanied by improvements in systolic thickening fractions (infarct zone,-10±7% versus 5±5%; BZ, 7±4% versus 23±6%; P<0.05). Transplantation of vascular cells derived from human induced pluripotent stem cells stimulated c-kit cell recruitment to BZ and the rate of bromodeoxyuridine incorporation in both c-kit cells and cardiomyocytes (P<0.05). Using a magnetic resonance spectroscopic saturation transfer technique, we found that the rate of ATP hydrolysis in BZ of MI hearts was severely reduced, and the severity of this reduction was linearly related to the severity of the elevations of wall stresses (r=0.82, P<0.05). This decline in BZ ATP utilization was markedly attenuated in the cell-treatment group. Conclusions-: Transplantation of vascular cells derived from human induced pluripotent stem cells mobilized endogenous progenitor cells into the BZ, attenuated regional wall stress, stimulated neovascularization, and improved BZ perfusion, which in turn resulted in marked increases in BZ contractile function and ATP turnover rate. © 2013 American Heart Association, Inc.


Hentrich M.,Ludwig Maximilians University of Munich | Hoffmann C.,University of Hamburg | Mosthaf F.,Hematology | Muller M.,Vivantes Auguste Viktoria Hospital | And 3 more authors.
Annals of Hematology | Year: 2014

AIDS-related aggressive B cell lymphoma (HIV-NHL) is the second most common HIV-associated malignancy. In contrast, Hodgkin-lymphoma (HL) is one of the most common non-AIDS-defining malignancies. Current evidence-based recommendations for the treatment of HIV-associated lymphoma (HIV-lymphoma) are not available. A panel of experts in the field of HIV-related lymphoma performed literature searches of the PubMed, Medline, and Cochrane databases. The consensus process was carried out as an e-mail and meeting-based discussion group. Six cycles of R-CHOP or R-EPOCH are standard of care for patients (pts) with diffuse large B cell lymphoma (DLBCL). Pts with Burkitt lymphoma and good performance status should receive dose-intensive regimens such as the GMALL B-ALL/NHL protocol. Standard therapy has not been defined for pts with plasmablastic and primary effusion lymphoma. Pts with lymphoma in sensitive relapse should receive high-dose chemotherapy followed by autologous stem cell transplantation. Stage- and risk adapted treatment yields high remission and survival rates in pts with HIV-HL similar to those achieved in HIV-negative HL pts. Combination antiretroviral therapy (cART) should be applied concurrently to chemotherapy provided that pharmacokinetic interactions are being considered. Pts with HIV-lymphoma should usually be treated in an identical manner to HIV-negative patients. © 2014 Springer-Verlag.


Gozzetti A.,Hematology | Cerase A.,Unit NINT Neuroimaging and Neurointervention
Central Nervous System Agents in Medicinal Chemistry | Year: 2014

Central nervous system localization of multiple myeloma (CNS-MM) accounts for about 1% of all MM. Treatment is still unsatisfactory. Many treatments have been described in the literature: chemotherapy (CHT), intrathecal therapy (IT), and radiotherapy (RT), with survivals reported between one month and six months. Recent drugs such as the immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib) have changed the treatment of patients with MM, both younger and older, with a significant improvement in response and survival. The activity of new drugs in CNSMM has been reported but is still not well known. Bortezomib does not cross the blood brain barrier (BBB), and IMID’s seem to have only a minimal crossover. The role of novel agents in CNS MM management will be discussed as well as the potential role of other new immunomodulatory drugs (pomalidomide) and proteasome inhibitors that seem to cross the BBB and hold promise into the treatment of this rare and still incurable localization of the disease. © 2014 Bentham Science Publishers.


Risitano A.M.,Hematology | Marotta S.,Hematology
Seminars in Immunology | Year: 2016

The introduction in the clinic of anti-complement agents represented a major achievement which gave to physicians a novel etiologic treatment for different human diseases. Indeed, the first anti-complement agent eculizumab has changed the treatment paradigm of paroxysmal nocturnal hemoglobinuria (PNH), dramatically impacting its severe clinical course. In addition, eculizumab is the first agent approved for atypical Hemolytic Uremic Syndrome (aHUS), a life-threatening inherited thrombotic microangiopathy. Nevertheless, such remarkable milestone in medicine has brought to the fore additional challenges for the scientific community. Indeed, the list of complement-mediated anemias is not limited to PNH and aHUS, and other human diseases can be considered for anti-complement treatment. They include other thrombotic microangiopathies, as well as some antibody-mediated hemolytic anemias. Furthermore, more than ten years of experience with eculizumab led to a better understanding of the individual steps of the complement cascade involved in the pathophysiology of different human diseases. Based on this, new unmet clinical needs are emerging; a number of different strategies are currently under development to improve current anti-complement treatment, trying to address these specific clinical needs. They include: (i) alternative anti-C5 agents, which may improve the heaviness of eculizumab treatment; (ii) broad-spectrum anti-C3 agents, which may improve the efficacy of anti-C5 treatment by intercepting the complement cascade upstream (i.e., preventing C3-mediated extravascular hemolysis in PNH); (iii) targeted inhibitors of selective complement activating pathways, which may prevent early pathogenic events of specific human diseases (e.g., anti-classical pathway for antibody-mediated anemias, or anti-alternative pathway for PNH and aHUS). Here we briefly summarize the status of art of current and future complement inhibition for different complement-mediated anemias, trying to identify the most promising approaches for each individual disease. © 2016 Elsevier Ltd

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