[Show abstract][Hide abstract] ABSTRACT: It is known that extranodal head and neck diffuse large B cell lymphomas (eHN-DLBCL) can affect various anatomical structures what is not well-known, however, is whether they differ in terms of clinical presentation and outcome. Clinical data of the multi-institutional series, the largest of its kind as yet, has been analysed with the aim of answering these open questions and providing long-term follow-up information. Data from 488 patients affected by stage I/II eHN-DLBCL was collected: 300 of the Waldeyer’s Ring (WR), 38 of the parotid and salivary glands (PSG), 48 of the thyroid gland (TG), 53 of the nasal cavity and paranasal sinuses (NPS), 24 of the palate and oral cavity (POC) and 25 with more than one involved site. Different eHN-DLBCL arising have distinct characteristics at presentation. The intermediate high risk-modified IPI was 67 % in TG, 44 % in WR, 38 % in PSG and POC and 20 % in MS. The worst 5-year survival rate had TG-DLBCL (61 %) due to the 61 % of patients with a mIPI >1. The addition of radiotherapy (cRT) to remitters did not translate into a survival advantage (5-year disease-free survival of 67 % in the cRT group vs. 70 % in the other). Three of four central nervous system recurrences occurred in NPS-DLBCL. Survival of HN-DLBCL was inferior to nodal DLBCL. This study showed that eHN-DLBCL remitters have an inferior survival when compared to nodal DLBCL, and that the addition of cRT does not provide a survival advantage. Since the standard of care nowadays is chemo-immunotherapy, survival of these patients might have been improved.
Annals of Hematology 02/2014; 93(2). · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This phase I multicenter study was aimed at assessing the feasibility and safety of intravenous administration of third party-bone marrow derived Mesenchymal Stromal Cells (MSC) expanded in Platelet Lysate (PL) in 40 patients (15 children, 25 adults), experiencing steroid-resistant grade II-IV GvHD. Patients received a median of 3 MSC infusions after having failed conventional immunosuppressive therapy. A median cell dose of 1.5 x 10(6)/kg per infusion was administered. No acute toxicity was reported. Overall, 86 AE and SAE were reported in the study, most of which (72.1%) of infectious nature. Overall response rate, measured at 28 days following the last MSC injection, was 67.5%, with 27.5% complete response. The latter was significantly more frequent in patients exhibiting grade II GvHD as compared to higher grades (61.5% versus 11.1%, p=0.002), and was borderline significant in children as compared to adults (46.7 vs 16.0%, p=0.065). Overall survival at 1 and 2 years from the first MSC administration was 50.0% and 38.6%, with a median survival time of 1.1 years. In conclusion, MSC can be safely administered on top of conventional immunosuppression for steroid resistant GvHD treatment. Eudract Number 2008-007869-23, NCT01764100.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2013; · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six-eight rituximab infusions and four-six intensive chemotherapy courses (attenuated in patients aged >55 years) with high-dose methotrexate, fractionated ifosfamide/cyclophosphamide, other drugs in rotation, and intrathecal chemoprophylaxis. One-hundred five patients were treated (median age 47 years, range 17-78 years); 48% had Burkitt leukemia, 25% were older than 60 years, 37% exhibited an Eastern Cooperative Oncology Group performance score >1, and 14% were HIV-positive. Complete response rate and 3-year overall and disease-free survival were 79%, 67% and 75%, respectively, ranging from 100% to 45% for survival (P=0.000) and from 100% to 60% for disease-free survival (P=0.01) in patients with low, intermediate and high adapted international prognostic index. In multivariate analysis, only age (< vs >60 years) and performance status (0-1 vs >1) retained prognostic significance, identifying three risk groups with overall and disease-free survival probabilities of 88% and 87.5%, 57% (P=0.0000) and 70.5%, 20% and 28.5% (P=0.0001), respectively. Relapse rate was only 7% in patients treated with an intercycle interval <25 days. This regimen achieved 100% curability in patients with low adapted international prognostic index (21% of total), and very close to 90% in patients aged ≤60 years with performance score 0-1 (48% of total). Rapid Burkitt lymphoma/leukemia diagnosis with prompt patient referral to prevent clinical deterioration, and careful supervision of treatment without chemotherapy delay can achieve outstanding therapeutic results. ClinicalTrial.gov ID, NCT01290120.
[Show abstract][Hide abstract] ABSTRACT: The coexistence or the development of Philadelphia chromosome-negative myeloproliferative neoplasms after a lymphoproliferative disease in the same patient is an extremely rare event. We report the case of a 72-year-old man who developed JAK2V617F polycythemia vera 3 years after the diagnosis and treatment of primary diffuse large B cell non-Hodgkin's lymphoma of the central nervous system. We also review the literature regarding the pathogenesis underlying the association of myeloproliferative and lymphoproliferative chronic disorders.
[Show abstract][Hide abstract] ABSTRACT: Acute myeloid leukemia (AML) with deranged core-binding factor beta (CBFβ) is usually associated with a favourable prognosis with 50-70% of patients cured using contemporary treatments. We analyzed the prognostic significance of clinical features on 58 patients with CBFβ-AML aged ≤60 years. Increasing age was the only predictor for survival (p<0.001), with an optimal cut-point at 43 years. White blood cells (WBC) at diagnosis emerged as an independent risk factor for relapse incidence (p=0.017), with 1.1% increase of hazard for each 1.0x10(9) /L WBC increment. KIT mutations lacked prognostic value for survival and showed only a trend for relapse incidence (p=0.069).
American Journal of Hematology 04/2013; · 4.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Givinostat, a histone-deacetylase inhibitor (HDACi), inhibits proliferation of cells bearing the JAK2 V617F mutation and has shown significant activity with good tolerability in patients with chronic myeloproliferative neoplasms (MPN). In this multicentre, open-label, phase II study, 44 patients with polycythaemia vera (PV), unresponsive to the maximum tolerated doses (MTD) of hydroxycarbamide (HC), were treated with Givinostat (50 or 100 mg/d) in combination with MTD of HC. The European LeukaemiaNet response criteria were used to assess the primary endpoint after 12 weeks of treatment. Complete or partial response was observed in 55% and 50% of patients receiving 50 or 100 mg of Givinostat, respectively. Control of pruritus was observed in 64% and 67% of patients in the 50 and 100 mg groups, respectively. The combination of Givinostat and HC was well tolerated: eight patients (18%) discontinued, four in each treatment arm; grade 3 adverse events were reported in one patient (4·5%) in each treatment arm. The combined use of Givinostat and HC was safe and clinically effective in HC-unresponsive PV patients.
British Journal of Haematology 04/2013; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16-35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.
[Show abstract][Hide abstract] ABSTRACT: This prospective study compared diagnostic and prognostic value of conventional cytologic (CC) examination and flow cytometry (FCM) of baseline samples of cerebrospinal fluid (CSF) in 174 patients with newly diagnosed aggressive non-Hodgkin lymphoma (NHL). FCM detected a neoplastic population in the CSF of 18 of 174 patients (10%), CC only in 7 (4%; P < .001); 11 patients (14%) were discordant (FCM(+)/CC(-)). At a median follow-up of 46 months, there were 64 systemic progressions and 10 CNS relapses, including 2 patients with both systemic and CNS relapses. Two-year progression-free and overall survival were significantly higher in patients with FCM(-) CSF (62% and 72%) compared with those FCM(+) CSF (39% and 50%, respectively), with a 2-year CNS relapse cumulative incidence of 3% (95% confidence interval [CI], 0-7) versus 17% (95% CI, 0-34; P = .004), respectively. The risk of CNS progression was significantly higher in FMC(+)/CC(-) versus FCM(-)/CC(-) patients (hazard ratio = 8.16, 95% CI, 1.45-46). In conclusion, FCM positivity in the CSF of patients with high-risk NHL is associated with a significantly higher CNS relapse risk and poorer outcome. The combination of IV drugs with a higher CNS bioavailability and intrathecal chemotherapy is advisable to prevent CNS relapses in FCM(+) patients.
[Show abstract][Hide abstract] ABSTRACT: Consolidation radiotherapy (cRT) in patients with stage I/II diffuse large B-cell lymphoma of the Waldeyer's ring (WR-DLBCL) in complete remission (CR) after induction chemotherapy (CHT) is often associated with relevant acute and chronic toxicity, and its impact on survival remains to be defined. A total of 184 patients in CR after anthracycline-based chemotherapy were retrospectively analyzed: 62 underwent CHT alone (CHT group), while 122 (66%) patients were referred to cRT (CHT + RT group). After a median follow-up of 54 months, 36 patients (20%) experienced relapse: 19% in the CHT group and 20% in the CHT + RT group. At the time of analysis 47 (76%) CHT patients and 97 (80%) CHT + RT patients were alive. Five-year overall survival (OS), disease-free survival (DFS) and lymphoma-specific survival (LSS) were 80%, 74% and 86%, respectively. Five-year OS was significantly prolonged in the CHT + RT group, while DFS and LSS were similar between groups. This discrepancy was attributed to a high percentage of deaths due to unrelated causes in CHT patients. cRT does not prolong LSS in patients with early-stage WR-DLBCL in CR after anthracycline-containing chemotherapy. An international confirmatory trial is warranted.
[Show abstract][Hide abstract] ABSTRACT: Hydroxyurea (Hydroxycarbamide; HU) is commonly used for the long-term treatment of patients with Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs). It is considered a first-choice agent for the treatment of these disorders as underlined by the European Leukemia Net Consensus Conference , although it is formally approved for this indication in some countries only. The drug is reportedly well tolerated in the large majority of subjects, although systemic and/or localized toxicities have been reported. Consensus criteria for definition of "intolerance" to HU have been described;patients who develop intolerance are candidate for second-line therapy and, more recently, for investigational drugs. However, no epidemiologic information about the occurrence of the most clinically significant HU-associated adverse events is yet available. In this study, the authors report on a multicenter series of 3,411 patients who were treated with HU among which 184, accounting for 5% of total, developed significant drug-related toxicities. These data provide an estimate of the frequency and a detailed characterization of clinically significant HU-related toxicities; these information have relevance for the management of MPN patients who require second-line therapy after developing HU-related intolerance.
American Journal of Hematology 02/2012; 87(5):552-4. · 4.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the possible involvement of vascular damage in the pathogenesis of Alzheimer's disease (AD), by assessment of plasma levels of tissue factor pathway inhibitor (TFPI), a serine protease inhibitor induced by endothelial injury, and homocysteine (Hcy), a known risk factor for cerebrovascular disorders, folate levels were also measured. 110 probable AD, 38 mild cognitive impairment, 31 patients affected by idiopathic Parkinson's disease (without dementia) and 100 healthy controls, who displayed no vascular disorders were enrolled. TFPI and Hcy were significantly higher in AD patients with respect to other groups. The levels of TFPI and Hcy were positively correlated in hyperhomocysteinemic AD and mild cognitive impairment subjects, and were negatively correlated with folate levels. Our findings suggest that an impairment of endothelial function associated with high Hcy levels may occur in AD patients, despite the absence of manifest cerebrovascular lesions. Therefore, TFPI may represent a candidate marker of endothelial damage in AD and might be used for the identification and monitoring of patients that would benefit from folate supplementation treatment.
Neurobiology of aging 02/2012; 33(2):226-33. · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypomethylating drugs are useful and have been approved for the treatment of myelodysplastic syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS, have included only a small number of patients with CMML, and there are just a few specific reports on CMML patients. The Azacitidine is actually authorised for the treatment of CMML patients with 10-29% marrow blasts without myeloproliferative disorder, who are not eligible for haematopoietic stem cell transplantation. This hypomethylating agent in MDS is known for causing transient cytopenias, most often occurring during the first 2 cycles. Here we report a case of an atypical delayed and prolonged hematologic toxicity during Azacitidine treatment in a CMML patient; furthermore we also reviewed the literature regarding the efficacy of the drug and the management of hematologic adverse effects, in term of dose adjustments or alternative schedule of administration, in specific CMML setting.
Mediterranean Journal of Hematology and Infectious Diseases 01/2012; 4(1):e2012017.
[Show abstract][Hide abstract] ABSTRACT: Circulating endothelial cells (CECs) have been studied in cardiovascular disorders and as a marker of angiogenetic activity; clinical applications are limited by a lack of consensus on their phenotypic identification and quantification. We determined CECs in essential thrombocythemia (ET) patients, to investigate their possible pathogenetic role. We considered CECs as CD146⁺/CD45⁻ nucleated cells, detected in peripheral blood from 21 healthy controls and 39 ET patients, performing a combination of pre-enrichment of CD146⁺ circulating cells and multiparametric flow cytometry measurement (FCM). Levels of CECs in ET patients were higher with respect to controls (median 2844 CECs/mL vs. 121.3 CECs/mL, P < 0.0001). Apparently hydroxyurea treatment did not influence the levels of CECs. As another established marker of endothelial activation, we also assessed soluble E-selectin (sE-selectin) levels in 31 of the ET patients and compared with 39 healthy volunteers: median sE-selectin level in ET patients was 35.3 ng/mL, higher with respect to controls (24.48 ng/mL), P = 0.0369. Our data suggest that endothelium in ET is activated, reflecting a significant role of angiogenesis in this disorder and suggesting an important endothelial contribution in the hypercoagulable state of ET patients.
American Journal of Hematology 11/2011; 87(3):319-20. · 4.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prognostic significance of CD20 expression in acute lymphoblastic leukemia has been investigated in children and adults but is still a subject of debate. The aim of our study was to correlate CD20 expression with clinical-biological characteristics and outcome in 172 Philadelphia chromosome negative patients prospectively treated in a multicenter trial introducing the molecular evaluation of minimal residual disease for therapeutic purposes. We considered 20% as the threshold for CD20 positivity. Complete remission rate, minimal residual disease negativity rate at weeks 10, 16 and 22, and disease-free and overall survival were similar among CD20-positive and -negative patients, even considering minimal residual disease results and related therapeutic choices. Our study failed to demonstrate any prognostic significance for CD20 expression in Philadelphia chromosome negative acute lymphoblastic leukemia. This conclusion is supported for the first time by a comparable minimal residual disease response rate among CD20-positive and -negative and positive patients.
[Show abstract][Hide abstract] ABSTRACT: Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterized by elevated platelet counts and increased incidence of thrombosis and haemorrhage. Median age at diagnosis is 65-70 years. Life expectancy is similar to that of the healthy population. Symptoms and complications may affect quality of life (QoL); in particular, in elderly patients ET may represent an additional burden. We performed a survey in 494 elderly ET patients to evaluate patient-reported outcomes (PROs). Comorbidities were present in 305 (62%) patients. Factorial analysis based on survey items representing psychological aspects of daily life identified an "attitude domain" with four clusters of patients: (A) very pessimistic (n = 99), (B) pessimistic (n = 101), (C) optimistic (n = 90), and (D) very optimistic (n = 107). Patients in cluster A had more comorbidities (p = 0.003) while patients in cluster D required fewer medical visits and were less disturbed by medications (p < 0.0001). Independent factors predicting Short-Form Health Survey, version 2 physical QoL were grade of optimism (p < 0.0001), gender (p = 0.007), and Charlson comorbidity index (p < 0.0001)). Grade of optimism and disturbances related to medication predicted mental QOL (p < 0.0001). In conclusion, physicians should take into consideration PROs, as "attitude" is associated with physical and mental QoL. Treatment should be tailored to patients' needs according to comorbidities, lifestyle, and psychological conditions.
Annals of Hematology 10/2011; 91(4):527-32. · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Invasive fungal infections (IFIs) are considered a major problem among patients undergoing acute leukaemia (AL) induction treatment. PROphylaxis of Fungal invasive Infections in Leukaemia-Caspofungin (PROFIL-C) is a multicentre study aiming to assess the comparative yield of using caspofungin versus standard policy (SP) regimens and the overall impact of IFI in routine clinical care conditions.
All AL patients receiving IFI prophylaxis according to local SP were prospectively included in the study by Northern Italy Leukaemia Group (NILG) centres. To allow the comparison of caspofungin versus SP regimens as prophylaxis strategies, caspofungin treatment was assigned via a centralized randomized procedure. The study was registered at http://www.clinicaltrial.gov (NCT00501098).
Over a 2 year period, 175 patients were included. The overall incidence of IFI was 32/175 (18.3%) [10/175 (5.7%) probable/proven and 22/175 (12.6%) possible], with no statistically significant differences between caspofungin-based versus SP-based regimens [overall: 15/93 (16.1%) versus 17/82 (20.7%), relative risk (RR) 0.78, 95% confidence interval (CI) 0.42-1.46; probable/proven: 7/93 (7.5%) versus 3/82 (3.7%), RR 2.06, 95% CI 0.55-7.7; possible: 8/93 (8.6%) versus 14/82 (17.1%), RR 0.5, 95% CI 0.22-1.14]. Only one IFI-related death was recorded (10%).
The incidence and mortality of IFI were lower than expected in this strictly sequential cohort representative of the routine care in the NILG network. The efficacy and safety of caspofungin were similar to other prophylactic regimens.
Journal of Antimicrobial Chemotherapy 09/2011; 66(9):2140-5. · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated as the new standard of treatment for advanced Hodgkin's lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).
We randomly assigned 331 patients with previously untreated and unfavorable Hodgkin's lymphoma (stage IIB, III, or IV, or an international prognostic score of ≥3 on a scale of 0 to 7, with higher scores indicating increased risk), to receive either BEACOPP or ABVD, each followed by local radiotherapy when indicated. Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program. The median follow-up period was 61 months.
The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P=0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P=0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group.
Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term clinical outcome did not differ significantly between the two regimens. (Funded by Fondazione Michelangelo; ClinicalTrials.gov number, NCT01251107.).
New England Journal of Medicine 07/2011; 365(3):203-12. · 51.66 Impact Factor