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In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

In this randomized multicenter study of 136 patients, 6 courses of CHOP (cyclo-phosphamide/doxorubicin/vincristine/prednisone) followed by rituximab (CHOP-R) were compared with rituximab-supplemented high-dose sequential chemotherapy with autografting (R-HDS) to assess the value of intensified chemo-therapy as a first-line treatment for high-risk follicular lymphoma (FL) after the introduction of monoclonal antibodies. The analysis was intention to treat with event-free survival (EFS) as the primary endpoint. Complete remission (CR) was 62% with CHOP-R and 85% with R-HDS (P < .001). At a median follow-up (MFU) of 51 months, the 4-year EFS was 28% and 61%, respectively (P < .001), with no difference in overall survival (OS). Molecular remission (MR) was achieved in 44% of CHOP-R and 80% of R-HDS patients (P < .001), and was the strongest independent outcome predictor. Patients relapsing after CHOP-R underwent salvage R-HDS in 71% of cases. Salvage R-HDS had an 85% CR rate and a 68% 3-year EFS (MFU, 30 months). We conclude that (1) achieving MR is critical for effective disease control, regardless of which treatment is used; (2) R-HDS ensures superior disease control and molecular outcome than CHOP-R, but no OS improvement; and (3) CHOP-R failures have a good outcome after salvage R-HDS, suggesting that relapsed/refractory FL could be the most appropriate setting for R-HDS–like treatments. This trial was registered at www.clinicaltrials.gov as no. NCT00435955.

The Integruppo Italiano Linfomi (IIL) carried out a study to assess the outcomes of splenic marginal zone lymphoma and to identify prognostic factors in 309 patients. The 5-year cause-specific survival (CSS) rate was 76%. In univariate analysis, the parameters predictive of shorter CSS were hemoglobin levels below 12 g/dL (P < .001), albumin levels below 3.5 g/dL (P = .001), International Prognostic Index (IPI) scores of 2 to 3 (P < .001), lactate dehydrogenase (LDH) levels above normal (P < .001), age older than 60 years (P = .01), platelet counts below 100 000/μL (P = .04), HbsAg-positivity (P = .01), and no splenectomy at diagnosis (P = .006). Values that maintained a negative influence on CSS in multivariate analysis were hemoglobin level less than 12 g/dL, LDH level greater than normal, and albumin level less than 3.5 g/dL. Using these 3 variables, we grouped patients into 3 prognostic categories: low-risk group (41%) with no adverse factors, intermediate-risk group (34%) with one adverse factor, and high-risk group (25%) with 2 or 3 adverse factors. The 5-year CSS rate was 88% for the low-risk group, 73% for the intermediate-risk group, and 50% for the high-risk group. The cause-specific mortality rate (x 1000 person-years) was 20 for the low-risk group, 47 for the intermediate-risk group, and 174 for the high-risk group. This latter group accounted for 54% of all lymphoma-related deaths. In conclusion, with the use of readily available factors, this prognostic index may be an effective tool for evaluating the need for treatment and the intensity of therapy in an individual patient. © 2006 by The American Society of Hematology.

Background: Optimal therapeutic management of intravascular lymphoma (IVL) lacks precise guidelines. Patients and methods: The clinico-pathological features of 38 HIV-negative patients with IVL were reviewed to define efficacy of chemotherapy in these malignancies. Clinical characteristics of 22 patients treated with chemotherapy and of 16 untreated patients were compared in order to understand better the impact and causes of potential patient selection. Results: Median age was 70 years (range 34-90), with a male/female ratio of 0.9; 23 (61%) patients had Eastern Cooperative Oncology Group performance status (ECOG-PS) >1; 21 (55%) had systemic symptoms. Cutaneous lesions and anemia were significantly more common among patients treated with chemotherapy; central nervous system (CNS) and renal involvement were significantly more common among untreated patients. Chemotherapy was associated with a response rate of 59% and a 3-year overall survival of 33 ± 11%. Five of six patients with CNS involvement received chemotherapy: four of them died early; only one patient, treated with adriamycin, cyclophosphamide, vincristine, methotrexate, bleomycin and prednisolone (MACOP-B) followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), was alive at 19 months. High-dose chemotherapy supported by ASCT was indicated at diagnosis in another patient (43 years of age, stage I), who was alive at 71 months, and at relapse after cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in two patients who died early after transplantation. PS ≤1, disease limited to the skin, stage I, and use of chemotherapy were independently associated with better outcome. Conclusions: Anthracycline-based chemotherapy is the standard treatment for IVL. However, survival is disappointing, with a relevant impact of diagnostic delay and lethal complications. More intensive combinations, containing drugs with higher CNS bioavailability, are needed in cases with brain involvement, and the role of high-dose chemotherapy supported by ASCT should be further investigated in younger patients with unfavorable features. © 2004 European Society for Medical Oncology.

Mantle cell lymphoma (MCL) responds poorly to standard chemotherapy regimens used in non-Hodgkin's lymphoma. As a result, a combination of high-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is being investigated in patients with MCL. So far, however, there is no evidence for long-term remission -- believed, in part, to be due to contamination of the transfusion product with residual cancer cells. Many ex-vivo purging methods have been developed to remove tumour cells, but these are complicated, time-consuming and expensive. This study describes an in vivo purging method using rituximab to produce a tumour-free stem cell product for re-infusion following HDT. The regimen is split into a purging phase and a myeloablative phase, which together consist of four-step high-dose sequential chemotherapy (sHDT) and six infusions of rituximab immunotherapy. The sHDT comprises cyclophosphamide, cytosine arabinoside, melphalan and mitoxantrone plus melphalan. There are two separate stem cell harvests and three reinfusions. In a pilot study 28 patients with untreated MCL received standard chemotherapy followed by sHDT with rituximab in vivo purging. Preliminary results indicate that in PCR analyses of leukaphereses from 20 assessable patients, 100% lymphoma-negative harvests were achieved following in vivo purging. PCR analyses of the bone marrow following the four-step high-dose regimen with purging and transplantation showed that all patients achieved molecular remission. After a median follow-up of 22 months (range 10-42 months), two patients had died while 26 were alive and disease free. This method allows efficient in vivo purging in the context of an effective chemotherapy regimen and may have a role as first-line therapy in MCL patients who respond poorly to standard treatment.

MCL is a well-characterized generally aggressive lymphoma with a poor prognosis. However, patients with a more indolent disease have been reported in whom the initiation of therapy can be delayed without any consequence for the survival. In 2017 the World Health Organization updated the classification of MCL describing two main subtypes with specific molecular characteristics and clinical features, classical and indolent leukaemic nonnodal MCL. Recent research results suggested an improving outcome of this neoplasm. The addition of rituximab to conventional chemotherapy has increased overall response rates, but it did not improve overall survival compared to chemotherapy alone. The use of intensive frontline therapies including rituximab and consolidation with autologous stem cell transplantation ameliorated response rate and prolonged progression-free survival in young fit patients, but any impact on survival remains to be proven. Furthermore, the optimal timing, cytoreductive regimen and conditioning regimen, and the clinical implications of achieving a disease remission even at molecular level remain to be elucidated. The development of targeted therapies as the consequence of better understanding of pathogenetic pathways in MCL might improve the outcome of conventional chemotherapy and spare the toxicity of intense therapy in most patients. Cases not eligible for intensive regimens, may be considered for less demanding therapies, such as the combination of rituximab either with CHOP or with purine analogues, or bendamustine. Allogeneic SCT can be an effective option for relapsed disease in patients who are fit enough and have a compatible donor. Maintenance rituximab may be considered after response to immunochemotherapy as the first-line strategy in a wide range of patients. Finally, since the optimal approach to the management of MCL is still evolving, it is critical that these patients are enrolled in clinical trials to identify the better treatment options.

Bendamustine is an alkylating agent with a nitrogen mustard group and a purine-like benzimidazole group. The aim of this study was to collect all the Italian experiences with this drug in order to evaluate the results in term of response to therapy and toxicities. We analyzed lymphoma patients treated in 24 Italian haematological centres with bendamustine alone or in combination with anti-CD20 antibody. One hundred seventy-five relapsed or refractory lymphoma patients were enrolled. The median age was 69 years (range 26-87). Seventy-nine patients were relapsed, 35 were refractory and 61 presented a progressive disease after partial response. The diagnoses were 60 indolent non-follicular lymphomas, 34 diffuse large B-cell lymphomas, 48 follicular lymphomas, 30 mantle cell lymphomas and three peripheral T-cell lymphomas. All patients were evaluable for response: 52 (29%) with complete remission, 72 (43%) with partial response with an overall response rate of 71%, and 51 non-responders. With a median observation period of 10 months (1-43), 70% of patients are alive. In summary, this retrospective study shows that treatment with bendamustine alone or in combination with rituximab is a safe and effective regimen in a subset of multi-resistant patients.

By real-time quantitative polymerase chain reaction (RQ-PCR), we evaluated BCL2/IgH(+) cells in the bone marrow (BM) and peripheral blood (PB) from 86 patients with follicular lymphoma treated with the sequential administration of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab. At diagnosis, the amount of BCL2/IgH(+) cells in the BM was low (1 BCL2/IgH(+) cell in 1000-100 000 normal cells) in 43% of patients, intermediate (1 in 100-1000) in 34%, and high (> 1 in 100) in 23%. A 2 log decrease of BCL2/IgH(+) cells was achieved after CHOP and an additional 2 log reduction following rituximab. By multivariate analysis, a low level of BCL2/IgH(+) cells in the BM at diagnosis was the best predictor for the achievement of a complete clinical and molecular response. At 5 years, the event-free survival rates of patients with a low/intermediate or high tumor infiltration in the BM were 59% and 32%, respectively. The freedom from recurrence of patients who achieved a molecular response in the BM, no matter whether after CHOP alone or CHOP and rituximab, was 64% as compared to 32% for patients who did not (P < .006). RQ-PCR performed at presentation on BM samples predicts treatment response and long-term clinical outcome in patients with follicular lymphoma.

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. Methods: In this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with hematologic malignancies. The ideal conditioning regimen before allo-HSCT has not been established. We conducted a Phase II study to evaluate the tolerability and efficacy of clofarabine and treosulfan as conditioning regimen before allo-HSCT. The primary objective was to evaluate the cumulative incidence of nonrelapse mortality (NRM) on day +100. Forty-four patients (36 with acute myelogenous leukemia, 5 with acute lymphoblastic leukemia, 3 with myelodysplastic syndromes) were enrolled. The median patient age was 47 years, and the median duration of follow-up was 27 months. The conditioning regimen was based on clofarabine 40 mg/m2 (days -6 to -2) and treosulfan 14 g/m2 (days -6 to -4). Allogeneic hematopoietic stem cells were derived from a sibling (n = 22) or a well-matched unrelated donor (n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, rituximab, cyclosporine, and a short-course of methotrexate. The regimen allowed for rapid engraftment and a 100-day NRM of 18%, due mainly to bacterial infections. The incidences of grade II-IV acute GVHD and chronic GVHD were 16% and 19%, respectively. The rates of overall survival (OS), progression-free survival, and relapse at 2 years were 51%, 31%, and 50%, respectively. Significantly different outcomes were observed between patients with low-intermediate and patients with high-very high Disease Risk Index (DRI) scores (1-year OS, 78% and 24%, respectively). Our findings show that the use of treosulfan and clofarabine as a conditioning regimen for allo-HSCT is feasible, with a 78% 1-year OS in patients with a low-intermediate DRI score. However, 1-year NRM was 18%, and despite the intensified conditioning regimen, relapse incidence remains a major issue in patients with poor prognostic risk factors.

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 in 40 patients (15 children and 25 adults), experiencing steroid-resistant grade II to IV graft-versus-host disease (GVHD). Patients received a median of 3 MSC infusions after having failed conventional immunosuppressive therapy. A median cell dose of 1.5 × 106/kg per infusion was administered. No acute toxicity was reported. Overall, 86 adverse events and serious adverse events were reported in the study, most of which (72.1%) were of infectious nature. Overall response rate, measured at 28 days after 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 with higher grades (61.5% versus 11.1%, P = .002) and was borderline significant in children as compared with adults (46.7 versus 16.0%, P = .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.

A retrospective survey of patients with pathologically reviewed extragastric mucosa-associated lymphoma tissue (MALT) lymphomas from 20 institutions was performed. A total of 180 patients with histologically confirmed diagnosis of extragastric MALT lymphomas were studied. Their median age was 59 years (range, 21-92 years). Ann Arbor stage I disease was present in 115 patients (64%) and stage II disease in 16 (9%). Most cases were in the low or low-intermediate risk groups according to the International Prognostic Index (IPI). Forty-one (23%) patients had involvement of more than one extranodal site at diagnosis and in 24 cases (13%) the lymphoma presented at multiple mucosal sites (9 of them with only mucosal involvement, without bone marrow or nodal disease). Lymph node involvement was present in 21%. Patients were treated with a variety of therapeutic strategies, including chemotherapy in 78 cases. The median overall survival (OS) was not reached; the 5-year OS rate was 90% (95% CI, 82%-94%), the 5-year cause-specific survival (CSS) was 94% (95% CI, 87%-97%), and the 5-year progression-free survival (PFS) was 60% (95% CI, 50%-70%). Multivariate analysis showed that Ann Arbor stage was significantly associated with longer OS, nodal involvement with longer CSS, and favorable IPI score with better PFS. At a median follow-up of 3.4 years, 48 patients (27%; 95% CI, 20%-34%) had a relapse, 6 (3%; 95% CI, 1%-7%) showed histologic transformation, and 18 (10%; 95% CI, 6%-15%) experienced the development of a second tumor. Our data confirm the indolent nature of nongastric MALT lymphomas and the high rate of patients presenting with disseminated disease, which, when limited to mucosal sites, was not associated with a poorer outcome.

To the editor: Allogeneic hematopoietic stem cell transplantation (HSCT) can grant long-term control and cure of acute myeloid leukemia (AML) thanks to the antitumor effect of the transplanted immune system. Still, relapse remains an open issue: in the haploidentical setting, we and others

Background: In the rituximab era, the conventional International Prognostic index (IPI) lost at least in part its predictive power, while the National Comprehensive Cancer Network-IPI (NCCN-IPI) seems to be a new and valid prognosticator. However, it has not yet been evaluated in patients with localized disease and it has not been compared with the modified IPI (mIPI) of the pre-rituximab era. In order to evaluate the different prognosticators and to assess the importance of rituximab and radiotherapy (RT), we carried out the so far largest retrospective analysis of patients with localized diffuse large B-cell lymphoma (DLBCL). Patients and methods: We retrospectively assessed clinical and therapeutical data of 1405 patients treated in from 1987 to 2012 in 10 cancer centers in Italy and 1 in Austria. Results: All patients underwent an anthracycline containing polychemotherapy and 254 additional rituximab. The median follow-up was 5.7 years (range 0.1-23 years). The 5-year overall survival (OS) was 75%, being significantly superior in those who underwent additional rituximab, while RT consolidation did not improve the outcome of those who received immunochemotherapy. Patients with extranodal disease benefited from the addition of rituximab, while RT did not improve OS of the immunochemotherapy subgroup. In the pre-rituximab era, the mIPI showed a better performance than the others. In rituximab-treated patients, the NCCN-IPI had the highest discriminant value and the 5-years OS varied significantly (P < 0.001) between the three risk groups and was 98% in low-risk patients, 82% in those with a low-intermediate risk and 57% among high-intermediate and high-risk cases. Conclusions: The NCCN-IPI is so far the best prognosticator for patients with localized DLBCL who underwent R-CHOP(-like). The addition of rituximab is indispensable regardless of the risk category and site of involvement, while the addition of RT should be reserved to those cases who are ineligible to rituximab.

Bendamustine proved to be effective for the treatment of chronic lymphocytic leukemia (CLL). However, the relationship between its activity with clinico-biological prognosticators has been addressed only in few studies. We retrospectively evaluated the efficacy of bendamustine, in a real-life contest, on 142 patients, median age 70 years, median number of previous regimens 2 (0–8, 13% previously untreated). Bendamustine was administered for a median number of 4 cycles, in 84% of cases with rituximab. Overall (ORR) and complete response (CRR) rates were 68 and 16.5%, respectively. Multivariate analysis demonstrated a relationship between ORR and number of prior treatments (OR 0.25, 95% CI 0.08–0.71; P = 0.009), del(17p) (OR 0.10, 95% CI 0.03–0.32; P

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.

Patients who relapse after an autologous hematopoietic stem cell transplantation (SCT) have a very poor prognosis. We have retrospectively analyzed diffuse large B cell lymphoma patients who underwent an allo-SCT after an auto-SCT relapse reported in the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) database. From 1995 to 2008, 3449 autologous transplants were reported in the GITMO database. Eight hundred eighty-four patients relapsed or progressed after transplant; 165 patients, 19% of the relapsed patients, were treated with allo-transplant. The stem cell donor was related to the patient in 108 cases. A reduced intensity conditioning regimen was used in 116. After allo-SCT, 72 patients (43%) obtained a complete response and 9 obtained a partial response with an overall response rate of 49%; 84 patients (51%) experienced rapid progression of disease. Ninety-one patients died, 45 due to disease and 46 due to treatment-related mortality. Acute graft-versus-host disease was recorded in 57 patients and a chronic GvHD in 38 patients. With a median follow-up of 24 months (2-144) after allo, overall survival (OS) was 39%, and after a median of 21 months (2-138) after allo, progression-free survival (PFS) was 32%. Multivariate analysis indicated that the only factors affecting OS were status at allo-SCT, and those affecting PFS were status at allo-SCT and stem cell donor. This retrospective analysis shows that about one-fifth of patients with diffuse large B cell lymphoma who experience relapse after autologous transplantation may be treated with allogeneic transplantation. Moreover, the only parameter affecting either OS or PFS was the response status at the time of allo-SCT.

Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in virtually all cases. Clinically, MCL shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. However, recently a subset of up to 15% long-term survivors has been identified with a rather indolent clinical course. Advanced stage disease is usually apparent already at first clinical manifestation; in general, conventional chemotherapy is only palliative and median duration of remissions is only 1-2 years. In 2000, the European MCL Network ( http://www.european-mcl.net ) was founded, which consists of 15 national lymphoma study groups supplemented by experts in hematopathology, cytogenetics and molecular genetics. During the last decade, the European consortium has successfully initiated the largest phase III trials in MCL worldwide. In the current study generation, the addition of high-dose Ara-C to a rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival. Similarly, in elderly patients, rituximab maintenance until progression led to a marked prolongation of remission duration. Emerging strategies include proteasome inhibitors, immune modulatory drugs (IMiDs), mammalian target of rapamycin (mTOR) inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. Future strategies will apply individualized approaches according to the molecular risk profile of the patient. At the annual conference in Warsaw, recent results of molecular pathogenesis, analyses of current clinical trials and new study concepts were discussed.

The therapeutic role of mediastinal radiotherapy and stem cell transplantation (SCT) in lymphoblastic lymphoma (LL) remains controversial. In a risk-oriented design, we adopted a flexible treatment program in which (1) patients with persistent mediastinal abnormality, evaluated by post-induction computed chest tomography, received mediastinal irradiation; and (2) those with persistence of minimal residual disease (MRD), evaluated by MRD analysis of the bone marrow, underwent SCT. Twenty-eight out of 30 patients (T-lineage, n = 24; B-lineage, n = 6) achieved a complete response. Of 21 patients with mediastinal mass, 13 (62%) achieved a complete response after chemotherapy alone, while 6 (28.5%) required additional irradiation. Eleven patients were evaluated for MRD: 6 were negative and 5 positive. On the basis of MRD findings and clinical risk characteristics, 14 patients underwent SCT, 13 received maintenance chemotherapy, and 1 had local radiotherapy. Five patients relapsed. Among the 14 non-irradiated patients with T-LL, the mediastinal recurrence rate was only 7%. After a median follow-up of 3.9 years, 21 patients who responded were alive without recurrence (75%). The projected 5-year survival, disease-free survival, and relapse rate were 72%, 77%, and 18%, respectively. This program induced high remission and survival rates, indicating the feasibility and the benefits potentially associated with a selective, response-oriented policy of mediastinal irradiation and a concurrent MRD-based strategy to assign adult LL patients to SCT.

The impact of different treatment modalities and prognostic factors on the clinical course of primary thyroid diffuse large B-cell lymphoma (PTDLBCL) is still the subject of research. This study was conducted to clarify these clinical aspects of this disorder. The clinical parameters of 48 patients with PTDLBCL at time of diagnosis were comparable to those of previous studies. Patients underwent either radiotherapy (RT) ±° surgery (SX), chemotherapy (CHT) alone or in combination with local treatments (RT or SX), or SX followed by CHT and RT. A 90% complete remission (CR) rate was observed among patients who underwent combined treatment modalities (CTM), compared to 76% among the others. The 5-year progression-free survival differed significantly between both groups (p = 0.028). Poor performance status and advanced age correlated with decreased survival. PTDLBCL is a curable disease prevalent in elderly patients. Combined treatment modalities were able to induce an elevated rate of CR, improving long-term survival in younger patients. However, the outcome in elderly patients still remains unsatisfactory. © 2011 Informa UK, Ltd.

International audience; Indolent primary cutaneous B cell lymphomas (PCBCL) generally have a good prognosis, but they often relapse leading in some cases to extracutaneous disease and therefore, to poor survival. We developed a prognostic model to improve the therapeutic approach to these lymphomas. Two hundred and seventeen patients with diagnosis of indolent PCBCL stage IE or IIE were assessed retrospectively. The prognostic model was built to fit a Cox proportional hazard model using all the covariates affecting progression-free survival (PFS) at 2 lesions were independent predictors for PFS. To each prognostic factor was assigned a value of 1. Patients were then stratified to three risk groups: score 0 (28%), low risk; score 1 (55%), intermediate risk; score 2 and 3 (17%), high risk with a 5-year PFS of 91%, 64%, and 48%, respectively (

Purpose High-dose chemotherapy with peripheral blood progenitor cell (PBPC) autograft is effective in high-risk lymphoma, particularly with the addition of rituximab; however, it is associated with risk of secondary malignancy. These issues have been addressed in a series of 1,347 patients with lymphoma treated with a high-dose sequential (HDS) program. Patients and Methods A total of 1,024 patients with B-cell lymphoma, 234 patients with Hodgkin's lymphoma, and 89 patients with T-cell lymphoma were treated with HDS between 1985 and 2005 at 11 Gruppo Italiano Terapie Innovative Linfomi centers. HDS was given as salvage treatment to 707 patients (52%); 655 patients (49%) received a modified HDS, with high-dose cytarabine and two consecutive PBPC harvests. Rituximab-supplemented HDS was given to 523 patients (39%). Results At a median follow-up of 7 years, the median overall survival (OS) was 16.2 years; in B-cell lymphoma the OS was significantly superior with rituximab HDS compared to HDS alone. The cumulative incidence at 5 and 10 years of secondary myelodysplasia/acute leukemia (sMDS/AL) were 3.09% and 4.52%, respectively, that of solid tumors were 2.54% and 6.79%, respectively. Factors associated with sMDS/AL were male sex and use of the second harvest PBPC for the graft; factors found to be associated with solid tumor were advanced age, post-HDS radiotherapy, and rituximab addition to HDS. Despite the increased risk of solid tumors, rituximab addition to HDS was still associated with survival advantages. Conclusion This analysis has relevant implications for the design and use of intensive chemoimmunotherapy with autograft. In addition, it offers useful insights toward the understanding and prevention of tumor development.

This study investigated whether the pre-surgical plasma levels of TAT and F1 + 2 of patients undergoing major surgery for localized tumours could identify patients at higher risk of thrombosis, and how heparin prophylaxis affected in vivo coagulation after cancer surgery. We measured the pre- and post-operative levels of TAT, F1 + 2, total factor VII (FVIIt) and zymogen FVII (FVIIz) in 117 cancer patients, with and without heparin prophylaxis. The end points of this study were DVT, initially detected by I-125-fibrinogen uptake test and confirmed by ascending venography. Pre-operative [TAT] and [F1 + 2] of the cancer patients were significantly higher than those of age-matched control subjects (n = 50) (P3.5 ng/ml identified patients at higher risk for post-operative DVT. Heparin reduced plasma TAT levels and FVII consumption following surgery, suggesting that heparin modulates coagulation associated with cancer surgery. The results of this study also suggest that the pre-operative [TAT] may identify patients with higher risk for post-operative DVT

Purpose The aim of the F2 study was to verify whether a prospective collection of data would enable the development of a more accurate prognostic index for follicular lymphoma (FL) by using parameters which could not be retrospectively studied before, and by choosing progression-free survival (PFS) as principal end point. Patients and Methods Between January 2003 and May 2005, 1,093 patients with a newly diagnosed FL were registered and 942 individuals receiving antilymphoma therapy were selected as the study population. The variables we used for score definition were selected by means of bootstrap resampling procedures on 832 patients with complete data. Procedures to select the model that would minimize errors were also performed. Results After a median follow-up of 38 months, 261 events for PFS evaluation were recorded. β2-microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, hemoglobin level lower than 12 g/dL, and age older than 60 years were factors independently predictive for PFS. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. The 3-year PFS rate was 91%, 69%, and 51% for patients at low, intermediate, and high risk, respectively (log-rank = 64.6; P < .00001). The 3-year survival rate was 99%, 96%, and 84% for patients at low, intermediate, and high risk, respectively (P < .0001). Conclusion Follicular Lymphoma International Prognostic Index 2 is a simple prognostic index based on easily available clinical data and may represent a promising new tool for the identification of patients with FL at different risk in the era of immunochemotherapy.

Purpose To investigate the impact of adding rituximab to intensive chemotherapy with peripheral-blood progenitor cell (PBPC) autograft for high-risk diffuse large B-cell lymphoma (DLB-CL) and follicular lymphoma (FL). Patients and Methods Data were collected from 10 centers associated with Gruppo Italiano Terapie Innnovative nei Linfomi for 522 patients with DLB-CL and 223 patients with FL (median age, 47 years) who received the original or a modified high-dose sequential (HDS) chemotherapy regimen. HDS was delivered to 396 patients without (R−) and to 349 patients with (R+) rituximab; 154 (39%) and 178 patients (51%) in the R− and R+ subsets, respectively, underwent HDS for relapsed/refractory disease. Results A total of 355 R− (90%) and 309 R+ patients (88%) completed the final PBPC autograft. Early treatment-related mortality was 3.3% for R− and 2.8% for R+ (P = not significant). Two parameters significantly influenced the outcome: disease status at HDS, with 5-year overall survival (OS) projections of 69% versus 57% for diagnosis versus refractory/relapsed status, respectively, and rituximab addition, with 5-year OS of 69% versus 60% in the R+ versus R− groups, respectively. In the multivariate analysis, these two variables maintained an independent prognostic value. The marked benefit of rituximab was evident in patients receiving HDS as salvage treatment: the 5-year OS projections for R+ versus R− were, respectively, 64% versus 38%, for patients with refractory disease or early relapse and 71% versus 57%, for patients with late relapse, partial response, or second/third relapse. Conclusion The results of this large series indicate that rituximab should be included in the current practice of PBPC autograft for DLB-CL and FL.

BACKGROUND: Hepatitis C virus (HCV) infection is frequently associated with B-cell non-Hodgkin's lymphomas. We investigated the prevalence of HCV infection in nongastric marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) in order to define the relationship between the viral infection and the presenting features, treatment, and outcome. METHODS: We retrospectively studied 172 patients with a histological diagnosis of marginal zone B-cell lymphoma of MALT, except for stomach, and with available HCV serology, among a series of 208 patients. RESULTS: HCV infection was documented in 60 patients (35%). Most HCV-positive patients (97%) showed a single MALT organ involvement. HCV-positive patients showed a more frequent involvement of skin (35%), salivary glands (25%), and orbit (15%). The majority of stage IV HCV-positive patients (71%) had a single MALT site with bone marrow involvement. The overall response rate was similar in HCV-positive (93%) and HCV-negative patients (87%). Overall survival (OS) and event-free survival (EFS) did not differ according to HCV infection. In multivariate analysis, advanced disease (stage III-IV) was associated with a poorer OS (P = 0.0001), irrespective of HCV serostatus. CONCLUSIONS: This study shows that nongastric marginal zone lymphomas are characterized by a high prevalence of HCV infection. Patients with involvement of a single MALT site have the highest prevalence of HCV. HCV-positive nongastric lymphomas of MALT show an indolent course similar to HCV-negative patients and seem an ideal target for exploiting the antilymphoma activity of antiviral treatments.

Purpose To evaluate the clinicohematologic variables at diagnosis that are prognostically related to neoplastic progression in patients with immunoglobulin M (IgM) monoclonal gammopathies of undetermined significance (MGUS), and indolent Waldenström's macroglobulinemia (IWM), and propose a scoring system to identify subsets of patients at different risk. Patients and Methods We evaluated 217 patients with IgM MGUS and 201 with IWM (male-female ratio, 131:86 and 117:84; mean age, 63.7 and 63.6 years, respectively) diagnosed on the basis of serum monoclonal component (MC) levels and bone marrow lymphoplasmacytic infiltration degree. The variables selected by univariate analyses were multivariately investigated; on the basis of their individual relative hazards, a scoring system was devised to identify subsets of patients at different risk of evolution. Results After a median follow-up of 56.1 and 60.2 months, 15 of 217 MGUS and 45 of 201 IWM patients, respectively, required chemotherapy for symptomatic WM (13 and 36), non-Hodgkin's lymphoma (2 and 6) and amyloidosis (0 and 3). The median time to evolution (TTE) was not reached for MGUS and was 141.5 months for IWM. The variables adversely related to evolution were qualitatively the same in both groups: MC levels, Hb concentrations and sex. A scoring system based on these parameters identified three risk groups with highly significant differences in TTE in both groups (P < .0001). Conclusion MGUS and IWM identify disease entities with different propensities for symptomatic neoplastic evolution. As both have the same prognostic determinants of progression, we propose a practical scoring system that, identifying different risks of malignant evolution, may allow an individualized clinical approach.

To assess the prognosis of peripheral T-cell lymphoma unspecified, we retrospectively analyzed 385 cases fulfilling the criteria defined by the World Health Organization classification. Factors associated with a worse overall survival (OS) in a univariate analysis were age older than 60 years ( P = .0002), equal to or more than 2 extranodal sites ( P = .0002), lactic dehydrogenase (LDH) value at normal levels or above ( P < .0001), performance status (PS) equal to or more than 2 ( P ≤ .0001), stage III or higher ( P = .0001), and bone marrow involvement ( P = .0001). Multivariate analysis showed that age (relative risk, 1.732; 95% CI, 1.300-2.309; P < .0001), PS (relative risk, 1.719; 95% CI, 1.269-2.327, P < .0001), LDH level (relative risk, 1.905; 95% CI, 1.415-2.564; P < .0001), and bone marrow involvement (relative risk, 1.454; 95% CI, 1.045-2.023; P = .026) were factors independently predictive for survival. Using these 4 variables we constructed a new prognostic model that singled out 4 groups at different risk: group 1, no adverse factors, with 5-year and 10-year OS of 62.3% and 54.9%, respectively; group 2, one factor, with a 5-year and 10-year OS of 52.9% and 38.8%, respectively; group 3, 2 factors, with 5-year and 10-year OS of 32.9% and 18.0%, respectively; group 4, 3 or 4 factors, with a 5-year and 10-year OS of 18.3 and 12.6%, respectively ( P ≤ .0001; log-rank, 66.79).

Background Reported data regarding intraocular lymphoma (IOL) management are anecdotal. Cases of IOL included in an international multicentre series of 378 immunocompetent patients with primary central nervous system lymphomas (PCNSLs) were reviewed. Patients and methods Staging included slit-lamp examination in 170 patients: IOL was diagnosed in 22 cases (13%). A concomitant brain lesion was detected in 21 cases. Planned treatment was chemotherapy followed by radiotherapy in 13 cases, chemotherapy alone in three and radiotherapy, followed by or not by chemotherapy in five; one patient was not treated. Chemotherapy included high-dose methotrexate in 12 cases. Ten patients received intrathecal chemotherapy. Radiotherapy consisted of whole brain irradiation, followed by or not by a tumour bed boost; ocular irradiation was planned in15 cases. Irradiation in one patient without brain lesions was limited to the orbits only (50 Gy). Results IOL was positively correlated to systemic symptoms and meningeal disease. Fifteen patients (71%) achieved an objective response; 16 patients experienced a failure (2-year failure-free survival34 ± 10%). Failures involved the eyes in eight cases, with a 2-year time to ocular relapse of 59 ± 11%. Ocular failure was less common in patients treated with chemotherapy plus ocular irradiation and was associated with a significantly shorter survival. Seven patients are alive [median follow-up 53 months, 2-year overall survival (OS): 39 ± 11%], five of whom were treated with ocular irradiation. The patient with isolated IOL is alive and disease-free at 14 months. OS of the entire series was similar to that of PCNSL patients with negative slit-lamp examination. Conclusions IOL is usually associated with concomitant brain disease and shows a survival similar to that of the rest of PCNSLs. Chemotherapy combined with ocular irradiation resulted in better control of ocular disease, which seems to be associated with survival. In view of the potential role of ocular irradiation, the use of chemotherapy alone in phase II trials should be critically reconsidered in PCNSL patients with ocular disease.

Abstract 743 Background: Acute Graft versus host disease (aGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). Conventional treatment with high dose steroids fails to achieve a complete and sustained response in more than 50% of patients. Several second line treatments have been described but none of these can be considered superior or a standard of care (Paul J. Martin et al, BBMT 2012). Among these treatments, the use of third party mesenchymal stromal cells (MSC) has been proposed (LeBlanc et al, Lancet 2008). In this study, we assessed the safety and efficacy of third party human MSC, in a prospective, multicenter, phase I study (EudraCT 2008–007869-23). Methods: Forty-seven patients with steroid-resistant, acute or chronic grade II-IV GvHD were enrolled into this study. Human MSC were obtained from bone marrow harvests of healthy donors and expanded in vitro using serum free medium supplemented with human platelet lysate (Capelli C et al, BMT, 2007; Capelli C. et al, Cytotherapy 2009). In vitro expanded MSC were produced in two officially authorized Cell Factories and tested in four Italian Hematology Units. The primary endpoint of this study was the safety. Secondary endpoints were the response of GvHD (evaluated 28 days after the last MSC infusion), as well as the overall survival and transplant-related deaths. Blood samples were periodically collected before and after MSC infusion to measure plasma levels of IL2Ralpha by ELISA, as previously described by our group (Dander E et al, Leukemia 2012). Results: Between August 2009, and June 2012, 47 patients (16 children, 31 adults, median age 25.5 years, range 1 to 67) were treated. The median dose of infused MSC was 1.5×106 cells per kg bodyweight. Enrolled patients presented with aGvHD in 37 cases, chronic overlap syndrome in 7 cases, and chronic classic GvHD in 3 cases. Fifteen pts had grade II GvHD, 23 grade III and 9 grade IV, according to NIH criteria. In 17 cases GvHD involved a single organ, in 24 cases 2, and in 6 cases 3 organs. Prior to MSC infusion 22 patients had received only high dose steroids, 12 patients received one cycle of pentostatin (1 mg/kg bodyweight for 3 days, Schmitt T. et al BMT, 2011: 46 580–585), while 13 received other conventional immunosuppressants. Patients received a median of 3 MSC infusions (range 1 to 8). No side effects were registered immediately after MSC infusion and no complications were lately referred as MSC-related. Overall, in 30 patients (63.8%) a clinical response of GvHD was registered. Thirteen of these patients (27.6%) had a complete response and 17 (36.1%) a partial response to treatment. Twenty-two of the 30 responding patients did not require further lines of immunosuppression after MSC infusion. Response was significantly more likely in patients exhibiting grade II GvHD versus those exhibiting more severe gradings (87.5% vs. 51.6%, p = 0.02) and in patients receiving MSC in a time interval of 30 days from the onset of GvHD (75.9% vs. 43.7%, p= 0.05). Current median follow up for this cohort is 200 days (range 30–1066). Responders show a significant lower transplant-related mortality (10.0% vs. 88.2%, p Measurements of plasmatic levels of IL2Ralpha, when comparing responders vs non-responders patients, showed a statistically significant difference in terms of fold decrease of the marker (p=0.027), corroborating clinical results. Similarly, a significant trend of fold decrease change (p=0.058) was observed when comparing responding patients receiving MSC within or after 30 days from the onset of the disease, in line with clinical results. Conclusions: This study confirms that human MSC prepared in academic cell therapy facilities may represent a safe and effective treatment of patients with steroid-refractory GvHD. Plasmatic inflammatory markers may help in evaluating and monitoring of clinical response. The sequential or combined administration of MSC and other immunosuppressants, such as pentostatin, is equally safe and feasible and deserves further investigation. We suggest to consider the use of MSC promptly, as early as possible, after steroid failure. Disclosures: No relevant conflicts of interest to declare.

SummaryA prospective, randomized, double-blind clinical trial was carried out in a single center to compare the clinical and laboratory quality of oral anticoagulant therapy monitored with recombinant tissue factor (RTF) or with a sensitive, human-derived, conventional thromboplastin (CT) in the PT test. Seven hundred and fifty-seven consecutive patients receiving oral anticoagulation for various indications were randomized to RTF (n = 379) or CT (n = 368) for 6 months. Total follow-up was 167 and 153 patient-years for RTF and TP groups respectively. Fifty-six bleeding events were observed: 31 in the RTF group and 25 in the TP group. The incidence of bleeding was 18.5 and 16.5% pt-yrs for RTF and TP patients respectively (n.s.). The event-free follow-up curves were not significantly different between the two groups. The laboratory quality of oral anticoagulation was evaluated with the “last check in file” method: therapeutic INR was found in the same propor-tipn of RTF and TP patients (70.2% vs 68.8%). Our study shows that RTF is as effective as a sensitive, conventional thromboplastin for monitoring oral anticoagulation.

Abstract 519 Introduction High-dose (hd) therapy with stem cell autograft is an effective treatment for both non-Hodgkin's (NHL) and Hodgkin's Lymphoma (HL). However, the occurrence of secondary malignancies, particularly myelodysplastic syndromes/acute leukemias (sMDS/AL), is a critical issue, representing a major cause of failure in patients potentially cured after hd-chemotherapy. Aim of the study To evaluate: frequency-cumulative incidence-risk factors, of both sMDS/AL and solid tumors in a large series of lymphoma patients, treated with the hd-sequential (HDS) chemotherapy approach, followed by peripheral blood progenitor cell (PBPC) autograft. Patients and Methods Data have been collected on 1,347 lymphoma patients treated in the last two decades at 11 Centers, associated to GITIL. Patients received either the original or modified HDS regimens; PBPC were collected after hd-cyclophosphamide, and, in a subgroup, after a 2nd round of mobilization with hd-Ara-C. The series included 1,024 B-cell NHL, 234 HL and 89 T-cell NHL; there were 695 high-grade, 278 low-grade and 140 mantle-cell lymphoma; median age was 46 yrs; 57% were male. Overall, 640 (47%) patients received HDS front-line. Autograft was usually performed with PBPC (median CD34+ cells: 7×106/kg); most patients (n=774) received PBPC collected at the 1st mobilization course, whereas some others (n=298) were autografted with PBPC collected following a 2nd high-dose course. The Mitoxantrone/L-PAM combination was the most frequently employed conditioning for autograft (n=643), followed by BEAM (n=301); TBI-conditioning regimen was employed only in 79 patients. Results At a median follow-up of 7 yrs, the 5 and 10 yr Overall Survival (OS) projections are 64% and 56%, respectively. Among B-cell NHL, 70.5% of patients treated with Rituximab-supplemented HDS are presently alive vs. 55.6 of those treated with Rituximab-free HDS (p=0.001). Overall, 54 (4.0%) patients developed s-MDS/AL, with a cumulative incidence of sMDS/AL of 3.1% at 5 yrs and 4.6% at 10 yrs. (Figure 1A). Median time of s-MDS/AL occurrence was 3.2 yrs (range: 1.3-13.7) since autograft. In addition, 64 patients had a diagnosis of solid tumor, at a median time of 5.5 yrs (range: 0.5-14.6) since autograft. The cumulative incidence of 2ry-solid tumor is 2.5 % at 5 yrs and 6.6 % at 10 yrs. (Figure 1B). In univariate analysis, age >45 yrs., male sex and autograft with PBPC collected at the 2nd mobilization round had a significantly higher risk of sMDS/AL; a trend for a higher incidence was observed in patients receiving HDS with Rituximab (p=0.066) and in those presenting with BM involvement (p=0.097); on multivariate analysis, male gender and autograft with PBPC of the 2nd mobilization round were the only parameters associated with sMDS/AL occurrence (SDHR: 2.74, p=0.004 and 2.44, p=0.002, respectively). Concerning solid tumors, in univariate analysis, age >45 yrs, Rituximab addition to HDS, HDS with hd-Ara-C, and autograft with PBPC collected at the 2nd mobilization round had a significantly higher risk of solid tumor; on multivariate analysis, age >45 yrs., Rituximab addition and consolidation Radiotherapy following HDS were the only parameters associated with solid tumor occurrence (SDHR: 2.10, p=0.002, 1.99, p=0.011 and 2.13, p=0.024, respectively). Conclusions The incidence of sMDS/AL observed following HDS is among the lowest reported so far in lymphoma patients treated with hd-therapy and autograft. However, the risk of solid tumor occurrence can not be ignored. Among risk factors, male gender and the quality, rather than the quantity, of grafted PBPC are the strongest factors associated with sMDS/AL. Other factors, namely older age, Rituximab addition and consolidation Radiotherapy, are mainly associated with the development of solid tumors. Despite the increased risk of secondary solid tumor, addition of Rituximab resulted in significant improvements in the overall survival of patients undergoing HDS. Further analysis are required to understand the biological meaning of the variable association between risk factor and secondary malignancy development. Disclosures: Tarella: Roche: Honoraria, research financial support. Rambaldi:Roche: Consultancy, Honoraria.